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Savall ASP, De Mello JD, Fidelis EM, Bortolotto VC, Dahleh MMM, Guerra GP, Prigol M, Puntel R, Boldori JR, Denardin CC, Sampaio TB, Pinton S. Eugenia uniflora Effects on the Depressive-like Behavior of MPTP-Exposed Female Rats: Apoptosis and α-Synuclein Modulation. Brain Sci 2025; 15:41. [PMID: 39851409 PMCID: PMC11764100 DOI: 10.3390/brainsci15010041] [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: 11/15/2024] [Revised: 12/31/2024] [Accepted: 01/01/2025] [Indexed: 01/26/2025] Open
Abstract
Background: Parkinson's disease (PD) is a neurodegenerative disorder marked by motor deficits and non-motor symptoms, such as depression, which are associated with dopaminergic loss and α-synuclein aggregation in the brain. Objectives: This study investigated the neuroprotective effects of a hydroalcoholic extract of the purple fruit of Eugenia uniflora (PFEU) on motor ability and depressive-like behaviors in a PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in female Wistar rats. Methods: Rats received intranasal administration of MPTP or vehicle, followed by 14 days of oral administration of PFEU (300 or 2000 mg/kg, administered once daily) or vehicle. Depressive-like behavior was assessed using the splash and forced swimming tests, while motor ability was evaluated using the rotarod and open field tests. On day 15, hippocampal tissue was collected for immunoreactivity analysis. Results: MPTP treatment induced depressive-like behavior, which was significantly reversed by PFEU, as evidenced by increased grooming and decreased immobility. No motor coordination or locomotion deficits were observed. Furthermore, PFEU treatment prevented the MPTP-induced increase in hippocampal α-synuclein, p-p53, and Bax while restoring Bcl-2 levels, suggesting neuroprotective effects through the modulation of apoptotic pathways and α-synuclein. Conclusions: These findings support PFEU's potential as a neuroprotective agent for MPTP-induced depressive-like behavior in female rats, highlighting its molecular mechanisms.
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Affiliation(s)
- Anne Suély Pinto Savall
- Research Group on Biochemistry and Toxicology in Eukaryotes, Federal University of Pampa—Campus Uruguaiana, Uruguaiana 97500-970, RS, Brazil; (A.S.P.S.); (E.M.F.)
| | - Jhuly Dorneles De Mello
- Research Group on Biochemistry and Toxicology in Eukaryotes, Federal University of Pampa—Campus Uruguaiana, Uruguaiana 97500-970, RS, Brazil; (A.S.P.S.); (E.M.F.)
| | - Eduarda Monteiro Fidelis
- Research Group on Biochemistry and Toxicology in Eukaryotes, Federal University of Pampa—Campus Uruguaiana, Uruguaiana 97500-970, RS, Brazil; (A.S.P.S.); (E.M.F.)
| | - Vandreza Cardoso Bortolotto
- Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules (LaftamBio), Federal University of Pampa—Campus Itaqui, Itaqui 97650-000, RS, Brazil
| | - Mustafa Munir Mustafa Dahleh
- Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules (LaftamBio), Federal University of Pampa—Campus Itaqui, Itaqui 97650-000, RS, Brazil
| | - Gustavo Petri Guerra
- Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules (LaftamBio), Federal University of Pampa—Campus Itaqui, Itaqui 97650-000, RS, Brazil
| | - Marina Prigol
- Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules (LaftamBio), Federal University of Pampa—Campus Itaqui, Itaqui 97650-000, RS, Brazil
| | - Robson Puntel
- Research Group on Biochemistry and Toxicology in Eukaryotes, Federal University of Pampa—Campus Uruguaiana, Uruguaiana 97500-970, RS, Brazil; (A.S.P.S.); (E.M.F.)
| | - Jean Ramos Boldori
- Research Group on Biochemistry and Toxicology of Bioactive Compounds (GBTOXBIO), Federal University of Pampa—Campus Uruguaiana, Uruguaiana 97500-970, RS, Brazil; (J.R.B.); (C.C.D.)
| | - Cristiane Casagrande Denardin
- Research Group on Biochemistry and Toxicology of Bioactive Compounds (GBTOXBIO), Federal University of Pampa—Campus Uruguaiana, Uruguaiana 97500-970, RS, Brazil; (J.R.B.); (C.C.D.)
| | - Tuane Bazanella Sampaio
- Department of Pharmacy, State University of Centro-Oeste—Campus Cedeteg, Guarapuava 85040-167, PR, Brazil;
| | - Simone Pinton
- Research Group on Biochemistry and Toxicology in Eukaryotes, Federal University of Pampa—Campus Uruguaiana, Uruguaiana 97500-970, RS, Brazil; (A.S.P.S.); (E.M.F.)
