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Gilbert DL, Kim DJB, Miller MM, Atkinson SD, Karkanias GB, Munschauer FE, Wanaski SP, Cunniff TM. Safety and Effect of 12-Month Ecopipam Treatment in Pediatric Patients with Tourette Syndrome. Mov Disord Clin Pract 2025. [PMID: 40353708 DOI: 10.1002/mdc3.70091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/20/2025] [Accepted: 04/03/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Tourette syndrome (TS) is a chronic neurodevelopmental tic disorder with a considerable quality of life (QOL) burden. OBJECTIVES The goal was to determine the long-term safety, tolerability, and clinical effects of ecopipam, a first-in-class dopamine D1 receptor antagonist, for TS. METHODS This 12-month, open-label extension (OLE) study enrolled patients age ≥6 to ≤18 years with confirmed TS who completed a phase 2b randomized, placebo-controlled, 12-week trial. Ecopipam was titrated over 4 weeks to achieve a target oral dose of 1.8 mg/kg/day. Study visits occurred at baseline, monthly for 12 months, and 7 and 14 days after last dose. RESULTS A total of 121 patients were included (74% male; 68% age 12-18 years), and 80 (66%) completed the study. Ecopipam was well tolerated. The most common adverse events were nasopharyngitis (14.0%) and anxiety (9.1%). At month 12, there were no significant changes from baseline in body mass index Z-score (mean [standard deviation] change, 0.05 [0.43]; P = 0.35), glycated hemoglobin (0.03% [0.31]; P = 0.60), or total cholesterol (0.2 mmol/L [0.7]; P = 0.14). No notable changes in scales assessing akathisia, movement disorders, anxiety, or depression occurred. At all time points, significant improvements (P < 0.001 vs. baseline) in both the Yale Global Tic Severity Scale Total Tic Score and the Gilles de la Tourette Syndrome Quality of Life Scale for Children and Adolescents total score were observed. CONCLUSIONS Twelve months of ecopipam dosing was well tolerated during this study and no new adverse events were detected. Compared to baseline, significantly reduced TS symptom severity and improved QOL were observed in children and adolescents.
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Affiliation(s)
- Donald L Gilbert
- Division of Neurology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Moran PM, Granger KT. IUPHAR review: Moving beyond dopamine-based therapeutic strategies for schizophrenia. Pharmacol Res 2025; 216:107727. [PMID: 40320224 DOI: 10.1016/j.phrs.2025.107727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 03/27/2025] [Accepted: 04/01/2025] [Indexed: 05/12/2025]
Abstract
In the following we comprehensively review approaches to treating schizophrenia that do not primarily involve dopamine antagonism or partial agonism. Following 70 years of broadly similar dopamine D2 receptor antagonist/partial agonist drugs, Cobenfy™ was approved as a novel antipsychotic in September 2024. Cobenfy™ is a combination formulation of xanomeline, a muscarinic cholinergic M1/M4 receptor agonist and trospium, a peripherally restricted muscarinic antagonist included to offset peripheral side effects of xanomeline. This approval has reinvigorated optimism in the field and raised important questions for the future direction of antipsychotic drug development. We review therapeutic strategies beyond dopamine that have been and are currently being investigated to address whether there are a sufficient number of novel approaches to maintain the momentum of this breakthrough and question why it has taken so long. The current pipeline of late-stage compounds is low and potentially constrained by historical setbacks and challenges in clinical trial design for schizophrenia. This success rate has future potential to improve given the range of biomarkers in development designed to enable greater precision in future clinical trials. Cobenfy™ approval demonstrates that with combination formulations designed to improve side effect profiles and optimised clinical trial design it is possible to generate tolerable and efficacious treatment options for patients beyond a solely dopaminergic framework. We conclude that advances in understanding the neurobiology of schizophrenia, while not complete, has generated a diverse and well justified pool of potentially novel and repurpose-ready approaches, with mechanisms beyond simple dopamine D2 antagonism/partial agonism.
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Affiliation(s)
- Paula M Moran
- School of Psychology, University of Nottingham, University Park, NG72RD, UK.
| | - Kiri T Granger
- Monument Therapeutics Ltd., Alderley Park, Congleton Road, Cheshire, Macclesfield SK10 4TG, UK.
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Rahman FI, Webster TM, Hopkins CR. Update on mGlu4 modulator patents: 2017 to present. Expert Opin Ther Pat 2025; 35:463-475. [PMID: 39948693 PMCID: PMC12048291 DOI: 10.1080/13543776.2025.2467679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 02/07/2025] [Indexed: 02/23/2025]
Abstract
INTRODUCTION Metabotropic glutamate receptor 4 (mGluR4) regulates disease by modulating neurotransmitter release and synaptic plasticity and has been implicated in various diseases, including neurodegenerative disorders and psychiatric conditions, where its dysregulation can impact synaptic function and neuronal signaling. AREAS COVERED This review covers the patents and key literature concerning mGluR4 PAMs by utilizing the search engines: SciFinder, Google Patents, and PubMed from 2017 to 2024. It summarizes the key exemplified compounds, relevant SAR, and key biological data presented in the patents and primary literature. The key findings and potential path forward are also discussed. EXPERT OPINION The mGluR4 receptor serves as a novel target for the treatment of neurodegenerative disorders (namely Parkinson's disease), multiple sclerosis, and chronic pain along with other brain disorders. Two compounds have been advanced to early-stage clinical trials from Prexton Therapeutics and Appello Pharmaceuticals. The first compound from Prexton failed due to efficacy and the Appello compound has yet to have results disclosed. The results from this trial will be an important test for whether future mGluR4 PAMs are advanced into clinical trials.
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Affiliation(s)
- Fahad Imtiaz Rahman
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Thomas M. Webster
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Corey R. Hopkins
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
- UNMC Center for Drug Design and Innovation, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Liu K, Hui Y, Yang Y, Guo Y, Zhang L. Blockade of mGluR1 and mGluR5 in the lateral habenula produces the opposite effects in the regulation of depressive-like behaviors in the hemiparkinsonian rats. Exp Neurol 2025; 386:115154. [PMID: 39848560 DOI: 10.1016/j.expneurol.2025.115154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 12/24/2024] [Accepted: 01/17/2025] [Indexed: 01/25/2025]
Abstract
Depression is one of the most common non-motor symptoms in Parkinson's disease (PD) and the hyperactivity of the lateral habenula (LHb) may contribute to depression. The present study was performed to investigate the effects and mechanisms of group I metabotropic glutamate receptors (mGluRs) in the LHb on PD-related depressive-like behaviors. Unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) were used to establish the PD rat model. The group I mGluRs agonist and antagonists for mGluR1 and mGluR5 were microinjected into the LHb to observe their effects on PD-related depressive-like behaviors, electrical activities of the LHb, release of monoamines in the medial prefrontal cortex (mPFC) in sham and the lesioned rats. Lesions of the SNc induced depressive-like behaviors and hyperactivity of LHb neurons. Activation of group I mGluRs by 3,5-DHPG induced or enhanced depressive-like behaviors, increased the firing rate of the LHb neurons, and decreased dopamine (DA) and serotonin (5-HT) levels in the mPFC in the two groups of rats. Blockade of mGluR1 by YM298198 also produced similar effects with 3,5-DHPG, however, blockade of mGluR5 by MTEP produced opposite effects. Western blotting data showed that lesions of the SNc in rats down-regulated the expression of mGluR1 and mGluR5 in the LHb. These results suggest that mGluR1 and mGluR5 in the LHb induce opposite effects on depressive-like behaviors, which may attribute to the changed firing rate of LHb neurons by the presynaptic and postsynaptic mechanisms, and the changes in the monoamine levels.
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Affiliation(s)
- Kuncheng Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Department of Neurology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Yanping Hui
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, China
| | - Yaxin Yang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, China
| | - Yuan Guo
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
| | - Li Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
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Zucca S, Brunori G, Dunn HA, Lankford CK, Sutton LP, Algibez Flores B, Maza NA, Sial O, Crynen G, Luján R, Martemyanov KA. Trans-synaptic modulation of cholinergic circuits tunes opioid reinforcement. Proc Natl Acad Sci U S A 2025; 122:e2409325122. [PMID: 40112116 PMCID: PMC11962452 DOI: 10.1073/pnas.2409325122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 02/16/2025] [Indexed: 03/22/2025] Open
Abstract
Opioids trigger structural and functional neural adaptations of the reward circuit that lead to dependence. Synaptic cell adhesion molecules (CAMs) play a pivotal role in circuit organization and present prime candidates for orchestrating remodeling of neural connections in response to drug exposure. However, the contribution of CAMs to opioid-induced rewiring of the reward circuit has not been explored. Here, we used unbiased molecular profiling to identify CAMs in the nucleus accumbens (NAc) modulated by morphine administration. We found that opioid exposure induces the expression of ELFN1, a CAM selectively expressed in cholinergic interneurons in the NAc. We determined that ELFN1 acts trans-synaptically to modulate the strength and plasticity of the glutamatergic inputs onto cholinergic neurons via the recruitment of presynaptic metabotropic glutamate receptor 4 (mGlu4). Disruption of Elfn1 diminished morphine reward and intake in self-administering mice. Together, our findings identify a key molecular factor responsible for adjusting the strength of opioid effects by modulating the configuration of striatal circuitry in an experience-dependent fashion and unveil potential therapeutic target for combating opioid abuse.
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Affiliation(s)
- Stefano Zucca
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL33458
| | - Gloria Brunori
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL33458
| | - Henry A. Dunn
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL33458
| | - Colten K. Lankford
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL33458
| | - Laurie P. Sutton
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL33458
| | - Beatriz Algibez Flores
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL33458
| | - Nycole A. Maza
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL33458
| | - Omar Sial
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL33458
| | - Gogce Crynen
- Bioinformatics and Statistics Core, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL33458
| | - Rafael Luján
- Synaptic Structure Laboratory, Instituto de Biomedicina, Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, Campus Biosanitario, Albacete02001, Spain
| | - Kirill A. Martemyanov
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL33458
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Pruett DG, Hunter C, Scartozzi A, Shaw DM, Kraft SJ, Jones RM, Shuey MM, Below JE. Characterizing drug-induced stuttering in electronic health records. JOURNAL OF COMMUNICATION DISORDERS 2025; 113:106475. [PMID: 39615072 PMCID: PMC11948996 DOI: 10.1016/j.jcomdis.2024.106475] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 10/29/2024] [Accepted: 11/01/2024] [Indexed: 02/09/2025]
Abstract
PURPOSE Drug-induced stuttering is a phenomenon where the onset of stuttered speech is caused by exposure to pharmaceutical chemical substances. This acquired form of stuttering features many of the same overt speech behaviors as developmental stuttering. Investigations of drug-induced stuttering have been limited to adverse drug reaction reports and case studies. This study leveraged electronic health records (EHRs) at a major university medical center to identify drug-induced stuttering within medical notes, followed by classification of implicated drug types. METHODS A previous systematic EHR review of approximately 3 million individuals to identify cases of developmental stuttering resulted in 40 suspected cases of drug-induced stuttering. In the present study, these cases were reviewed comprehensively to evaluate: name, class, and mechanism of action of suspected drug, level of evidence for the implicated drug as a causal agent, therapeutic measures taken, and progression or remission of stuttering. RESULTS Eighteen different drugs were linked to possible drug-induced stuttering in 22 individuals. Antiseizure agents, CNS stimulants, and antidepressants were the most common drug classes implicated in drug-induced stuttering. topiramate (Topamax) was the most commonly implicated drug across all records reviewed. CONCLUSIONS This study represents the first analysis of health system data examining drugs implicated in drug-induced stuttering in a clinical setting. Augmenting previous case reports and database reviews, a variety of drugs were identified; however, improved reporting of drug-associated speech fluency changes within the EHR are needed to further amass evidence for suspected drugs and their associated epidemiological and clinical characteristics.
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Affiliation(s)
- Dillon G Pruett
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, USA.
| | - Christine Hunter
- Lipscomb University College of Pharmacy and Health Sciences, USA
| | - Alyssa Scartozzi
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, USA
| | - Douglas M Shaw
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, USA
| | - Shelly Jo Kraft
- Department of Communication Sciences and Disorders, Wayne State University, USA
| | - Robin M Jones
- Department of Hearing and Speech Sciences, Vanderbilt University Medical Center, USA
| | - Megan M Shuey
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, USA
| | - Jennifer E Below
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, USA
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Lin X, Provasi D, Niswender CM, Asher WB, Javitch JA. Elucidating the molecular logic of a metabotropic glutamate receptor heterodimer. Nat Commun 2024; 15:8552. [PMID: 39362861 PMCID: PMC11450022 DOI: 10.1038/s41467-024-52822-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 09/20/2024] [Indexed: 10/05/2024] Open
Abstract
Metabotropic glutamate (mGlu) receptor protomers can heterodimerize, leading to different pharmacology compared to their homodimeric counterparts. Here, we use complemented donor-acceptor resonance energy transfer (CODA-RET) technology that distinguishes signaling from defined mGlu heterodimers or homodimers, together with targeted mutagenesis of receptor protomers and computational docking, to elucidate the mechanism of activation and differential pharmacology in mGlu2/4 heteromers. We demonstrate that positive allosteric modulators (PAMs) that bind an upper allosteric pocket in the mGlu4 transmembrane domain are active at both mGlu4/4 homomers and mGlu2/4 heteromers, while those that bind a lower allosteric pocket within the same domain are efficacious in homomers but not heteromers. We further demonstrate that both protomers of mGlu2/4 heteromers are cis-activated by their orthosteric agonists, signaling independently with no trans-activation detected. Intriguingly, however, upper pocket mGlu4 PAMs enable trans-activation in mGlu2/4 heteromers from mGlu4 to the mGlu2 protomer and also enhance cis-activation of the mGlu2 protomer. While mGlu2 PAMs enhanced mGlu2 cis-activation in the heterodimer, we were unable to detect trans-activation in the opposite direction from mGlu2 to the mGlu4 protomer, suggesting an asymmetry of signaling. These insights into the molecular logic of this receptor heteromer are critical to building toward precision targeted therapies for multiple neuropsychiatric disorders.
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Affiliation(s)
- Xin Lin
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
- Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
| | - Davide Provasi
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Colleen M Niswender
- Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA
- Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA
- Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, TN, USA
| | - Wesley B Asher
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
- Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
| | - Jonathan A Javitch
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
- Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
- Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
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Doppler CEJ, Seger A, Farrher E, Régio Brambilla C, Hensel L, Filss CP, Hellmich M, Gogishvili A, Shah NJ, Lerche CW, Neumaier B, Langen KJ, Fink GR, Sommerauer M. Glutamate Signaling in Patients With Parkinson Disease With REM Sleep Behavior Disorder. Neurology 2024; 102:e209271. [PMID: 38630966 DOI: 10.1212/wnl.0000000000209271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Clinical heterogeneity of patients with Parkinson disease (PD) is well recognized. PD with REM sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher nonmotor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning imbalances in neurotransmitter systems remain elusive. METHODS Combining magnetic resonance (MR) spectroscopy and [11C]ABP688 PET on a PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with PD. Patients were grouped according to their RBD status in overnight video-polysomnography and compared with age-matched and sex-matched healthy control (HC) participants. Total volumes of distribution (VT) of [11C]ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between 45 and 60 minutes of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single-voxel stimulated echo acquisition mode MR spectroscopy of the left basal ganglia. RESULTS We measured globally elevated VT of [11C]ABP688 in 16 patients with PD and RBD compared with 17 patients without RBD and 15 HC participants (F(2,45) = 5.579, p = 0.007). Conversely, glutamatergic metabolites did not differ between groups and did not correlate with the regional VT of [11C]ABP688. VT of [11C]ABP688 correlated with the amount of REM sleep without atonia (F(1,42) = 5.600, p = 0.023) and with dopaminergic treatment response in patients with PD (F(1,30) = 5.823, p = 0.022). DISCUSSION Our results suggest that patients with PD and RBD exhibit altered glutamatergic signaling indicated by higher VT of [11C]ABP688 despite unaffected glutamate levels. The imbalance of glutamate receptors and MR spectroscopy glutamate metabolite levels indicates a novel mechanism contributing to the heterogeneity of PD and warrants further investigation of drugs targeting mGluR5.
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Affiliation(s)
- Christopher E J Doppler
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - Aline Seger
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - Ezequiel Farrher
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - Cláudia Régio Brambilla
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - Lukas Hensel
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - Christian P Filss
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - Martin Hellmich
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - Ana Gogishvili
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - N Jon Shah
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - Christoph W Lerche
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - Bernd Neumaier
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - Karl-Josef Langen
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - Gereon R Fink
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
| | - Michael Sommerauer
- From the Cognitive Neuroscience (C.E.J.D., A.S., L.H., G.R.F., M.S.), Institute of Neuroscience and Medicine (INM-3), Forschungszentrum Jülich; Department of Neurology (C.E.J.D., A.S., L.H., G.R.F., M.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Köln; Institute of Neuroscience and Medicine (INM-4) (E.F., C.R.B., A.G., N.J.S., C.W.L., K.-J.L.), Forschungszentrum Jülich; Department of Nuclear Medicine (C.P.F., K.-J.L.), RWTH University Hospital, Aachen; Institute of Medical Statistics and Computational Biology (M.H.), Faculty of Medicine and University Hospital of Cologne, University of Cologne; Faculty of Medicine (A.G.), RWTH Aachen University, Germany; Engineering Physics Department (A.G.), Georgian Technical University, Tbilisi, Georgia; Institute of Neuroscience and Medicine (INM-11) (N.J.S.), Molecular Neuroscience and Neuroimaging, JARA, Forschungszentrum Jülich; JARA-BRAIN-Translational Medicine (N.J.S.), Aachen; Department of Neurology (N.J.S.), RWTH Aachen University; and Institute of Neuroscience and Medicine (INM-5) (B.N.), Forschungszentrum Jülich, Germany
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9
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Finlay CJ, Jackson MJ, Fisher R, Bundgaard C, Rose S, Duty S. Metabotropic Glutamate Receptor 4 (mGlu4) Positive Allosteric Modulators Lack Efficacy in Rat and Marmoset Models of L-DOPA-Induced Dyskinesia. JOURNAL OF PARKINSON'S DISEASE 2024; 14:245-259. [PMID: 38427500 PMCID: PMC10977372 DOI: 10.3233/jpd-230296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/22/2024] [Indexed: 03/03/2024]
Abstract
Background Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson's disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release. Objective We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia. Methods The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats. Results Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats. Conclusions This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.
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Affiliation(s)
- Clare J. Finlay
- Wolfson Sensory, Pain and Regeneration Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
| | - Michael J. Jackson
- Neurodegenerative Diseases Research Group, Faculty of Life Science and Medicine, King’s College London, London, UK
| | - Ria Fisher
- Neurodegenerative Diseases Research Group, Faculty of Life Science and Medicine, King’s College London, London, UK
| | | | - Sarah Rose
- Neurodegenerative Diseases Research Group, Faculty of Life Science and Medicine, King’s College London, London, UK
| | - Susan Duty
- Wolfson Sensory, Pain and Regeneration Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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10
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Bove F, Angeloni B, Sanginario P, Rossini PM, Calabresi P, Di Iorio R. Neuroplasticity in levodopa-induced dyskinesias: An overview on pathophysiology and therapeutic targets. Prog Neurobiol 2024; 232:102548. [PMID: 38040324 DOI: 10.1016/j.pneurobio.2023.102548] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 10/29/2023] [Accepted: 11/26/2023] [Indexed: 12/03/2023]
Abstract
Levodopa-induced dyskinesias (LIDs) are a common complication in patients with Parkinson's disease (PD). A complex cascade of electrophysiological and molecular events that induce aberrant plasticity in the cortico-basal ganglia system plays a key role in the pathophysiology of LIDs. In the striatum, multiple neurotransmitters regulate the different forms of physiological synaptic plasticity to provide it in a bidirectional and Hebbian manner. In PD, impairment of both long-term potentiation (LTP) and long-term depression (LTD) progresses with disease and dopaminergic denervation of striatum. The altered balance between LTP and LTD processes leads to unidirectional changes in plasticity that cause network dysregulation and the development of involuntary movements. These alterations have been documented, in both experimental models and PD patients, not only in deep brain structures but also at motor cortex. Invasive and non-invasive neuromodulation treatments, as deep brain stimulation, transcranial magnetic stimulation, or transcranial direct current stimulation, may provide strategies to modulate the aberrant plasticity in the cortico-basal ganglia network of patients affected by LIDs, thus restoring normal neurophysiological functioning and treating dyskinesias. In this review, we discuss the evidence for neuroplasticity impairment in experimental PD models and in patients affected by LIDs, and potential neuromodulation strategies that may modulate aberrant plasticity.
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Affiliation(s)
- Francesco Bove
- Neurology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Benedetta Angeloni
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Pasquale Sanginario
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Paolo Maria Rossini
- Brain Connectivity Laboratory, Department of Neuroscience and Neurorehabilitation, IRCCS San Raffaele Roma, Rome, Italy
| | - Paolo Calabresi
- Neurology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Riccardo Di Iorio
- Neurology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.
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11
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Kochoian BA, Bure C, Papa SM. Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia. Cells 2023; 12:2754. [PMID: 38067182 PMCID: PMC10706484 DOI: 10.3390/cells12232754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/22/2023] [Accepted: 11/28/2023] [Indexed: 12/18/2023] Open
Abstract
A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson's disease (PD). Yet, LIDs remain a clinical challenge for the management of patients with advanced disease. Glutamatergic dysregulation of striatal projection neurons (SPNs) appears to be a key contributor to altered motor responses to L-DOPA. Targeting striatal hyperactivity at the glutamatergic neurotransmission level led to significant preclinical and clinical trials of a variety of antiglutamatergic agents. In fact, the only FDA-approved treatment for LIDs is amantadine, a drug with NMDAR antagonistic actions. Still, novel agents with improved pharmacological profiles are needed for LID therapy. Recently other therapeutic targets to reduce dysregulated SPN activity at the signal transduction level have emerged. In particular, mechanisms regulating the levels of cyclic nucleotides play a major role in the transduction of dopamine signals in SPNs. The phosphodiesterases (PDEs), a large family of enzymes that degrade cyclic nucleotides in a specific manner, are of special interest. We will review the research for antiglutamatergic and PDE inhibition strategies in view of the future development of novel LID therapies.
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Affiliation(s)
- Brik A. Kochoian
- Emory National Primate Research Center, Emory University, Atlanta, GA 30329, USA; (B.A.K.); (C.B.)
| | - Cassandra Bure
- Emory National Primate Research Center, Emory University, Atlanta, GA 30329, USA; (B.A.K.); (C.B.)
| | - Stella M. Papa
- Emory National Primate Research Center, Emory University, Atlanta, GA 30329, USA; (B.A.K.); (C.B.)
- Department of Neurology, Emory University School of Medicine, Atlanta, GA 30329, USA
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12
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Sharma R, Neupane C, Pham TL, Lee M, Lee S, Lee SY, Nam MH, Kim CS, Park JB. Tonic Activation of NR2D-Containing NMDARs Exacerbates Dopaminergic Neuronal Loss in MPTP-Injected Parkinsonian Mice. J Neurosci 2023; 43:7730-7744. [PMID: 37726169 PMCID: PMC10648527 DOI: 10.1523/jneurosci.1955-22.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 09/01/2023] [Accepted: 09/08/2023] [Indexed: 09/21/2023] Open
Abstract
NR2D subunit-containing NMDA receptors (NMDARs) gradually disappear during brain maturation but can be recruited by pathophysiological stimuli in the adult brain. Here, we report that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication recruited NR2D subunit-containing NMDARs that generated an Mg2+-resistant tonic NMDA current (INMDA) in dopaminergic (DA) neurons in the midbrain of mature male mice. MPTP selectively generated an Mg2+-resistant tonic INMDA in DA neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). Consistently, MPTP increased NR2D but not NR2B expression in the midbrain regions. Pharmacological or genetic NR2D interventions abolished the generation of Mg2+-resistant tonic INMDA in SNpc DA neurons, and thus attenuated subsequent DA neuronal loss and gait deficits in MPTP-treated mice. These results show that extrasynaptic NR2D recruitment generates Mg2+-resistant tonic INMDA and exacerbates DA neuronal loss, thus contributing to MPTP-induced Parkinsonism. The state-dependent NR2D recruitment could be a novel therapeutic target for mitigating cell type-specific neuronal death in neurodegenerative diseases.SIGNIFICANCE STATEMENT NR2D subunit-containing NMDA receptors (NMDARs) are widely expressed in the brain during late embryonic and early postnatal development, and then downregulated during brain maturation and preserved at low levels in a few regions of the adult brain. Certain stimuli can recruit NR2D subunits to generate tonic persistent NMDAR currents in nondepolarized neurons in the mature brain. Our results show that MPTP intoxication recruits NR2D subunits in midbrain dopaminergic (DA) neurons, which leads to tonic NMDAR current-promoting dopaminergic neuronal death and consequent abnormal gait behavior in the MPTP mouse model of Parkinson's disease (PD). This is the first study to indicate that extrasynaptic NR2D recruitment could be a target for preventing neuronal death in neurodegenerative diseases.
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Affiliation(s)
- Ramesh Sharma
- Department of Biomedicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Physiology, Chungnam National University, Daejeon 35015, Republic of Korea
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08852, Republic of Korea
| | - Chiranjivi Neupane
- Department of Biomedicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Physiology, Chungnam National University, Daejeon 35015, Republic of Korea
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08852, Republic of Korea
| | - Thuy Linh Pham
- Department of Biomedicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Physiology, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Miae Lee
- Physiology, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Sanghoon Lee
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08852, Republic of Korea
| | - So Yeong Lee
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08852, Republic of Korea
| | - Min-Ho Nam
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Cuk-Seong Kim
- Department of Biomedicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Physiology, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Jin Bong Park
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08852, Republic of Korea
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13
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Ling Q, Liu A, Li Y, Mi T, Chan P, Liu Y, Chen X. Homogeneous-Multiset-CCA-Based Brain Covariation and Contravariance Connectivity Network Modeling. IEEE Trans Neural Syst Rehabil Eng 2023; 31:3556-3565. [PMID: 37682656 DOI: 10.1109/tnsre.2023.3310340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/10/2023]
Abstract
Brain connectivity networks based on functional magnetic resonance imaging (fMRI) have expanded our understanding of brain functions in both healthy and diseased states. However, most current studies construct connectivity networks using averaged regional time courses with the strong assumption that the activities of voxels contained in each brain region are similar, ignoring their possible variations. Additionally, pairwise correlation analysis is often adopted with more attention to positive relationships, while joint interactions at the network level as well as anti-correlations are less investigated. In this paper, to provide a new strategy for regional activity representation and brain connectivity modeling, a novel homogeneous multiset canonical correlation analysis (HMCCA) model is proposed, which enforces sign constraints on the weights of voxels to guarantee homogeneity within each brain region. It is capable of obtaining regional representative signals and constructing covariation and contravariance networks simultaneously, at both group and subject levels. Validations on two sessions of fMRI data verified its reproducibility and reliability when dealing with brain connectivity networks. Further experiments on subjects with and without Parkinson's disease (PD) revealed significant alterations in brain connectivity patterns, which were further associated with clinical scores and demonstrated superior prediction ability, indicating its potential in clinical practice.