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Zamanian MY, Nazifi M, Khachatryan LG, Taheri N, Ivraghi MS, Menon SV, Husseen B, Prasad KDV, Petkov I, Nikbakht N. The Neuroprotective Effects of Agmatine on Parkinson's Disease: Focus on Oxidative Stress, Inflammation and Molecular Mechanisms. Inflammation 2024:10.1007/s10753-024-02139-7. [PMID: 39225914 DOI: 10.1007/s10753-024-02139-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 08/28/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
Agmatine (AGM), a naturally occurring polyamine derived from L-arginine, has shown significant potential for neuroprotection in Parkinson's Disease (PD) due to its multifaceted biological activities, including antioxidant, anti-inflammatory, and anti-apoptotic effects. This review explores the therapeutic potential of AGM in treating PD, focusing on its neuroprotective mechanisms and evidence from preclinical studies. AGM has been demonstrated to mitigate the neurotoxic effects of rotenone (ROT) by improving motor function, reducing oxidative stress markers, and decreasing levels of pro-inflammatory cytokines in animal models. Additionally, AGM protects against the loss of TH + neurons, crucial for dopamine synthesis. The neuroprotective properties of AGM are attributed to its ability to modulate several key pathways implicated in PD pathogenesis, such as inhibition of NMDA receptors, activation of Nrf2, and suppression of the HMGB1/ RAGE/ TLR4/ MyD88/ NF-κB signaling cascade. Furthermore, the potential of agmatine to promote neurorestoration is highlighted by its role in enhancing neuroplasticity elements such as CREB, BDNF, and ERK1/2. This review highlights agmatine's promising therapeutic potential in PD management, suggesting that it could offer both symptomatic relief and neuroprotective benefits, thereby modifying the disease course and improving the quality of life for patients. Further research is warranted to translate these preclinical findings into clinical applications.
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Affiliation(s)
- Mohammad Yasin Zamanian
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, 6718773654, Iran.
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, 6718773654, Iran.
| | - Mozhgan Nazifi
- Department of Neurology, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Lusine G Khachatryan
- Department of Pediatric Diseases, Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University (Sechenov University), N.F, Moscow, Russia
| | - Niloofar Taheri
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | | | - Soumya V Menon
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Beneen Husseen
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq
- Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical Laboratory Technique College, the Islamic University of Babylon, Babylon, Iraq
| | - K D V Prasad
- Symbiosis Institute of Business Management, Hyderabad, India
- Symbiosis International (Deemed University), Pune, India
| | - Iliya Petkov
- Department of Neurology, Medical University - Sofia, Sofia, Bulgaria
| | - Nikta Nikbakht
- Department of Physical Medicine and Rehabilitation, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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Pinjala P, Tryphena KP, Kulkarni A, Goswami PG, Khatri DK. Dimethyl Fumarate Exerts a Neuroprotective Effect by Enhancing Mitophagy via the NRF2/BNIP3/PINK1 Axis in the MPP + Iodide-Induced Parkinson's Disease Mice Model. J Alzheimers Dis Rep 2024; 8:329-344. [PMID: 38405353 PMCID: PMC10894611 DOI: 10.3233/adr-230128] [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: 09/12/2023] [Accepted: 12/28/2023] [Indexed: 02/27/2024] Open
Abstract
Background Parkinson's disease (PD) is a progressive neurodegenerative disorder linked to the loss of dopaminergic neurons in the substantia nigra. Mitophagy, mitochondrial selective autophagy, is critical in maintaining mitochondrial and subsequently neuronal homeostasis. Its impairment is strongly implicated in PD and is associated with accelerated neurodegeneration. Objective To study the positive effect of dimethyl fumarate (DMF) on mitophagy via the NRF2/BNIP3/PINK1 axis activation in PD disease models. Methods The neuroprotective effect of DMF was explored in in vitro and in vivo PD models. MTT assay was performed to determine the DMF dose followed by JC-1 assay to study its mitoprotective effect in MPP+ exposed SHSY5Y cells. For the in vivo study, C57BL/6 mice were divided into six groups: Normal Control (NC), Disease Control (DC), Sham (Saline i.c.v.), Low Dose (MPP+ iodide+DMF 15 mg/kg), Mid Dose (MPP+ iodide+DMF 30 mg/kg), and High Dose (MPP+ iodide+DMF 60 mg/kg). The neuroprotective effect of DMF was assessed by performing rotarod, open field test, and pole test, and biochemical parameter analysis using immunofluorescence, western blot, and RT-PCR. Results DMF treatment significantly alleviated the loss of TH positive dopaminergic neurons and enhanced mitophagy by increasing PINK1, Parkin, BNIP3, and LC3 levels in the MPP+ iodide-induced PD mice model. DMF treatment groups showed good locomotor activity and rearing time when compared to the DC group. Conclusions DMF confers neuroprotection by activating the BNIP3/PINK1/Parkin pathway, enhancing the autophagosome formation via LC3, and improving mitophagy in PD models, and could be a potential therapeutic option in PD.