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14
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Nicoletti F, Di Menna L, Iacovelli L, Orlando R, Zuena AR, Conn PJ, Dogra S, Joffe ME. GPCR interactions involving metabotropic glutamate receptors and their relevance to the pathophysiology and treatment of CNS disorders. Neuropharmacology 2023; 235:109569. [PMID: 37142158 DOI: 10.1016/j.neuropharm.2023.109569] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/18/2023] [Accepted: 05/02/2023] [Indexed: 05/06/2023]
Abstract
Cellular responses to metabotropic glutamate (mGlu) receptor activation are shaped by mechanisms of receptor-receptor interaction. mGlu receptor subtypes form homodimers, intra- or inter-group heterodimers, and heteromeric complexes with other G protein-coupled receptors (GPCRs). In addition, mGlu receptors may functionally interact with other receptors through the βγ subunits released from G proteins in response to receptor activation or other mechanisms. Here, we discuss the interactions between (i) mGlu1 and GABAB receptors in cerebellar Purkinje cells; (ii) mGlu2 and 5-HT2Aserotonergic receptors in the prefrontal cortex; (iii) mGlu5 and A2A receptors or mGlu5 and D1 dopamine receptors in medium spiny projection neurons of the indirect and direct pathways of the basal ganglia motor circuit; (iv) mGlu5 and A2A receptors in relation to the pathophysiology of Alzheimer's disease; and (v) mGlu7 and A1 adenosine or α- or β1 adrenergic receptors. In addition, we describe in detail a novel form of non-heterodimeric interaction between mGlu3 and mGlu5 receptors, which appears to be critically involved in mechanisms of activity-dependent synaptic plasticity in the prefrontal cortex and hippocampus. Finally, we highlight the potential implication of these interactions in the pathophysiology and treatment of cerebellar disorders, schizophrenia, Alzheimer's disease, Parkinson's disease, l-DOPA-induced dyskinesias, stress-related disorders, and cognitive dysfunctions.
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Affiliation(s)
- Ferdinando Nicoletti
- Department of Physiology and Pharmacology, Sapienza University of Rome, Italy; IRCCS Neuromed, Pozzilli, Italy.
| | | | - Luisa Iacovelli
- Department of Physiology and Pharmacology, Sapienza University of Rome, Italy
| | - Rosamaria Orlando
- Department of Physiology and Pharmacology, Sapienza University of Rome, Italy; IRCCS Neuromed, Pozzilli, Italy
| | - Anna Rita Zuena
- Department of Physiology and Pharmacology, Sapienza University of Rome, Italy
| | - P Jeffrey Conn
- Department of Pharmacology, Italy; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, 37232, USA
| | - Shalini Dogra
- Department of Pharmacology, Italy; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, 37232, USA
| | - Max E Joffe
- Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15219, USA
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15
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Yadav P, Podia M, Kumari SP, Mani I. Glutamate receptor endocytosis and signaling in neurological conditions. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 196:167-207. [PMID: 36813358 DOI: 10.1016/bs.pmbts.2022.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The non-essential amino acid glutamate acts as a major excitatory neurotransmitter and plays a significant role in the central nervous system (CNS). It binds with two different types of receptors, ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs), responsible for the postsynaptic excitation of neurons. They are important for memory, neural development and communication, and learning. Endocytosis and subcellular trafficking of the receptor are essential for the regulation of receptor expression on the cell membrane and excitation of the cells. The endocytosis and trafficking of the receptor are dependent on its type, ligand, agonist, and antagonist present. This chapter discusses the types of glutamate receptors, their subtypes, and the regulation of their internalization and trafficking. The roles of glutamate receptors in neurological diseases are also briefly discussed.
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Affiliation(s)
- Prerna Yadav
- Department of Microbiology, University of Delhi, New Delhi, India
| | - Mansi Podia
- Department of Microbiology, University of Delhi, New Delhi, India
| | - Shashi Prabha Kumari
- Department of Microbiology, Ram Lal Anand College, University of Delhi, New Delhi, India
| | - Indra Mani
- Department of Microbiology, Gargi College, University of Delhi, New Delhi, India.
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16
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Rinaldi D, Alborghetti M, Bianchini E, Sforza M, Galli S, Pontieri FE. Monoamine-oxidase Type B Inhibitors and Cognitive Functions in Parkinson's Disease: Beyond the Primary Mechanism of Action. Curr Neuropharmacol 2023; 21:1214-1223. [PMID: 36065929 PMCID: PMC10286595 DOI: 10.2174/1570159x20666220905102144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 03/23/2022] [Accepted: 04/24/2022] [Indexed: 11/22/2022] Open
Abstract
Symptoms of cognitive impairment are rather common since the early stage of Parkinson's disease (PD); they aggravate with disease progression and may lead to dementia in a significant proportion of cases. Worsening of cognitive symptoms in PD patients depends on the progression of subcortical dopaminergic damage as well as the involvement of other brain neurotransmitter systems in cortical and subcortical regions. Beyond the negative impact on disability and quality of life, the presence and severity of cognitive symptoms may limit adjustments of dopamine replacement therapy along the disease course. This review focuses on the consequences of the administration of monoamine-oxidase type Binhibitors (MAOB-I) on cognition in PD patients. Two drugs (selegiline and rasagiline) are available for the treatment of motor symptoms of PD as monotherapy or in combination with L-DOPA or dopamine agonists in stable and fluctuating patients; a further drug (safinamide) is usable in fluctuating subjects solely. The results of available studies indicate differential effects according to disease stage and drug features. In early, non-fluctuating patients, selegiline and rasagiline ameliorated prefrontal executive functions, similarly to other dopaminergic drugs. Benefit on some executive functions was maintained in more advanced, fluctuating patients, despite the tendency of worsening prefrontal inhibitory control activity. Interestingly, high-dose safinamide improved inhibitory control in fluctuating patients. The benefit of high-dose safinamide on prefrontal inhibitory control mechanisms may stem from its dual mechanism of action, allowing reduction of excessive glutamatergic transmission, in turn secondary to increased cortical dopaminergic input.
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Affiliation(s)
- Domiziana Rinaldi
- Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso, Sapienza Università di Roma, Italy
- IRCCS Fondazione Santa Lucia, Roma, Italy
| | - Marika Alborghetti
- Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso, Sapienza Università di Roma, Italy
- IRCCS Fondazione Santa Lucia, Roma, Italy
| | - Edoardo Bianchini
- Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso, Sapienza Università di Roma, Italy
| | - Michela Sforza
- Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso, Sapienza Università di Roma, Italy
- IRCCS Fondazione Santa Lucia, Roma, Italy
| | - Silvia Galli
- Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso, Sapienza Università di Roma, Italy
| | - Francesco E. Pontieri
- Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso, Sapienza Università di Roma, Italy
- IRCCS Fondazione Santa Lucia, Roma, Italy
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17
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Hoglund BK, Carfagno V, Olive MF, Leyrer-Jackson JM. Metabotropic glutamate receptors and cognition: From underlying plasticity and neuroprotection to cognitive disorders and therapeutic targets. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 168:367-413. [PMID: 36868635 DOI: 10.1016/bs.irn.2022.10.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors that play pivotal roles in mediating the activity of neurons and other cell types within the brain, communication between cell types, synaptic plasticity, and gene expression. As such, these receptors play an important role in a number of cognitive processes. In this chapter, we discuss the role of mGlu receptors in various forms of cognition and their underlying physiology, with an emphasis on cognitive dysfunction. Specifically, we highlight evidence that links mGlu physiology to cognitive dysfunction across brain disorders including Parkinson's disease, Alzheimer's disease, Fragile X syndrome, post-traumatic stress disorder, and schizophrenia. We also provide recent evidence demonstrating that mGlu receptors may elicit neuroprotective effects in particular disease states. Lastly, we discuss how mGlu receptors can be targeted utilizing positive and negative allosteric modulators as well as subtype specific agonists and antagonist to restore cognitive function across these disorders.
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Affiliation(s)
- Brandon K Hoglund
- Department of Medical Education, School of Medicine, Creighton University, Phoenix, AZ, United States
| | - Vincent Carfagno
- School of Medicine, Midwestern University, Glendale, AZ, United States
| | - M Foster Olive
- Department of Psychology, Arizona State University, Tempe, AZ, United States
| | - Jonna M Leyrer-Jackson
- Department of Medical Education, School of Medicine, Creighton University, Phoenix, AZ, United States.
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18
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Zhao G, Zhang D, Qiao D, Liu X. Exercise improves behavioral dysfunction and inhibits the spontaneous excitatory postsynaptic current of D2-medium spiny neurons. Front Aging Neurosci 2022; 14:1001256. [PMID: 36533169 PMCID: PMC9752814 DOI: 10.3389/fnagi.2022.1001256] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 11/15/2022] [Indexed: 10/17/2023] Open
Abstract
The abnormal function of striatal medium spiny neurons (MSNs) leads to the excitation-inhibition imbalance of the basal ganglia, which is an important pathogenic factor of Parkinson's disease (PD). Exercise improves the dysfunction of basal ganglia through neuroprotective and neuroreparative effects, which may be related to the functional changes of expresses D2 receptors MSNs (D2-MSNs). In this study, D2-Cre mice were selected as the research objects, the PD model was induced by unilateral injection of 6-hydroxydopamine (6-OHDA) in the striatum, and the 4-week treadmill training method was used for exercise intervention. Using optogenetics and behavioral tests, we determined that the average total movement distance of PD and PD + Ex groups was significantly lower than that of the Control group, while that of the PD + Ex and PD + Laser groups was significantly higher than that of the PD group, and the two intervention methods of exercise and optogenetic-stimulation of the D2-MSNs had basically similar effects on improving the autonomic behavior of PD mice. To further investigate the cellular mechanisms, whole-cell patch clamp recordings were carried out on D2-MSNs. We found that exercise decreased the frequency and amplitude of spontaneous excitatory postsynaptic current (sEPSC) and increased the paired-pulse radio of D2-MSNs while leaving basic electrophysiological properties of MSNs unaffected. Combined with behavioral improvement and enhanced D2R protein expression, our findings suggest the inhibited sEPSC of D2-MSNs may contribute to the behavioral improvement after exercise.
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Affiliation(s)
- Gang Zhao
- Physical Education College, Soochow University, Suzhou, China
- Physical Education and Sports College, Beijing Normal University, Beijing, China
| | - Danyu Zhang
- Physical Education and Sports College, Beijing Normal University, Beijing, China
| | - Decai Qiao
- Physical Education and Sports College, Beijing Normal University, Beijing, China
| | - Xiaoli Liu
- Physical Education and Sports College, Beijing Normal University, Beijing, China
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19
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Matrisciano F, Locci V, Dong E, Nicoletti F, Guidotti A, Grayson DR. Altered Expression and In Vivo Activity of mGlu5 Variant a Receptors in the Striatum of BTBR Mice: Novel Insights Into the Pathophysiology of Adult Idiopathic Forms of Autism Spectrum Disorders. Curr Neuropharmacol 2022; 20:2354-2368. [PMID: 35139800 PMCID: PMC9890299 DOI: 10.2174/1567202619999220209112609] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/27/2022] [Accepted: 01/31/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND mGlu5 metabotropic glutamate receptors are considered as candidate drug targets in the treatment of "monogenic" forms of autism spectrum disorders (ASD), such as Fragile- X syndrome (FXS). However, despite promising preclinical data, clinical trials using mGlu5 receptor antagonists to treat FXS showed no beneficial effects. OBJECTIVE Here, we studied the expression and function of mGlu5 receptors in the striatum of adult BTBR mice, which model idiopathic forms of ASD, and behavioral phenotype. METHODS Behavioral tests were associated with biochemistry analysis including qPCR and western blot for mRNA and protein expression. In vivo analysis of polyphosphoinositides hydrolysis was performed to study the mGlu5-mediated intracellular signaling in the striatum of adult BTBR mice under basal conditions and after MTEP exposure. RESULTS Expression of mGlu5 receptors and mGlu5 receptor-mediated polyphosphoinositides hydrolysis were considerably high in the striatum of BTBR mice, sensitive to MTEP treatment. Changes in the expression of genes encoding for proteins involved in excitatory and inhibitory neurotransmission and synaptic plasticity, including Fmr1, Dlg4, Shank3, Brd4, bdnf-exon IX, Mef2c, and Arc, GriA2, Glun1, Nr2A, and Grm1, Grm2, GriA1, and Gad1 were also found. Behaviorally, BTBR mice showed high repetitive stereotypical behaviors, including self-grooming and deficits in social interactions. Acute or repeated injections with MTEP reversed the stereotyped behavior and the social interaction deficit. Similar effects were observed with the NMDA receptor blockers MK-801 or ketamine. CONCLUSION These findings support a pivotal role of mGlu5 receptor abnormal expression and function in idiopathic ASD adult forms and unveil novel potential targets for therapy.
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Affiliation(s)
- Francesco Matrisciano
- The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Valentina Locci
- The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA
| | - Erbo Dong
- The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA
- Center for Alcohol Research in Epigenetics Department of Psychiatry College of Medicine University of Illinois Chicago, Chicago, IL 60612, USA
| | - Ferdinando Nicoletti
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
- IRCCS Neuromed, Pozzilli, Italy
| | - Alessandro Guidotti
- The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA
- Center for Alcohol Research in Epigenetics Department of Psychiatry College of Medicine University of Illinois Chicago, Chicago, IL 60612, USA
| | - Dennis R. Grayson
- The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA
- Center for Alcohol Research in Epigenetics Department of Psychiatry College of Medicine University of Illinois Chicago, Chicago, IL 60612, USA
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20
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Cesaroni V, Blandini F, Cerri S. Dyskinesia and Parkinson's disease: animal model, drug targets, and agents in preclinical testing. Expert Opin Ther Targets 2022; 26:837-851. [PMID: 36469635 DOI: 10.1080/14728222.2022.2153036] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. PD patients exhibit a classic spectrum of motor symptoms, arising when dopamine neurons in the substantia nigra pars compacta are reduced by 60%. The dopamine precursor L-DOPA represents the most effective therapy for improving PD motor dysfunctions, thus far available. Unfortunately, long-term treatment with L-DOPA is associated with the development of severe side effects, resulting in abnormal involuntary movements termed levodopa-induced dyskinesia (LID). Amantadine is the only drug currently approved for the treatment of LID indicating that LID management is still an unmet need in PD and encouraging the search for novel anti-dyskinetic drugs or the assessment of combined therapies with different molecular targets. AREAS COVERED This review provides an overview of the main preclinical models used to study LID and of the latest preclinical evidence on experimental and clinically available pharmacological approaches targeting non-dopaminergic systems. EXPERT OPINION LIDs are supported by complex molecular and neurobiological mechanisms that are still being studied today. This complexity suggests the need of developing personalized pharmacological approach to obtain an effective amelioration of LID condition and improve the quality of life of PD patients.
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Affiliation(s)
- Valentina Cesaroni
- Unit of Cellular and Molecular Neurobiology, IRCCS Mondino Foundation 27100, Pavia, Italy
| | - Fabio Blandini
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico 20122, Milan, Italy
| | - Silvia Cerri
- Unit of Cellular and Molecular Neurobiology, IRCCS Mondino Foundation 27100, Pavia, Italy
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21
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VGLUT3 Ablation Differentially Modulates Glutamate Receptor Densities in Mouse Brain. eNeuro 2022; 9:ENEURO.0041-22.2022. [PMID: 35443989 PMCID: PMC9087739 DOI: 10.1523/eneuro.0041-22.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 04/04/2022] [Accepted: 04/10/2022] [Indexed: 11/21/2022] Open
Abstract
Type 3 vesicular glutamate transporter (VGLUT3) represents a unique modulator of glutamate release from both nonglutamatergic and glutamatergic varicosities within the brain. Despite its limited abundance, VGLUT3 is vital for the regulation of glutamate signaling and, therefore, modulates the activity of various brain microcircuits. However, little is known about how glutamate receptors are regulated by VGLUT3 across different brain regions. Here, we used VGLUT3 constitutive knock-out (VGLUT3-/-) mice and explored how VGLUT3 deletion influences total and cell surface expression of different ionotropic and metabotropic glutamate receptors. VGLUT3 deletion upregulated the overall expression of metabotropic glutamate receptors mGluR5 and mGluR2/3 in the cerebral cortex. In contrast, no change in the total expression of ionotropic NMDAR glutamate receptors were observed in the cerebral cortex of VGLUT3-/- mice. We noted significant reduction in cell surface levels of mGluR5, NMDAR2A, NMDAR2B, as well as reductions in dopaminergic D1 receptors and muscarinic M1 acetylcholine receptors in the hippocampus of VGLUT3-/- mice. Furthermore, mGluR2/3 total expression and mGluR5 cell surface levels were elevated in the striatum of VGLUT3-/- mice. Last, AMPAR subunit GluA1 was significantly upregulated throughout cortical, hippocampal, and striatal brain regions of VGLUT3-/- mice. Together, these findings complement and further support the evidence that VGLUT3 dynamically regulates glutamate receptor densities in several brain regions. These results suggest that VGLUT3 may play an intricate role in shaping glutamatergic signaling and plasticity in several brain areas.
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22
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Seo SY, Yang JH, Kim S, Sohn S, Oh JH, Mao L, Wang JQ, Choe ES. Interaction of JNK and mGluR5 in the regulation of psychomotor behaviours after repeated cocaine administration. Addict Biol 2022; 27:e13127. [PMID: 35229936 DOI: 10.1111/adb.13127] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 12/01/2021] [Accepted: 12/03/2021] [Indexed: 11/30/2022]
Abstract
Activation of protein kinases after cocaine administration controls psychomotor behaviours by interacting with metabotropic receptors in the brain. This study identified how c-Jun N-terminal kinase (JNK) interacts with metabotropic glutamate receptor 5 (mGluR5) in vitro and in the caudate and putamen (CPu). The potential role of this interaction in the regulation of psychomotor behaviour was also evaluated after administration of cocaine. Active JNK phosphorylates a threonine residue at position 1055 in the carboxyl terminus (CT) of mGluR5 in vitro. The binding of active JNK to the D-motif within CT2 is necessary for that phosphorylation. Interaction of phosphorylated JNK and mGluR5 occurs in the CPu. Unilateral interference of the interaction decreases the repeated cocaine-induced increases in locomotor activity and conditioned place preference. These findings suggest that activation of JNK has the capability to interact with mGluR5 in the CPu. Phosphorylation of mGluR5 following the JNK-mGluR5 interaction may be responsible for the potentiation of behavioural sensitisation and cocaine-wanting behaviour in response to cocaine administration.
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Affiliation(s)
- Su Yeon Seo
- Department of Biological Sciences Pusan National University Busan South Korea
| | - Ju Hwan Yang
- Department of Biological Sciences Pusan National University Busan South Korea
| | - Sunghyun Kim
- Department of Biological Sciences Pusan National University Busan South Korea
| | - Sumin Sohn
- Department of Biological Sciences Pusan National University Busan South Korea
| | - Jeong Hwan Oh
- Department of Biological Sciences Pusan National University Busan South Korea
| | - Li‐Min Mao
- Department of Anesthesiology and Basic Medical Science University of Missouri–Kansas City Kansas City Missouri USA
| | - John Q. Wang
- Department of Anesthesiology and Basic Medical Science University of Missouri–Kansas City Kansas City Missouri USA
| | - Eun Sang Choe
- Department of Biological Sciences Pusan National University Busan South Korea
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23
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Angela Cenci M, Skovgård K, Odin P. Non-dopaminergic approaches to the treatment of motor complications in Parkinson's disease. Neuropharmacology 2022; 210:109027. [DOI: 10.1016/j.neuropharm.2022.109027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/06/2022] [Accepted: 03/09/2022] [Indexed: 12/21/2022]
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Nikvarz N, Sabouri S. Drug-induced stuttering: A comprehensive literature review. World J Psychiatry 2022; 12:236-263. [PMID: 35317340 PMCID: PMC8900588 DOI: 10.5498/wjp.v12.i2.236] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/29/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced stuttering (DIS) is a type of neurogenic stuttering (NS). Although DIS has not been reported as frequently as other cases of NS in the literature, it is not a negligible adverse drug reaction (ADR) which can significantly affect the quality of life if not treated. This literature review aims to evaluate the epidemiological and clinical characteristics of DIS and suggests some pathophysiological mechanisms for this ADR. Relevant English-language reports in Google Scholar, PubMed, Web of Science, and Scopus were identified and assessed without time restriction. Finally, a total of 62 reports were included. Twenty-seven drugs caused 86 episodes of stuttering in 82 cases. The most episodes of DIS were related to antipsychotic drugs (57%), mostly including clozapine, followed by central nervous system agents (11.6%) and anticonvulsant drugs (9.3%). The majority of the cases were male and between the ages of 31 and 40 years. Repetitions were the most frequent core manifestations of DIS. In 55.8% of the episodes of DIS, the offending drug was withdrawn to manage stuttering, which resulted in significant improvement or complete relief of stuttering in all cases. Based on the suggested pathophysiological mechanisms for developmental stuttering and neurotransmitters dysfunctions involved in speech dysfluency, it seems that the abnormalities of several neurotransmitters, especially dopamine and glutamate, in different circuits and areas of the brain, including cortico-basal ganglia-thalamocortical loop and white matter fiber tracts, may be engaged in the pathogenesis of DIS.
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Affiliation(s)
- Naemeh Nikvarz
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman 7616911319, Iran
| | - Salehe Sabouri
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman 7616911319, Iran
- Department of Pharmaceutical Biotechnology, Kerman University of Medical Sciences, Kerman 7616911319, Iran
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25
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Prevention of L-Dopa-Induced Dyskinesias by MPEP Blockade of Metabotropic Glutamate Receptor 5 Is Associated with Reduced Inflammation in the Brain of Parkinsonian Monkeys. Cells 2022; 11:cells11040691. [PMID: 35203338 PMCID: PMC8870609 DOI: 10.3390/cells11040691] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/08/2022] [Accepted: 02/09/2022] [Indexed: 02/01/2023] Open
Abstract
Proinflammatory markers were found in brains of Parkinson’s disease (PD) patients. After years of L-Dopa symptomatic treatment, most PD patients develop dyskinesias. The relationship between inflammation and L-Dopa-induced dyskinesias (LID) is still unclear. We previously reported that MPEP (a metabotropic glutamate receptor 5 antagonist) reduced the development of LID in de novo MPTP-lesioned monkeys. We thus investigated if MPEP reduced the brain inflammatory response in these MPTP-lesioned monkeys and the relationship to LID. The panmacrophage/microglia marker Iba1, the phagocytosis-related receptor CD68, and the astroglial protein GFAP were measured by Western blots. The L-Dopa-treated dyskinetic MPTP monkeys had increased Iba1 content in the putamen, substantia nigra, and globus pallidus, which was prevented by MPEP cotreatment; similar findings were observed for CD68 contents in the putamen and globus pallidus. There was a strong positive correlation between dyskinesia scores and microglial markers in these regions. GFAP contents were elevated in MPTP + L-Dopa-treated monkeys among these brain regions and prevented by MPEP in the putamen and subthalamic nucleus. In conclusion, these results showed increased inflammatory markers in the basal ganglia associated with LID and revealed that MPEP inhibition of glutamate activity reduced LID and levels of inflammatory markers.
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26
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Bove F, Calabresi P. Plasticity, genetics, and epigenetics in l-dopa-induced dyskinesias. HANDBOOK OF CLINICAL NEUROLOGY 2022; 184:167-184. [PMID: 35034732 DOI: 10.1016/b978-0-12-819410-2.00009-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
l-Dopa-induced dyskinesias (LIDs) are a frequent complication in l-dopa-treated patients affected by Parkinson's disease (PD). In the last years, several progresses in the knowledge of LIDs mechanisms have led to the identification of several molecular and electrophysiologic events. A complex cascade of intracellular events underlies the pathophysiology of LIDs, and, among these, aberrant plasticity in the cortico-basal ganglia system, at striatal and cortical level, plays a key role. Furthermore, several recent studies have investigated genetic susceptibility and epigenetic modifications in LIDs pathophysiology that might have future relevance in clinical practice and pharmacologic research. These progresses might lead to the development of specific strategies not only to treat, but also to prevent or delay the development of LIDs in PD.
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Affiliation(s)
- Francesco Bove
- UOC Neurologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Paolo Calabresi
- UOC Neurologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy.
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27
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Optogenetic inhibition of indirect pathway neurons in the dorsomedial striatum reduces excessive grooming in Sapap3-knockout mice. Neuropsychopharmacology 2022; 47:477-487. [PMID: 34417544 PMCID: PMC8674346 DOI: 10.1038/s41386-021-01161-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 08/07/2021] [Accepted: 08/13/2021] [Indexed: 02/07/2023]
Abstract
Excessive grooming of Sapap3-KO mice has been used as a model of obsessive-compulsive disorder (OCD). Previous studies suggest that dysregulation of cortico-striatal circuits is critically important in the generation of compulsive behaviors, and it has been proposed that the alteration in the activity patterns of striatal circuitry underlies the excessive grooming observed in Sapap3-KO mice. To test this hypothesis, we used in-vivo calcium imaging of individual cells to record striatal activity in these animals and optogenetic inhibition to manipulate this activity. We identified striatal neurons that are modulated during grooming behavior and found that their proportion is significantly larger in Sapap3-KO mice compared to wild-type littermates. Inhibition of striatal cells in Sapap3-KO mice increased the number of grooming episodes observed. Remarkably, the specific inhibition of indirect pathway neurons decreased the occurrence of grooming events. Our results indicate that there is striatal neural activity related to excessive grooming engagement in Sapap3-KO mice. We also demonstrate, for the first time, that specific inhibition of striatal indirect pathway neurons reduces this compulsive phenotype, suggesting that treatments that alleviate compulsive symptoms in OCD patients may exert their effects through this specific striatal population.
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Rai SN, Singh P, Varshney R, Chaturvedi VK, Vamanu E, Singh MP, Singh BK. Promising drug targets and associated therapeutic interventions in Parkinson's disease. Neural Regen Res 2021; 16:1730-1739. [PMID: 33510062 PMCID: PMC8328771 DOI: 10.4103/1673-5374.306066] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/26/2020] [Accepted: 12/17/2020] [Indexed: 12/11/2022] Open
Abstract
Parkinson's disease (PD) is one of the most debilitating brain diseases. Despite the availability of symptomatic treatments, response towards the health of PD patients remains scarce. To fulfil the medical needs of the PD patients, an efficacious and etiological treatment is required. In this review, we have compiled the information covering limitations of current therapeutic options in PD, novel drug targets for PD, and finally, the role of some critical beneficial natural products to control the progression of PD.