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Affiliation(s)
- Poojitha Pinjala
- Department of Pharmacology and Toxicology, Molecular and Cellular Neuroscience Lab, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Kamatham Pushpa Tryphena
- Department of Pharmacology and Toxicology, Molecular and Cellular Neuroscience Lab, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Amrita Kulkarni
- Department of Pharmacology and Toxicology, Molecular and Cellular Neuroscience Lab, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Prince Giri Goswami
- Department of Pharmacology and Toxicology, Molecular and Cellular Neuroscience Lab, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Dharmendra Kumar Khatri
- Department of Pharmacology and Toxicology, Molecular and Cellular Neuroscience Lab, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
- Department of Pharmacology, Shobhaben Pratapbai Patel School of Pharmacy and Technology Management, SVKM’s Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-be-University, Mumbai, India
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Saha P, Panda S, Holkar A, Vashishth R, Rana SS, Arumugam M, Ashraf GM, Haque S, Ahmad F. Neuroprotection by agmatine: Possible involvement of the gut microbiome? Ageing Res Rev 2023; 91:102056. [PMID: 37673131 DOI: 10.1016/j.arr.2023.102056] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/09/2023] [Accepted: 08/31/2023] [Indexed: 09/08/2023]
Abstract
Agmatine, an endogenous polyamine derived from L-arginine, elicits tremendous multimodal neuromodulant properties. Alterations in agmatinergic signalling are closely linked to the pathogeneses of several brain disorders. Importantly, exogenous agmatine has been shown to act as a potent neuroprotectant in varied pathologies, including brain ageing and associated comorbidities. The antioxidant, anxiolytic, analgesic, antidepressant and memory-enhancing activities of agmatine may derive from its ability to regulate several cellular pathways; including cell metabolism, survival and differentiation, nitric oxide signalling, protein translation, oxidative homeostasis and neurotransmitter signalling. This review briefly discusses mammalian metabolism of agmatine and then proceeds to summarize our current understanding of neuromodulation and neuroprotection mediated by agmatine. Further, the emerging exciting bidirectional links between agmatine and the resident gut microbiome and their implications for brain pathophysiology and ageing are also discussed.
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Affiliation(s)
- Priyanka Saha
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Subhrajita Panda
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Aayusha Holkar
- Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Rahul Vashishth
- Department of Biosciences, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Sandeep Singh Rana
- Department of Biosciences, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Mohanapriya Arumugam
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Ghulam Md Ashraf
- University of Sharjah, College of Health Sciences, and Research Institute for Medical and Health Sciences, Department of Medical Laboratory Sciences, Sharjah 27272, United Arab Emirates.
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan 45142, Saudi Arabia; Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon; Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Faraz Ahmad
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India.