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Affiliation(s)
| | - Payal Singh
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ritu Varshney
- Department of Bioengineering and Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gujarat, India
| | | | - Emanuel Vamanu
- Faculty of Biotechnology, University of Agronomic Science and Veterinary Medicine, Bucharest, Romania
| | - M. P. Singh
- Centre of Biotechnology, University of Allahabad, Prayagraj, India
| | - Brijesh Kumar Singh
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
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29
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Mann E, Jackson M, Lincoln L, Fisher R, Rose S, Duty S. Antiparkinsonian Effects of a Metabotropic Glutamate Receptor 4 Agonist in MPTP-Treated Marmosets. JOURNAL OF PARKINSONS DISEASE 2021; 10:959-967. [PMID: 32250315 DOI: 10.3233/jpd-191824] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Increased firing across glutamatergic synapses may contribute to both the motor dysfunction and L-DOPA-induced dyskinesia seen in Parkinson's disease. Given their ability to reduce glutamate release, activation of group III metabotropic glutamate receptors such as metabotropic glutamate receptor 4 may prove effective against both motor dysfunction and dyskinesia in Parkinson's disease. OBJECTIVE We hypothesised that activation of metabotropic glutamate receptor 4 by an orthosteric agonist ((2S)-2-amino-4-(hydroxy(hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl)phosphoryl)butanoic acid, LSP1-2111) would produce antiparkinsonian activity and reduce expression of dyskinesia in a 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset model of Parkinson's disease. METHODS Common marmosets were previously treated with MPTP and pre-primed with L-DOPA for up to 28 days to express dyskinesia. LSP1-2111 (1, 3, or 6 mg/kg s.c.) or vehicle (0.9% saline s.c.) were administered immediately prior to L-DOPA (8 mg/kg + benserazide (10 mg/kg) p.o.) or vehicle (10% sucrose p.o.). Locomotor activity was measured in automated test cages and animals were scored for dyskinesia and disability. RESULTS As expected, L-DOPA reversed motor disability and induced moderate dyskinesia. By contrast, LSP1-2111 alone significantly reduced the motor disability without any accompanying expression of dyskinesia. When administered in combination with L-DOPA, LSP1-2111 did not significantly reduce the severity of L-DOPA-induced dyskinesia. CONCLUSION Systemic administration of LSP1-2111 reduces motor disability without causing dyskinesia in MPTP-treated marmosets, supporting a role for metabotropic glutamate receptor 4 orthosteric agonists as promising monotherapy for PD. Conversely, this study found no evidence to support their use as antidyskinetic agents within the dose range tested.
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Affiliation(s)
- Elizabeth Mann
- Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Michael Jackson
- Neurodegenerative Diseases Research Group, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Louise Lincoln
- Neurodegenerative Diseases Research Group, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Ria Fisher
- Neurodegenerative Diseases Research Group, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Sarah Rose
- Neurodegenerative Diseases Research Group, Faculty of Life Science and Medicine, King's College London, London, UK
| | - Susan Duty
- Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
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30
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Zheng C, Zhang F. New insights into pathogenesis of l-DOPA-induced dyskinesia. Neurotoxicology 2021; 86:104-113. [PMID: 34331976 DOI: 10.1016/j.neuro.2021.07.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/25/2021] [Accepted: 07/26/2021] [Indexed: 10/20/2022]
Abstract
Parkinson's disease (PD) is a progressive and self-propelling neurodegenerative disorder, which is characterized by motor symptoms, such as rigidity, tremor, slowness of movement and problems with gait. These symptoms become worse over time. To date, Dopamine (DA) replacement therapy with 3, 4-dihydroxy-l-phenylalanine (L-DOPA) is still the most effective pharmacotherapy for motor symptoms of PD. Unfortunately, motor fluctuations consisting of wearing-off effect actions and dyskinesia tend to occur in a few years of starting l-DOPA. Currently, l-DOPA-induced dyskinesia (LID) is troublesome and the pathogenesis of LID requires further investigation. Importantly, a new intervention for LID is imminent. Thus, this review mainly summarized the clinical features, risk factors and pathogenesis of LID to provide updatefor the development of therapeutic targets and new approaches for the treatment of LID.
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Affiliation(s)
- Changqing Zheng
- Laboratory Animal Center and Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Feng Zhang
- Laboratory Animal Center and Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China.
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31
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Su LD, Wang N, Han J, Shen Y. Group 1 Metabotropic Glutamate Receptors in Neurological and Psychiatric Diseases: Mechanisms and Prospective. Neuroscientist 2021; 28:453-468. [PMID: 34088252 PMCID: PMC9449437 DOI: 10.1177/10738584211021018] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors
that are activated by glutamate in the central nervous system (CNS).
Basically, mGluRs contribute to fine-tuning of synaptic efficacy and
control the accuracy and sharpness of neurotransmission. Among eight
subtypes, mGluR1 and mGluR5 belong to group 1 (Gp1) family, and are
implicated in multiple CNS disorders, such as Alzheimer’s disease,
autism, Parkinson’s disease, and so on. In the present review, we
systematically discussed underlying mechanisms and prospective of Gp1
mGluRs in a group of neurological and psychiatric diseases, including
Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder,
epilepsy, Huntington’s disease, intellectual disability, Down’s
syndrome, Rett syndrome, attention-deficit hyperactivity disorder,
addiction, anxiety, nociception, schizophrenia, and depression, in
order to provide more insights into the therapeutic potential of Gp1
mGluRs.
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Affiliation(s)
- Li-Da Su
- Neuroscience Care Unit, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Na Wang
- School of Medicine, Zhejiang University City College, Hangzhou, China
| | - Junhai Han
- School of Life Science and Technology, the Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
| | - Ying Shen
- Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China
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32
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Fabbrini A, Guerra A. Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia. J Exp Pharmacol 2021; 13:469-485. [PMID: 33953618 PMCID: PMC8092630 DOI: 10.2147/jep.s265282] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 03/30/2021] [Indexed: 12/21/2022] Open
Abstract
L-dopa-induced dyskinesia (LID) is the most frequent motor complication associated with chronic L-dopa treatment in Parkinson’s disease (PD). Recent advances in the understanding of the pathophysiological mechanisms underlying LID suggest that abnormalities in multiple neurotransmitter systems, in addition to dopaminergic nigrostriatal denervation and altered dopamine release and reuptake dynamics at the synaptic level, are involved in LID development. Increased knowledge of neurobiological LID substrates has led to the development of several drug candidates to alleviate this motor complication. However, with the exception of amantadine, none of the pharmacological therapies tested in humans have demonstrated clinically relevant beneficial effects. Therefore, LID management is still one of the most challenging problems in the treatment of PD patients. In this review, we first describe the known pathophysiological mechanisms of LID. We then provide an updated report of experimental pharmacotherapies tested in clinical trials of PD patients and drugs currently under study to alleviate LID. Finally, we discuss available pharmacological LID treatment approaches and offer our opinion of possible issues to be clarified and future therapeutic strategies.
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Affiliation(s)
- Andrea Fabbrini
- Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy
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33
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Upreti C, Woodruff CM, Zhang XL, Yim MJ, Zhou ZY, Pagano AM, Rehanian DS, Yin D, Kandel ER, Stanton PK, Nicholls RE. Loss of retinoid X receptor gamma subunit impairs group 1 mGluR mediated electrophysiological responses and group 1 mGluR dependent behaviors. Sci Rep 2021; 11:5552. [PMID: 33692389 PMCID: PMC7946894 DOI: 10.1038/s41598-021-84943-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 02/17/2021] [Indexed: 11/09/2022] Open
Abstract
Retinoid X receptors are members of the nuclear receptor family that regulate gene expression in response to retinoic acid and related ligands. Group 1 metabotropic glutamate receptors are G-protein coupled transmembrane receptors that activate intracellular signaling cascades in response to the neurotransmitter, glutamate. These two classes of molecules have been studied independently and found to play important roles in regulating neuronal physiology with potential clinical implications for disorders such as depression, schizophrenia, Parkinson's and Alzheimer's disease. Here we show that mice lacking the retinoid X receptor subunit, RXRγ, exhibit impairments in group 1 mGluR-mediated electrophysiological responses at hippocampal Schaffer collateral-CA1 pyramidal cell synapses, including impaired group 1 mGluR-dependent long-term synaptic depression (LTD), reduced group 1 mGluR-induced calcium release, and loss of group 1 mGluR-activated voltage-sensitive currents. These animals also exhibit impairments in a subset of group 1 mGluR-dependent behaviors, including motor performance, spatial object recognition, and prepulse inhibition. Together, these observations demonstrate convergence between the RXRγ and group 1 mGluR signaling pathways that may function to coordinate their regulation of neuronal activity. They also identify RXRγ as a potential target for the treatment of disorders in which group 1 mGluR signaling has been implicated.
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Affiliation(s)
- Chirag Upreti
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA
| | - Caitlin M Woodruff
- Department of Neuroscience, Columbia University, 3227 Broadway, New York, NY, 10027, USA
| | - Xiao-Lei Zhang
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA
| | - Michael J Yim
- Department of Neuroscience, Columbia University, 3227 Broadway, New York, NY, 10027, USA
| | - Zhen-Yu Zhou
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.,Department of Neurology, New York Medical College, Valhalla, NY, 10595, USA
| | - Andrew M Pagano
- Department of Neuroscience, Columbia University, 3227 Broadway, New York, NY, 10027, USA
| | - Dina S Rehanian
- Department of Pathology and Cell Biology, Columbia University, 630 West 168thStreet, New York, NY, 10032, USA.,Taub Institute for Research on Alzheimer's Disease and Aging Brain, Columbia University, 630 West 168thStreet, New York, NY, 10032, USA
| | - Deqi Yin
- Department of Neuroscience, Columbia University, 3227 Broadway, New York, NY, 10027, USA.,Howard Hughes Medical Institute, Columbia University, 3227 Broadway, New York, NY, 10027, USA
| | - Eric R Kandel
- Department of Neuroscience, Columbia University, 3227 Broadway, New York, NY, 10027, USA.,Howard Hughes Medical Institute, Columbia University, 3227 Broadway, New York, NY, 10027, USA.,Kavli Institute for Brain Science, Columbia University, 3227 Broadway, New York, NY, 10027, USA.,Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, 3227 Broadway, New York, NY, 10027, USA
| | - Patric K Stanton
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.,Department of Neurology, New York Medical College, Valhalla, NY, 10595, USA
| | - Russell E Nicholls
- Department of Pathology and Cell Biology, Columbia University, 630 West 168thStreet, New York, NY, 10032, USA. .,Taub Institute for Research on Alzheimer's Disease and Aging Brain, Columbia University, 630 West 168thStreet, New York, NY, 10032, USA.
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34
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Dong J, Hawes S, Wu J, Le W, Cai H. Connectivity and Functionality of the Globus Pallidus Externa Under Normal Conditions and Parkinson's Disease. Front Neural Circuits 2021; 15:645287. [PMID: 33737869 PMCID: PMC7960779 DOI: 10.3389/fncir.2021.645287] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/05/2021] [Indexed: 12/18/2022] Open
Abstract
The globus pallidus externa (GPe) functions as a central hub in the basal ganglia for processing motor and non-motor information through the creation of complex connections with the other basal ganglia nuclei and brain regions. Recently, with the adoption of sophisticated genetic tools, substantial advances have been made in understanding the distinct molecular, anatomical, electrophysiological, and functional properties of GPe neurons and non-neuronal cells. Impairments in dopamine transmission in the basal ganglia contribute to Parkinson's disease (PD), the most common movement disorder that severely affects the patients' life quality. Altered GPe neuron activity and synaptic connections have also been found in both PD patients and pre-clinical models. In this review, we will summarize the main findings on the composition, connectivity and functionality of different GPe cell populations and the potential GPe-related mechanisms of PD symptoms to better understand the cell type and circuit-specific roles of GPe in both normal and PD conditions.
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Affiliation(s)
- Jie Dong
- Laboratory of Neurogenetics, Transgenic Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
| | - Sarah Hawes
- Laboratory of Neurogenetics, Transgenic Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
| | - Junbing Wu
- Child Health Institute of New Jersey, Rutgers University, New Brunswick, NJ, United States
| | - Weidong Le
- Liaoning Provincial Center for Clinical Research on Neurological Diseases & Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Medical School of University of Electronic Science and Technology of China, Institute of Neurology, Sichuan Provincial Hospital, Sichuan Academy of Medical Science, Chengdu, China
| | - Huaibin Cai
- Laboratory of Neurogenetics, Transgenic Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
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35
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Yang JH, Sohn S, Kim S, Kim J, Oh JH, Ryu IS, Go BS, Choe ES. Repeated nicotine exposure increases the intracellular interaction between ERK-mGluR5 in the nucleus accumbens more in adult than adolescent rats. Addict Biol 2021; 26:e12913. [PMID: 32339332 DOI: 10.1111/adb.12913] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 03/20/2020] [Accepted: 04/09/2020] [Indexed: 11/27/2022]
Abstract
Intracellular interactions between protein kinases and metabotropic receptors in the striatum regulate behavioral changes in response to drug exposure. We investigated the difference in the degree of interaction between extracellular signal-regulated kinase (ERK) and metabotropic glutamate receptor subtype 5 (mGluR5) in the nucleus accumbens (NAc) after repeated exposure to nicotine in adult and adolescent rats. The results showed that repeated exposure to nicotine (0.5 mg/kg/day, s.c.) for seven consecutive days increased ERK phosphorylation more in adults than in adolescents. Furthermore, membrane expression of mGluR5 in gamma-aminobutyric acid (GABA) medium spiny neurons was higher in adults than adolescents as a result of repeated exposure to nicotine. Blockade of mGluR5 with MPEP (0.5 nmol/side) decreased the repeated nicotine-induced increase in ERK phosphorylation. Either blockade of mGluR5 or inhibition of ERK with SL327 (150 nmol/side) decreased the repeated nicotine-induced increase in the level of inositol-1,4,5-triphosphate (IP3 ), a key transducer associated with mGluR5-coupled signaling cascades. Similarly, interference of binding between activated ERK and mGluR5 by the blocking peptide, Tat-mGluR5-i (2 nmol/side), decreased the repeated nicotine-induced increases in IP3 and locomotor activity in adults. These findings suggest that the intracellular interaction between ERK and mGluR5 in the NAc is stronger in adult than in adolescent rats, which enhances the understanding of age-associated behavioral changes that occur after repeated exposure to nicotine.
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Affiliation(s)
- Ju Hwan Yang
- Department of Biological Sciences Pusan National University Busan South Korea
| | - Sumin Sohn
- Department of Biological Sciences Pusan National University Busan South Korea
| | - Sunghyun Kim
- Department of Biological Sciences Pusan National University Busan South Korea
| | - Jieun Kim
- Department of Biological Sciences Pusan National University Busan South Korea
| | - Jeong Hwan Oh
- Department of Biological Sciences Pusan National University Busan South Korea
- Institute of Fisheries Sciences Pukyong National University Busan South Korea
| | - In Soo Ryu
- Department of Biological Sciences Pusan National University Busan South Korea
- Korea Institute of Toxicology Daejeon South Korea
| | - Bok Soon Go
- Department of Biological Sciences Pusan National University Busan South Korea
| | - Eun Sang Choe
- Department of Biological Sciences Pusan National University Busan South Korea
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36
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Study of influence of the glutamatergic concentration of [ 18F]FPEB binding to metabotropic glutamate receptor subtype 5 with N-acetylcysteine challenge in rats and SRM/PET study in human healthy volunteers. Transl Psychiatry 2021; 11:66. [PMID: 33473111 PMCID: PMC7817831 DOI: 10.1038/s41398-020-01152-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/01/2020] [Accepted: 12/04/2020] [Indexed: 11/08/2022] Open
Abstract
Altered glutamate signaling is thought to be involved in a myriad of psychiatric disorders. Positron emission tomography (PET) imaging with [18F]FPEB allows assessing dynamic changes in metabotropic glutamate receptor 5 (mGluR5) availability underlying neuropathological conditions. The influence of endogenous glutamatergic levels into receptor binding has not been well established yet. The purpose of this study was to explore the [18F]FPEB binding regarding to physiological fluctuations or acute changes of glutamate synaptic concentrations by a translational approach; a PET/MRS imaging study in 12 healthy human volunteers combined to a PET imaging after an N-acetylcysteine (NAc) pharmacological challenge in rodents. No significant differences were observed with small-animal PET in the test and retest conditions on the one hand and the NAc condition on the other hand for any regions. To test for an interaction of mGuR5 density and glutamatergic concentrations in healthy subjects, we correlated the [18F]FPEB BPND with Glu/Cr, Gln/Cr, Glx/Cr ratios in the anterior cingulate cortex VOI; respectively, no significance correlation has been revealed (Glu/Cr: r = 0.51, p = 0.09; Gln/Cr: r = -0.46, p = 0.13; Glx/Cr: r = -0.035, p = 0.92).These data suggest that the in vivo binding of [18F]FPEB to an allosteric site of the mGluR5 is not modulated by endogenous glutamate in vivo. Thus, [18F]FPEB appears unable to measure acute fluctuations in endogenous levels of glutamate.
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37
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Gandhi T, Lee CC. Neural Mechanisms Underlying Repetitive Behaviors in Rodent Models of Autism Spectrum Disorders. Front Cell Neurosci 2021; 14:592710. [PMID: 33519379 PMCID: PMC7840495 DOI: 10.3389/fncel.2020.592710] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 12/09/2020] [Indexed: 12/15/2022] Open
Abstract
Autism spectrum disorder (ASD) is comprised of several conditions characterized by alterations in social interaction, communication, and repetitive behaviors. Genetic and environmental factors contribute to the heterogeneous development of ASD behaviors. Several rodent models display ASD-like phenotypes, including repetitive behaviors. In this review article, we discuss the potential neural mechanisms involved in repetitive behaviors in rodent models of ASD and related neuropsychiatric disorders. We review signaling pathways, neural circuits, and anatomical alterations in rodent models that display robust stereotypic behaviors. Understanding the mechanisms and circuit alterations underlying repetitive behaviors in rodent models of ASD will inform translational research and provide useful insight into therapeutic strategies for the treatment of repetitive behaviors in ASD and other neuropsychiatric disorders.
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Affiliation(s)
- Tanya Gandhi
- Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA, United States
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38
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Marrocco J, Verhaeghe R, Bucci D, Di Menna L, Traficante A, Bouwalerh H, Van Camp G, Ghiglieri V, Picconi B, Calabresi P, Ravasi L, Cisani F, Bagheri F, Pittaluga A, Bruno V, Battaglia G, Morley-Fletcher S, Nicoletti F, Maccari S. Maternal stress programs accelerated aging of the basal ganglia motor system in offspring. Neurobiol Stress 2020; 13:100265. [PMID: 33344718 PMCID: PMC7739146 DOI: 10.1016/j.ynstr.2020.100265] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/11/2020] [Accepted: 10/22/2020] [Indexed: 11/26/2022] Open
Abstract
Early-life stress involved in the programming of stress-related illnesses can have a toxic influence on the functioning of the nigrostriatal motor system during aging. We examined the effects of perinatal stress (PRS) on the neurochemical, electrophysiological, histological, neuroimaging, and behavioral correlates of striatal motor function in adult (4 months of age) and old (21 months of age) male rats. Adult PRS offspring rats showed reduced dopamine (DA) release in the striatum associated with reductions in tyrosine hydroxylase-positive (TH+) cells and DA transporter (DAT) levels, with no loss of striatal dopaminergic terminals as assessed by positron emission tomography analysis with fluorine-18-l-dihydroxyphenylalanine. Striatal levels of DA and its metabolites were increased in PRS rats. In contrast, D2 DA receptor signaling was reduced and A2A adenosine receptor signaling was increased in the striatum of adult PRS rats. This indicated enhanced activity of the indirect pathway of the basal ganglia motor circuit. Adult PRS rats also showed poorer performance in the grip strength test and motor learning tasks. The aged PRS rats also showed a persistent reduction in striatal DA release and defective motor skills in the pasta matrix and ladder rung walking tests. In addition, the old rats showed large increases in the levels of SNAP-25 and synaptophysin, which are synaptic vesicle-related proteins in the striatum, and in the PRS group only, reductions in Syntaxin-1 and Rab3a protein levels were observed. Our findings indicated that the age-dependent threshold for motor dysfunction was lowered in PRS rats. This area of research is underdeveloped, and our study suggests that early-life stress can contribute to an increased understanding of how aging diseases are programmed in early-life.
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Affiliation(s)
- Jordan Marrocco
- Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 10065, NY, USA
| | - Remy Verhaeghe
- IRCCS Neuromed, Località Camerelle, 86077, Pozzilli, Italy
| | - Domenico Bucci
- IRCCS Neuromed, Località Camerelle, 86077, Pozzilli, Italy
| | - Luisa Di Menna
- IRCCS Neuromed, Località Camerelle, 86077, Pozzilli, Italy
| | | | - Hammou Bouwalerh
- Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000, Lille, France.,International Associated Laboratory (LIA) "Perinatal Stress and Neurodegenerative Diseases": University of Lille - CNRS, UMR 8576, Sapienza University of Rome and IRCCS Neuromed, Italy
| | - Gilles Van Camp
- Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000, Lille, France.,International Associated Laboratory (LIA) "Perinatal Stress and Neurodegenerative Diseases": University of Lille - CNRS, UMR 8576, Sapienza University of Rome and IRCCS Neuromed, Italy
| | - Veronica Ghiglieri
- IRCCS Santa Lucia Foundation, Laboratory of Neurophysiology, via del Fosso di Fiorano, 64, 00143, Rome, Italy.,Department of Medicine, University of Perugia, Italy
| | - Barbara Picconi
- Laboratory of Experimental Neurophysiology, IRCCS San Raffaele Pisana, Rome, Italy
| | - Paolo Calabresi
- Neurologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Piazzale Agostino Gemelli 8, 00168, Rome, Italy
| | - Laura Ravasi
- EA1046, IMPRT-IFR114, Faculty of Medicine, University of Lille, 59000, Lille, France
| | - Francesca Cisani
- Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000, Lille, France.,Dept. of Pharmacology, School of Medical and Pharmaceutical Sciences, Center of Excellence for Biochemical Research (CEBR), University of Genova, Italy
| | - Farzaneh Bagheri
- Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000, Lille, France.,School of Biology, Damghan University, Damghan, Iran
| | - Anna Pittaluga
- Dept. of Pharmacology, School of Medical and Pharmaceutical Sciences, Center of Excellence for Biochemical Research (CEBR), University of Genova, Italy.,IRCCS San Martino Hospital Genova Italy, Italy
| | - Valeria Bruno
- IRCCS Neuromed, Località Camerelle, 86077, Pozzilli, Italy.,Departments of Physiology and Pharmacology "V. Erspamer", University Sapienza of Rome, 00185, Rome, Italy
| | - Giuseppe Battaglia
- IRCCS Neuromed, Località Camerelle, 86077, Pozzilli, Italy.,Departments of Physiology and Pharmacology "V. Erspamer", University Sapienza of Rome, 00185, Rome, Italy
| | - Sara Morley-Fletcher
- Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000, Lille, France.,International Associated Laboratory (LIA) "Perinatal Stress and Neurodegenerative Diseases": University of Lille - CNRS, UMR 8576, Sapienza University of Rome and IRCCS Neuromed, Italy
| | - Ferdinando Nicoletti
- IRCCS Neuromed, Località Camerelle, 86077, Pozzilli, Italy.,Departments of Physiology and Pharmacology "V. Erspamer", University Sapienza of Rome, 00185, Rome, Italy
| | - Stefania Maccari
- Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000, Lille, France.,Science and Medical - Surgical Biotechnology, University Sapienza of Rome, 00185, Rome, Italy
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Mantel T, Altenmüller E, Li Y, Lee A, Meindl T, Jochim A, Zimmer C, Haslinger B. Structure-function abnormalities in cortical sensory projections in embouchure dystonia. NEUROIMAGE-CLINICAL 2020; 28:102410. [PMID: 32932052 PMCID: PMC7495104 DOI: 10.1016/j.nicl.2020.102410] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/29/2020] [Accepted: 08/30/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND Embouchure dystonia (ED) is a task-specific focal dystonia in professional brass players leading to abnormal orofacial muscle posturing/spasms during performance. Previous studies have outlined abnormal cortical sensorimotor function during sensory/motor tasks and in the resting state as well as abnormal cortical sensorimotor structure. Yet, potentially underlying white-matter tract abnormalities in this network disease are unknown. OBJECTIVE To delineate structure-function abnormalities within cerebral sensorimotor trajectories in ED. METHOD Probabilistic tractography and seed-based functional connectivity analysis were performed in 16/16 ED patients/healthy brass players within a simple literature-informed network model of cortical sensorimotor processing encompassing supplementary motor, superior parietal, primary somatosensory and motor cortex as well as the putamen. Post-hoc grey matter volumetry was performed within cortices of abnormal trajectories. RESULTS ED patients showed average axial diffusivity reduction within projections between the primary somatosensory cortex and putamen, with converse increases within projections between supplementary motor and superior parietal cortex in both hemispheres. Increase in the mode of anisotropy in patients was accompanying the latter left-hemispheric projection, as well as in the supplementary motor area's projection to the left primary motor cortex. Patient's left primary somatosensory functional connectivity with the putamen was abnormally reduced and significantly associated with the axial diffusivity reduction. Left primary somatosensory grey matter volume was increased in patients. CONCLUSION Correlates of abnormal tract integrity within primary somatosensory cortico-subcortical projections and higher-order sensorimotor projections support the key role of dysfunctional sensory information propagation in ED pathophysiology. Differential directionality of cortico-cortical and cortico-subcortical abnormalities hints at non-uniform sensory system changes.
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Affiliation(s)
- Tobias Mantel
- Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, Munich, Germany
| | - Eckart Altenmüller
- Hochschule für Musik, Theater und Medien Hannover, Emmichplatz 1, Hanover, Germany
| | - Yong Li
- Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, Munich, Germany
| | - André Lee
- Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, Munich, Germany; Hochschule für Musik, Theater und Medien Hannover, Emmichplatz 1, Hanover, Germany
| | - Tobias Meindl
- Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, Munich, Germany
| | - Angela Jochim
- Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, Munich, Germany
| | - Claus Zimmer
- Department of Neuroradiology, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, Munich, Germany
| | - Bernhard Haslinger
- Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, Munich, Germany.
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40
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Tan Y, Xu Y, Cheng C, Zheng C, Zeng W, Wang J, Zhang X, Yang X, Wang J, Yang X, Nie S, Cao X. LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP. Front Pharmacol 2020; 11:183. [PMID: 32180729 PMCID: PMC7059821 DOI: 10.3389/fphar.2020.00183] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 02/10/2020] [Indexed: 12/13/2022] Open
Abstract
Glutamate overactivity in basal ganglia critically contributes to the exacerbation of dopaminergic neuron degeneration in Parkinson's disease (PD). Activation of group II metabotropic glutamate receptors (mGlu2/3 receptors), which can decrease excitatory glutamate neurotransmission, provides an opportunity to slow down the degeneration of the dopaminergic system. However, the roles of mGlu2/3 receptors in relation to PD pathology were partially recognized. By using mGlu2/3 receptors agonist (LY354740) and mGlu2/3 receptors antagonist (LY341495) in mice challenged with different cumulative doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we demonstrated that systemic injection of LY354740 reduced the level of extracellular glutamate and the extent of nigro-striatal degeneration in both acute and sub-acute MPTP mice, while LY341495 amplified the lesions in sub-acute MPTP mice only. LY354740 treatment improved behavioral dysfunctions mainly in acute MPTP mice and LY341495 treatment seemed to aggravate motor deficits in sub-acute MPTP mice. In addition, ligands of mGlu2/3 receptors also influenced the total amount of glutamate and dopamine in brain tissue. Interestingly, compared with normal mice, MPTP-treated mice abnormally up-regulated the expression of polo-like kinase 2 (PLK2)/pS129 α-synuclein and phosphorylation of Fyn/N-methyl-D-aspartate receptor subunit 2A/2B (GluN2A/2B). Both acute and sub-acute MPTP mice treated with LY354740 dose-dependently reduced all the above abnormal expression. Compared with MPTP mice treated with vehicle, mice pretreated with LY341495 exhibited much higher expression of p-Fyn Tyr416/p-GluN2B Tyr1472 and PLK2/pS129 α-synuclein in sub-acute MPTP mice models. Thus, our current data indicated that mGlu2/3 receptors ligands could influence MPTP-induced toxicity, which supported a role for mGlu2/3 receptors in PD pathogenesis.