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Boi L, Fisone G. Investigating affective neuropsychiatric symptoms in rodent models of Parkinson's disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 174:119-186. [PMID: 38341228 DOI: 10.1016/bs.irn.2023.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/12/2024]
Abstract
Affective neuropsychiatric disorders such as depression, anxiety and apathy are among the most frequent non-motor symptoms observed in people with Parkinson's disease (PD). These conditions often emerge during the prodromal phase of the disease and are generally considered to result from neurodegenerative processes in meso-corticolimbic structures, occurring in parallel to the loss of nigrostriatal dopaminergic neurons. Depression, anxiety, and apathy are often treated with conventional medications, including selective serotonin reuptake inhibitors, tricyclic antidepressants, and dopaminergic agonists. The ability of these pharmacological interventions to consistently counteract such neuropsychiatric symptoms in PD is still relatively limited and the development of reliable experimental models represents an important tool to identify more effective treatments. This chapter provides information on rodent models of PD utilized to study these affective neuropsychiatric symptoms. Neurotoxin-based and genetic models are discussed, together with the main behavioral tests utilized to identify depression- and anxiety-like behaviors, anhedonia, and apathy. The ability of various therapeutic approaches to counteract the symptoms observed in the various models is also reviewed.
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Affiliation(s)
- Laura Boi
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Gilberto Fisone
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
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Basílio LSP, Vanz Borges C, Minatel IO, Vargas PF, Tecchio MA, Vianello F, Lima GPP. New beverage based on grapes and purple-fleshed sweet potatoes: Use of non-standard tubers. FOOD BIOSCI 2022. [DOI: 10.1016/j.fbio.2022.101626] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Mou YK, Guan LN, Yao XY, Wang JH, Song XY, Ji YQ, Ren C, Wei SZ. Application of Neurotoxin-Induced Animal Models in the Study of Parkinson's Disease-Related Depression: Profile and Proposal. Front Aging Neurosci 2022; 14:890512. [PMID: 35645772 PMCID: PMC9136050 DOI: 10.3389/fnagi.2022.890512] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 04/27/2022] [Indexed: 01/17/2023] Open
Abstract
Depression can be a non-motor symptom, a risk factor, and even a co-morbidity of Parkinson's disease (PD). In either case, depression seriously affects the quality of life of PD patients. Unfortunately, at present, a large number of clinical and basic studies focused on the pathophysiological mechanism of PD and the prevention and treatment of motor symptoms. Although there has been increasing attention to PD-related depression, it is difficult to achieve early detection and early intervention, because the clinical guidelines mostly refer to depression developed after or accompanied by motor impairments. Why is there such a dilemma? This is because there has been no suitable preclinical animal model for studying the relationship between depression and PD, and the assessment of depressive behavior in PD preclinical models is as well a very challenging task since it is not free from the confounding from the motor impairment. As a common method to simulate PD symptoms, neurotoxin-induced PD models have been widely used. Studies have found that neurotoxin-induced PD model animals could exhibit depression-like behaviors, which sometimes manifested earlier than motor impairments. Therefore, there have been attempts to establish the PD-related depression model by neurotoxin induction. However, due to a lack of unified protocol, the reported results were diverse. For the purpose of further promoting the improvement and optimization of the animal models and the study of PD-related depression, we reviewed the establishment and evaluation strategies of the current animal models of PD-related depression based on both the existing literature and our own research experience, and discussed the possible mechanism and interventions, in order to provide a reference for future research in this area.
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Affiliation(s)
- Ya-Kui Mou
- Department of Otolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Li-Na Guan
- Department of Neurosurgical Intensive Care Unit, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Xiao-Yan Yao
- Department of Neurology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Jia-Hui Wang
- Department of Central Laboratory, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Xiao-Yu Song
- Department of Otolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Yong-Qiang Ji
- Department of Nephrology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Chao Ren
- Department of Otolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Department of Neurology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Shi-Zhuang Wei
- Department of Otolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
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Lataliza AAB, de Assis PM, da Rocha Laurindo L, Gonçalves ECD, Raposo NRB, Dutra RC. Antidepressant-like effect of rosmarinic acid during LPS-induced neuroinflammatory model: The potential role of cannabinoid receptors/PPAR-γ signaling pathway. Phytother Res 2021; 35:6974-6989. [PMID: 34709695 DOI: 10.1002/ptr.7318] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 09/17/2021] [Accepted: 10/13/2021] [Indexed: 01/03/2023]
Abstract
Rosmarinic acid (RA), an ester of caffeic acid and 3, 4-dihydroxyphenyllactic acid, has anti-inflammatory and neuroprotective activities. Herein, this study investigated in silico the drug-likeness and the potential molecular targets to RA. Moreover, it tested the antidepressant-like potential of RA in the lipopolysaccharide (LPS)-induced depression model. RA (MW = 360.31 g/mol) meets the criteria of both Lipinski's rule of five and the Ghose filter. It also attends to relevant pharmacokinetic parameters. Target prediction analysis identified RA's potential targets and biological activities, including the peroxisome proliferator-activated receptor (PPAR) and the cannabinoid receptors CB1 and CB2 . In vivo, RA's acute, repetitive, and therapeutic administration showed antidepressant-like effect since it significantly reduced the immobility time in the tail suspension test and increased grooming time in the splash test. Further, the pretreatment with antagonists of CB1 , CB2 , and PPAR-γ receptors significantly blocked the antidepressant-like effect of RA. Altogether, our findings suggest that cannabinoid receptors/PPAR-γ signaling pathways are involved with the antidepressant-like effect of RA. Moreover, this molecule meets important physicochemical and pharmacokinetic parameters that favor its bioavailability. RA constitutes a promising, innovative, and safe molecule for the pharmacotherapy of major depressive disorder.