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Affiliation(s)
- Yang Tan
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Xu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chi Cheng
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cong Zheng
- Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China
| | - Weiqi Zeng
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ji Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoqian Zhang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoman Yang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jialing Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaomei Yang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuke Nie
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xuebing Cao
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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41
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Distinct anti-dyskinetic effects of amantadine and group II metabotropic glutamate receptor agonist LY354740 in a rodent model: An electrophysiological perspective. Neurobiol Dis 2020; 139:104807. [PMID: 32088382 DOI: 10.1016/j.nbd.2020.104807] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 01/29/2020] [Accepted: 02/18/2020] [Indexed: 01/05/2023] Open
Abstract
L-DOPA-induced dyskinesia (LID) is a major complication of long-term dopamine replacement therapy in Parkinson's disease. Characteristic neural oscillation and abnormal activity of striatal projection neurons (SPNs) are typical pathological events of LID, which would be reliable biomarkers for assessment of novel anti-dyskinetic approach if fully profiled. Glutamate dysregulation plays a critical role in the development of LID, and the group II metabotropic glutamate receptors (mGluR2/3) is believed to regulate the release of glutamate on the presynaptic terminals and inhibits postsynaptic excitation. However, the anti-dyskinetic effect of modulating mGluR2/3 is still unclear. In this study, rats with unilateral dopaminergic lesion were injected with L-DOPA (12 mg/kg, i.p.) for seven days, while motor behavior was correlated with in vivo electrophysiology analyzing LFP and single-cell activity in both primary motor cortex and dorsolateral striatum. Our study showed that as LID established, high γ oscillation (hγ) predominated during LID, the number of unstable responses of SPN to dopamine increased, and the coherence between these patterns of oscillation and spiking activity also increased. We found that pretreatment of NMDA receptor antagonist, amantadine 60 mg/kg, i.p. (AMAN) significantly reduced abnormal involuntary movements (AIMs), in parallel with the reduction of hγ oscillation, and more markedly with a decrease in unstable responses of SPNs. In contrast, a mGluR2/3 agonist, LY354740 12 mg/kg, i.p. (LY) significantly shortened the duration of LID but merely exhibited a weak effect in diminishing the intensity of LID or reversing SPN responses. Together results indicate that AIMs in the rat model of PD are associated with abnormal corticostriatal signaling, which could be reversed by NMDAR antagonism more efficiently than mGluR2/3 agonism.
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Hamadjida A, Sid‐Otmane L, Kwan C, Frouni I, Nafade V, Bédard D, Gagnon D, Wallman M, Rouillard C, Parent A, Parent M, Huot P. The highly selective mGlu
2
receptor positive allosteric modulator LY‐487,379 alleviates
l
‐DOPA‐induced dyskinesia in the 6‐OHDA‐lesioned rat model of Parkinson's disease. Eur J Neurosci 2020; 51:2412-2422. [DOI: 10.1111/ejn.14679] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 01/06/2020] [Accepted: 01/08/2020] [Indexed: 11/27/2022]
Affiliation(s)
- Adjia Hamadjida
- Neurodegenerative Disease Group Montreal Neurological Institute Montreal QC Canada
| | - Lamia Sid‐Otmane
- Département de Pharmacologie et Physiologie Université de Montréal Montreal QC Canada
| | - Cynthia Kwan
- Neurodegenerative Disease Group Montreal Neurological Institute Montreal QC Canada
| | - Imane Frouni
- Neurodegenerative Disease Group Montreal Neurological Institute Montreal QC Canada
- Département de Pharmacologie et Physiologie Université de Montréal Montreal QC Canada
| | - Vaidehi Nafade
- Neurodegenerative Disease Group Montreal Neurological Institute Montreal QC Canada
| | - Dominique Bédard
- Neurodegenerative Disease Group Montreal Neurological Institute Montreal QC Canada
| | - Dave Gagnon
- Centre de Recherche CERVO Quebec City QC Canada
| | | | - Claude Rouillard
- Centre de Recherche du Centre Hospitalier Universitaire de Québec Quebec City QC Canada
| | | | | | - Philippe Huot
- Neurodegenerative Disease Group Montreal Neurological Institute Montreal QC Canada
- Département de Pharmacologie et Physiologie Université de Montréal Montreal QC Canada
- Department of Neurology and Neurosurgery McGill University Montreal QC Canada
- Movement Disorder Clinic Division of Neurology Department of Neuroscience McGill University Health Centre Montreal QC Canada
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Wu CS, Jew CP, Sun H, Ballester Rosado CJ, Lu HC. mGlu5 in GABAergic neurons modulates spontaneous and psychostimulant-induced locomotor activity. Psychopharmacology (Berl) 2020; 237:345-361. [PMID: 31646346 PMCID: PMC7024012 DOI: 10.1007/s00213-019-05367-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 09/22/2019] [Indexed: 12/17/2022]
Abstract
RATIONALE A role of group I metabotropic glutamate receptor 5 (mGlu5) in regulating spontaneous locomotion and psychostimulant-induced hyperactivity has been proposed. OBJECTIVES This study aims to determine if mGlu5 in GABAergic neurons regulates spontaneous or psychostimulant-induced locomotion. METHODS We generated mice specifically lacking mGlu5 in forebrain GABAergic neuron by crossing DLX-Cre mice with mGlu5flox/flox mice to generate DLX-mGlu5 KO mice. The locomotion of adult mice was examined in the open-field assay (OFA) and home cage setting. The effects of the mGlu5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP), cocaine, and methylphenidate on acute motor behaviors in DLX-mGlu5 KO and littermate control mice were assessed in OFA. Striatal synaptic plasticity of these mice was examined with field potential electrophysiological recordings. RESULTS Deleting mGlu5 from forebrain GABAergic neurons results in failure to induce long-term depression (LTD) in the dorsal striatum and absence of habituated locomotion in both novel and familiar settings. In a familiar environment (home cage), DLX-mGlu5 KO mice were hyperactive. In the OFA, DLX-mGlu5 KO mice exhibited initial hypo-activity, and then gradually increased their locomotion with time, resulting in no habituation response. DLX-mGlu5 KO mice exhibited almost no locomotor response to MPEP (40 mg/kg), while the same dose elicited hyperlocomotion in control mice. The DLX-mGlu5 KO mice also showed reduced hyperactivity response to cocaine, while they retained normal hyperactivity response to methylphenidate, albeit with delayed onset. CONCLUSION mGlu5 in forebrain GABAergic neurons is critical to trigger habituation upon the initiation of locomotion as well as to mediate MPEP-induced hyperlocomotion and modulate psychostimulant-induced hyperactivity.
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Affiliation(s)
- Chia-Shan Wu
- The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA.
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA.
- Department of Nutrition and Food Science, Texas A&M University, 123 Cater-Mattil, 2253 TAMU, College Station, TX, 77843, USA.
| | - Christopher P Jew
- The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Hao Sun
- The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA
| | - Carlos J Ballester Rosado
- The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Hui-Chen Lu
- The Cain Foundation Laboratories, Baylor College of Medicine, Houston, 77030, TX, USA.
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, 77030, TX, USA.
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
- Linda and Jack Gill Center, Department of Psychological and Brain Sciences, Indiana University, 1101 E. 10th Street, Bloomington, IN, 47405, USA.
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Schneider A, Sari AT, Alhaddad H, Sari Y. Overview of Therapeutic Drugs and Methods for the Treatment of Parkinson's Disease. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2020; 19:195-206. [PMID: 32448109 DOI: 10.2174/1871527319666200525011110] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/21/2020] [Accepted: 04/23/2020] [Indexed: 12/28/2022]
Abstract
Parkinson's Disease (PD) is a neurodegenerative disease involving degeneration of dopaminergic neurons of the nigrostriatal pathways. Over the past decades, most of the medications for the treatment of PD patients have been used to modulate dopamine concentrations in the basal ganglia. This includes levodopa and its inhibitory metabolizing enzymes. In addition to modulating dopamine concentrations in the brain, there are D2-like dopamine receptor agonists that mimic the action of dopamine to compensate for the deficit in dopamine found in PD patients. Muscarinic antagonists' drugs are used rarely due to some side effects. Monoamine oxidase inhibitors are among the first in line, and are considered popular drugs that reduce the metabolism of dopamine in PD patients. Furthermore, we discussed in this review the existence of certain glutamate receptor antagonists for the treatment of PD. Alternatively, we further discussed the potential therapeutic role of adenosine (2A) receptor antagonists, such as tozadenant and istradefylline in the treatment of PD. We also discussed the important role of serotonin1A receptor agonist, adrenergic autoreceptors (α2) antagonists and calcium channel blockers in the treatment of PD. Finally, neurotrophic factors, such as glial cell line-derived neurotrophic growth factor and brain-derived neurotrophic factor are considered the primary factors for neuroprotection in PD.
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Affiliation(s)
- Andrew Schneider
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, United States
| | - Adam T Sari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, United States
| | - Hasan Alhaddad
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, United States
| | - Youssef Sari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, United States
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45
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Ledonne A, Mercuri NB. On the Modulatory Roles of Neuregulins/ErbB Signaling on Synaptic Plasticity. Int J Mol Sci 2019; 21:ijms21010275. [PMID: 31906113 PMCID: PMC6981567 DOI: 10.3390/ijms21010275] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 12/27/2019] [Accepted: 12/29/2019] [Indexed: 12/14/2022] Open
Abstract
Neuregulins (NRGs) are a family of epidermal growth factor-related proteins, acting on tyrosine kinase receptors of the ErbB family. NRGs play an essential role in the development of the nervous system, since they orchestrate vital functions such as cell differentiation, axonal growth, myelination, and synapse formation. They are also crucially involved in the functioning of adult brain, by directly modulating neuronal excitability, neurotransmission, and synaptic plasticity. Here, we provide a review of the literature documenting the roles of NRGs/ErbB signaling in the modulation of synaptic plasticity, focusing on evidence reported in the hippocampus and midbrain dopamine (DA) nuclei. The emerging picture shows multifaceted roles of NRGs/ErbB receptors, which critically modulate different forms of synaptic plasticity (LTP, LTD, and depotentiation) affecting glutamatergic, GABAergic, and DAergic synapses, by various mechanisms. Further, we discuss the relevance of NRGs/ErbB-dependent synaptic plasticity in the control of brain processes, like learning and memory and the known involvement of NRGs/ErbB signaling in the modulation of synaptic plasticity in brain’s pathological conditions. Current evidence points to a central role of NRGs/ErbB receptors in controlling glutamatergic LTP/LTD and GABAergic LTD at hippocampal CA3–CA1 synapses, as well as glutamatergic LTD in midbrain DA neurons, thus supporting that NRGs/ErbB signaling is essential for proper brain functions, cognitive processes, and complex behaviors. This suggests that dysregulated NRGs/ErbB-dependent synaptic plasticity might contribute to mechanisms underlying different neurological and psychiatric disorders.
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Affiliation(s)
- Ada Ledonne
- Department of Experimental Neuroscience, Santa Lucia Foundation, Via del Fosso di Fiorano, no 64, 00143 Rome, Italy;
- Correspondence: ; Tel.: +3906-501703160; Fax: +3906-501703307
| | - Nicola B. Mercuri
- Department of Experimental Neuroscience, Santa Lucia Foundation, Via del Fosso di Fiorano, no 64, 00143 Rome, Italy;
- Department of Systems Medicine, University of Rome “Tor Vergata”, Via Montpellier no 1, 00133 Rome, Italy
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Pretzsch CM, Voinescu B, Lythgoe D, Horder J, Mendez MA, Wichers R, Ajram L, Ivin G, Heasman M, Edden RAE, Williams S, Murphy DGM, Daly E, McAlonan GM. Effects of cannabidivarin (CBDV) on brain excitation and inhibition systems in adults with and without Autism Spectrum Disorder (ASD): a single dose trial during magnetic resonance spectroscopy. Transl Psychiatry 2019; 9:313. [PMID: 31748505 PMCID: PMC6868232 DOI: 10.1038/s41398-019-0654-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 10/02/2019] [Accepted: 11/01/2019] [Indexed: 01/04/2023] Open
Abstract
Autism spectrum disorder (ASD) is a high cost neurodevelopmental condition; and there are currently no effective pharmacological treatments for its core symptoms. This has led some families and researchers to trial alternative remedies - including the non-intoxicating Cannabis sativa-derived compound cannabidivarin (CBDV). However, how CBDV affects the human brain is unknown. Previous (pre)clinical evidence suggests that CBDV may modulate brain excitatory-inhibitory systems, which are implicated in ASD. Hence, our main aim was to test, for the first time, if CBDV shifts glutamate and/or GABA metabolites - markers of the brain's primary excitatory and inhibitory system - in both the 'typical' and autistic brain. Our subsidiary aim was to determine whether, within ASD, brain responsivity to CBDV challenge is related to baseline biological phenotype. We tested this using a repeated-measures, double-blind, randomized-order, cross-over design. We used magnetic resonance spectroscopy (MRS) to compare glutamate (Glx = glutamate + glutamine) and GABA + (GABA + macromolecules) levels following placebo (baseline) and 600 mg CBDV in 34 healthy men with (n = 17) and without (n = 17) ASD. Data acquisition from regions previously reliably linked to ASD (dorsomedial prefrontal cortex, DMPFC; left basal ganglia, BG) commenced 2 h (peak plasma levels) after placebo/CBDV administration. Where CBDV significantly shifted metabolite levels, we examined the relationship of this change with baseline metabolite levels. Test sessions were at least 13 days apart to ensure CBDV wash-out. CBDV significantly increased Glx in the BG of both groups. However, this impact was not uniform across individuals. In the ASD group, and not in the typically developing controls, the 'shift' in Glx correlated negatively with baseline Glx concentration. In contrast, CBDV had no significant impact on Glx in the DMPFC, or on GABA+ in either voxel in either group. Our findings suggest that, as measured by MRS, CBDV modulates the glutamate-GABA system in the BG but not in frontal regions. Moreover, there is individual variation in response depending on baseline biochemistry. Future studies should examine the effect of CBDV on behaviour and if the response to an acute dose of CBDV could predict a potential clinical treatment response in ASD.
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Affiliation(s)
- Charlotte M Pretzsch
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Bogdan Voinescu
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - David Lythgoe
- Department of Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Jamie Horder
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Maria Andreina Mendez
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Robert Wichers
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Laura Ajram
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Glynis Ivin
- South London and Maudsley NHS Foundation Trust Pharmacy, London, UK
| | - Martin Heasman
- South London and Maudsley NHS Foundation Trust Pharmacy, London, UK
| | - Richard A E Edden
- Russel H Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Steven Williams
- Department of Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Declan G M Murphy
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Eileen Daly
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Gráinne M McAlonan
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
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Müller Herde A, Mihov Y, Krämer SD, Mu L, Adamantidis A, Ametamey SM, Hasler G. Chronic Nicotine Exposure Alters Metabotropic Glutamate Receptor 5: Longitudinal PET Study and Behavioural Assessment in Rats. Neurotox Res 2019; 36:806-816. [PMID: 31119680 DOI: 10.1007/s12640-019-00055-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 03/22/2019] [Accepted: 04/26/2019] [Indexed: 12/13/2022]
Abstract
Using positron emission tomography (PET), a profound alteration of the metabotropic glutamate receptor 5 (mGluR5) was found in human smoking addiction and abstinence. As human PET data either reflect the impact of chronic nicotine exposure or a pre-existing vulnerability to nicotine addiction, we designed a preclinical, longitudinal study to investigate the effect of chronic nicotine exposure on mGluR5 with the novel radiotracer [18F]PSS232 using PET. Twelve male dark Agouti rats at the age of 6 weeks were assigned randomly to three groups. From day 0 to day 250 the groups received 0 mg/L, 4 mg/L, or 8 mg/L nicotine solution in the drinking water. From day 250 to 320 all groups received nicotine-free drinking water. PET scans with [18F]PSS232 were performed in all animals on days 0, 250, and 320. To assess locomotion, seven tests in square open field arenas were carried out 72 days after the last PET scan. During the first four tests, rats received 0 mg/L nicotine and for the last three tests 4 mg/L nicotine in the drinking water. After 250 days of nicotine consumption [18F]PSS232 binding was reduced in the striatum, hippocampus, thalamus, and midbrain. At day 320, after nicotine withdrawal, [18F]PSS232 binding increased. These effects were more pronounced in the 4 mg/L nicotine group. Chronic administration of nicotine through the drinking water reduced exploratory behaviour. This preliminary longitudinal PET study demonstrates that chronic nicotine administration alters behaviour and mGluR5 availability. Chronic nicotine administration leads to decreased [18F]PSS232 binding which normalizes after prolonged nicotine withdrawal.
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Affiliation(s)
- Adrienne Müller Herde
- Center for Radiopharmaceutical Sciences of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, 8093, Zurich, Switzerland
| | - Yoan Mihov
- Translational Research Center, University Hospital of Psychiatry, University of Bern, 3000, Bern 60, Switzerland
| | - Stefanie D Krämer
- Center for Radiopharmaceutical Sciences of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, 8093, Zurich, Switzerland
| | - Linjing Mu
- Department of Nuclear Medicine, University Hospital Zurich, Center for Radiopharmaceutical Sciences of ETH, PSI, and USZ, 8091, Zurich, Switzerland
| | - Antoine Adamantidis
- Department of Biomedical Research, Inselspital University Hospital, University of Bern, 3000, Bern, Switzerland
- Centre for Experimental Neurology, Department of Neurology, Inselspital University Hospital, University of Bern, Bern, Switzerland
| | - Simon M Ametamey
- Center for Radiopharmaceutical Sciences of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, 8093, Zurich, Switzerland
| | - Gregor Hasler
- Psychiatry Research Unit, University of Fribourg, Chemin du Cardinal-Journet 3, Villars-sur-Glâne, 1752, Fribourg, Switzerland.
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Chen P, Li X. Study on Effect of Striatal mGluR2/3 in Alleviating Motor Dysfunction in Rat PD Model Treated by Exercise Therapy. Front Aging Neurosci 2019; 11:255. [PMID: 31632264 PMCID: PMC6783497 DOI: 10.3389/fnagi.2019.00255] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Accepted: 08/27/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Exercise therapy has been widely applied in clinical rehabilitation as an important practical and side effect-free adjuvant therapy, with a significant effect in alleviating motor dysfunction of patients with Parkinson's disease (PD) or animal PD models. This study focuses on the effect of exercise therapy in reducing the concentration of extracellular glutamate (Glu) in the striatum in a rat PD model by upregulating the expression of group II metabotropic Glu receptor (mGluR2/3), so as to alleviate motor dysfunction in the rat PD model. Methods: Neurotoxin 6-hydroxydopamine (6-OHDA) was injected into the right medial forebrain bundle (MFB) of the rats to establish the semi-lateral cerebral damage PD model. The sham-operated group was given an equal amount of normal saline at the same site and taken as the control group. The apomorphine (APO)-induced rotational behavior test combined with immunohistochemical staining with tyrosine hydroxylase (TH) in the substantia nigra (SNc) and striatum was performed to assess the reliability of the model. The exercise group was given treadmill exercise intervention for 4 weeks (11 m/min, 30 min/day, 5 days/week) 1 week after the operation. The open field test (OFT) was performed to assess the locomotor activity of the rats; the Western blot technique was used to detect SNc TH and striatal mGluR2/3 protein expressions; real-time polymerase chain reaction (RT-PCR) was applied to detect striatal mGluR2 and mGluR3 mRNA expressions; the microdialysis-high-performance liquid chromatography (HPLC) method was adopted to detect the concentration of extracellular Glu in striatal neurons. Results: Compared with the control group, the number of rotations of each model group at the first week was significantly increased (P < 0.01); compared with the PD group, the number of rotations of the PD + exercise group at the third week and the fifth week was significantly decreased (P < 0.05, P < 0.01). Compared with the control group, the total movement distance, the total movement time, and the mean velocity of each model group at the first week were significantly reduced (P < 0.05); compared with the PD group, the total movement distance, the total movement time, and the mean velocity of the PD + exercise group at the third week and the fifth week were significantly increased (P < 0.01). Compared with the control group, the count of immunopositive cells and protein expression of SNc TH, and the content of immunopositive fiber terminals in the striatal TH of each model group significantly declined (P < 0.01). Compared with the PD group, the striatal mGluR2/3 protein expression of the PD + exercise group significantly rose (P < 0.01). Compared with the control group, the concentration of extracellular Glu in striatal neurons of each model group at the first week significantly grew (P < 0.05); compared with the PD group, the concentration of extracellular Glu in striatal neurons of the PD + exercise group at the third week and the fifth week was significantly decreased (P < 0.01); compared with the PD + exercise group, the concentration of extracellular Glu in striatal neurons of the group injected with mGluR2/3 antagonist (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA) into the striatum at the third week and the fifth week was significantly increased (P < 0.05, P < 0.01). Compared with the control group, the striatal mGluR2/3 protein expression of the PD group was significantly downregulated (P < 0.01); compared with the PD group, the striatal mGluR2/3 protein expression of the PD + exercise group was significantly upregulated (P < 0.05); compared with the control group, the striatal mGluR3 mRNA expression of the PD group was significantly downregulated (P < 0.01); compared with the PD group, the striatal mGluR3 mRNA expression of the PD + exercise group was significantly upregulated (P < 0.01); 6-OHDA damage and exercise intervention had no significant effect on the striatal mGluR2 mRNA expression (P > 0.05). Compared with the PD + exercise group, the total movement distance, the total movement time, and the mean velocity of the PD + exercise + APICA group were significantly decreased (P < 0.05); compared with the PD group, the PD + exercise + APICA group had no significant change in the total movement distance, the total movement time, and the mean velocity (P > 0.05). Conclusion: These data collectively demonstrate that the mGluR2/3-mediated glutamatergic transmission in the striatum is sensitive to dopamine (DA) depletion and may serve as a target of exercise intervention for mediating the therapeutic effect of exercise intervention in a rat model of PD.
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Affiliation(s)
- Ping Chen
- College of Sport Science, JiShou Univerity, JiShou, China
- College of Physical Education and Sports, Beijing Normal University, Beijing, China
| | - Xiaodong Li
- College of Sport Science, JiShou Univerity, JiShou, China
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Masilamoni GJ, Smith Y. Group I metabotropic glutamate receptors in the primate motor thalamus: subsynaptic association with cortical and sub-cortical glutamatergic afferents. Brain Struct Funct 2019; 224:2787-2804. [PMID: 31422483 DOI: 10.1007/s00429-019-01937-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 08/07/2019] [Indexed: 12/21/2022]
Abstract
Preclinical evidence indicates that mGluR5 is a potential therapeutic target for Parkinson's disease and L-DOPA-induced dyskinesia. However, the mechanisms through which these therapeutic benefits are mediated remain poorly understood. Although the regulatory role of mGluR5 on glutamatergic transmission has been examined in various basal ganglia nuclei, very little is known about the localization and function of mGluR5 in the ventral motor and intralaminar thalamic nuclei, the main targets of basal ganglia output in mammals. Thus, we used immuno-electron microscopy to map the cellular and subcellular localization of group I mGluRs (mGluR1a and mGluR5) in the ventral motor and caudal intralaminar thalamic nuclei in rhesus monkeys. Furthermore, using double immuno-electron microscopy, we examined the subsynaptic localization of mGluR5 in relation to cortical and sub-cortical glutamatergic afferents. Four major conclusions can be drawn from these data. First, mGluR1a and mGluR5 are expressed postsynaptically on the plasma membrane of dendrites of projection neurons and GABAergic interneurons in the basal ganglia- and cerebellar-receiving regions of the ventral motor thalamus and in CM. Second, the plasma membrane-bound mGluR5 immunoreactivity is preferentially expressed perisynaptically at the edges of cortical and sub-cortical glutamatergic afferents. Third, the mGluR5 immunoreactivity is more strongly expressed in the lateral than the medial tiers of CM, suggesting a preferential association with thalamocortical over thalamostriatal neurons in the primate CM. Overall, mGluR5 is located to subserve powerful modulatory role of cortical and subcortical glutamatergic transmission in the primate ventral motor thalamus and CM.
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Affiliation(s)
- Gunasingh Jeyaraj Masilamoni
- Yerkes National Primate Research Center, Emory University, 954, Gatewood Rd NE, Atlanta, GA, 30329, USA. .,Udall Center of Excellence for Parkinson's Disease, Emory University School of Medicine, Atlanta, GA, 30322, USA.
| | - Yoland Smith
- Yerkes National Primate Research Center, Emory University, 954, Gatewood Rd NE, Atlanta, GA, 30329, USA.,Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA.,Udall Center of Excellence for Parkinson's Disease, Emory University School of Medicine, Atlanta, GA, 30322, USA
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50
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Arroyo-Araujo M, Graf R, Maco M, van Dam E, Schenker E, Drinkenburg W, Koopmans B, de Boer SF, Cullum-Doyle M, Noldus LPJJ, Loos M, van Dommelen W, Spooren W, Biemans B, Buhl DL, Kas MJ. Reproducibility via coordinated standardization: a multi-center study in a Shank2 genetic rat model for Autism Spectrum Disorders. Sci Rep 2019; 9:11602. [PMID: 31406134 PMCID: PMC6690904 DOI: 10.1038/s41598-019-47981-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 07/25/2019] [Indexed: 02/01/2023] Open
Abstract
Inconsistent findings between laboratories are hampering scientific progress and are of increasing public concern. Differences in laboratory environment is a known factor contributing to poor reproducibility of findings between research sites, and well-controlled multisite efforts are an important next step to identify the relevant factors needed to reduce variation in study outcome between laboratories. Through harmonization of apparatus, test protocol, and aligned and non-aligned environmental variables, the present study shows that behavioral pharmacological responses in Shank2 knockout (KO) rats, a model of synaptic dysfunction relevant to autism spectrum disorders, were highly replicable across three research centers. All three sites reliably observed a hyperactive and repetitive behavioral phenotype in KO rats compared to their wild-type littermates as well as a dose-dependent phenotype attenuation following acute injections of a selective mGluR1 antagonist. These results show that reproducibility in preclinical studies can be obtained and emphasizes the need for high quality and rigorous methodologies in scientific research. Considering the observed external validity, the present study also suggests mGluR1 as potential target for the treatment of autism spectrum disorders.
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Affiliation(s)
- María Arroyo-Araujo
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands
| | - Radka Graf
- Neuroscience and Pain Research Unit, Pfizer Inc., Cambridge, MA, USA
| | - Martine Maco
- Roche Innovation Center Basel, Basel, Switzerland
| | - Elsbeth van Dam
- Noldus Information Technology BV, Wageningen, The Netherlands
| | | | | | | | - Sietse F de Boer
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands
| | | | | | - Maarten Loos
- Sylics Synaptologics BV, Amsterdam, The Netherlands
| | | | - Will Spooren
- Neuroscience and Pain Research Unit, Pfizer Inc., Cambridge, MA, USA
| | | | - Derek L Buhl
- Neuroscience and Pain Research Unit, Pfizer Inc., Cambridge, MA, USA
| | - Martien J Kas
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands. .,Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
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