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Affiliation(s)
- Alexandre Augusto Barros Lataliza
- Laboratory of Autoimmunity and Immunopharmacology, Department of Health Sciences, Campus Araranguá, Universidade Federal de Santa Catarina, Araranguá, Brazil
- Post-Graduate Program of Neuroscience, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Pollyana Mendonça de Assis
- Center for Research and Innovation in Health Sciences (NUPICS), Faculty of Pharmacy, Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil
| | - Larissa da Rocha Laurindo
- Laboratory of Autoimmunity and Immunopharmacology, Department of Health Sciences, Campus Araranguá, Universidade Federal de Santa Catarina, Araranguá, Brazil
| | - Elaine Cristina Dalazen Gonçalves
- Laboratory of Autoimmunity and Immunopharmacology, Department of Health Sciences, Campus Araranguá, Universidade Federal de Santa Catarina, Araranguá, Brazil
- Post-Graduate Program of Neuroscience, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Nádia Rezende Barbosa Raposo
- Center for Research and Innovation in Health Sciences (NUPICS), Faculty of Pharmacy, Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil
| | - Rafael Cypriano Dutra
- Laboratory of Autoimmunity and Immunopharmacology, Department of Health Sciences, Campus Araranguá, Universidade Federal de Santa Catarina, Araranguá, Brazil
- Post-Graduate Program of Neuroscience, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil
- Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil
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Valverde AP, Camargo A, Rodrigues ALS. Agmatine as a novel candidate for rapid-onset antidepressant response. World J Psychiatry 2021; 11:981-996. [PMID: 34888168 PMCID: PMC8613765 DOI: 10.5498/wjp.v11.i11.981] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/09/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Major depressive disorder (MDD) is a disabling and highly prevalent mood disorder as well as a common cause of suicide. Chronic stress, inflammation, and intestinal dysbiosis have all been shown to play crucial roles in the pathophysiology of MDD. Although conventional antidepressants are widely used in the clinic, they can take weeks to months to produce therapeutic effects. The discovery that ketamine promotes fast and sustaining antidepressant responses is one of the most important breakthroughs in the pharmacotherapy of MDD. However, the adverse psychomimetic/dissociative and neurotoxic effects of ketamine discourage its chronic use. Therefore, agmatine, an endogenous glutamatergic modulator, has been postulated to elicit fast behavioral and synaptogenic effects by stimulating the mechanistic target of rapamycin complex 1 signaling pathway, similar to ketamine. However, recent evidence has demonstrated that the modulation of the NLR family pyrin domain containing 3 inflammasome and gut microbiota, which have been shown to play a crucial role in the pathophysiology of MDD, may also participate in the antidepressant-like effects of both ketamine and agmatine. This review seeks to provide evidence about the mechanisms that may underlie the fast antidepressant-like responses of agmatine in preclinical studies. Considering the anti-inflammatory properties of agmatine, it may also be further investigated as a useful compound for the management of MDD associated with a pro-inflammatory state. Moreover, the fast antidepressant-like response of agmatine noted in animal models should be investigated in clinical studies.
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Affiliation(s)
- Ana Paula Valverde
- Department of Biochemistry, Campus Universitário, Center for Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC 88040900, Brazil
| | - Anderson Camargo
- Department of Biochemistry, Campus Universitário, Center for Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC 88040900, Brazil
| | - Ana Lúcia S Rodrigues
- Department of Biochemistry, Campus Universitário, Center for Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC 88040900, Brazil
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Feng ST, Wang ZZ, Yuan YH, Wang XL, Guo ZY, Hu JH, Yan X, Chen NH, Zhang Y. Inhibition of dynamin-related protein 1 ameliorates the mitochondrial ultrastructure via PINK1 and Parkin in the mice model of Parkinson's disease. Eur J Pharmacol 2021; 907:174262. [PMID: 34146589 DOI: 10.1016/j.ejphar.2021.174262] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 06/10/2021] [Accepted: 06/14/2021] [Indexed: 12/12/2022]
Abstract
Parkinson's disease (PD) is the prevalent neurodegenerative disorder characterized by the degeneration of the nigrostriatal neurons. Dynamin-related protein 1 (Drp1) is a key regulator mediating mitochondrial fission and affecting mitophagy in neurons. It has been reported that the inhibition of Drp1 may be beneficial to PD. However, the role of Drp1 and mitophagy in PD remains elusive. Therefore, in this research, we investigated the role of Drp1 and the underlying mechanisms in the mice model of PD. We used the dynasore, a GTPase inhibitor, to inhibit the expression of Drp1. We found that inhibition of Drp1 could ameliorate the motor deficits and the expression of tyrosine hydroxylase in the mice of the PD model. But Drp1 inhibition did not affect mitochondria number and morphological parameters. Moreover, suppression of Drp1 up-regulated the mitochondrial expressions of PINK1 and Parkin while not affected the expressions of NIX and BNIP3. Conclusively, our findings suggest that the inhibition of Drp1 ameliorated the mitochondrial ultrastructure at least via regulating PINK1 and Parkin in the mice of the PD model. This study also implicates that inhibition of Drp1 might impact mitophagy and recover mitochondrial homeostasis in PD.
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Affiliation(s)
- Si-Tong Feng
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Zhen-Zhen Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Yu-He Yuan
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Xiao-Le Wang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Zhen-Yu Guo
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Jing-Hong Hu
- Center for Scientific Research, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xu Yan
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Nai-Hong Chen
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
| | - Yi Zhang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China.
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11
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Neuropsychiatric and Cognitive Deficits in Parkinson's Disease and Their Modeling in Rodents. Biomedicines 2021; 9:biomedicines9060684. [PMID: 34204380 PMCID: PMC8234051 DOI: 10.3390/biomedicines9060684] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 11/29/2022] Open
Abstract
Parkinson’s disease (PD) is associated with a large burden of non-motor symptoms including olfactory and autonomic dysfunction, as well as neuropsychiatric (depression, anxiety, apathy) and cognitive disorders (executive dysfunctions, memory and learning impairments). Some of these non-motor symptoms may precede the onset of motor symptoms by several years, and they significantly worsen during the course of the disease. The lack of systematic improvement of these non-motor features by dopamine replacement therapy underlines their multifactorial origin, with an involvement of monoaminergic and cholinergic systems, as well as alpha-synuclein pathology in frontal and limbic cortical circuits. Here we describe mood and neuropsychiatric disorders in PD and review their occurrence in rodent models of PD. Altogether, toxin-based rodent models of PD indicate a significant but non-exclusive contribution of mesencephalic dopaminergic loss in anxiety, apathy, and depressive-like behaviors, as well as in learning and memory deficits. Gene-based models display significant deficits in learning and memory, as well as executive functions, highlighting the contribution of alpha-synuclein pathology to these non-motor deficits. Collectively, neuropsychiatric and cognitive deficits are recapitulated to some extent in rodent models, providing partial but nevertheless useful options to understand the pathophysiology of non-motor symptoms and develop therapeutic options for these debilitating symptoms of PD.
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12
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Prasad EM, Hung SY. Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson's Disease. Antioxidants (Basel) 2020; 9:E1007. [PMID: 33081318 PMCID: PMC7602991 DOI: 10.3390/antiox9101007] [Citation(s) in RCA: 55] [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: 07/14/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Currently, neurodegenerative diseases are a major cause of disability around the world. Parkinson's disease (PD) is the second-leading cause of neurodegenerative disorder after Alzheimer's disease. In PD, continuous loss of dopaminergic neurons in the substantia nigra causes dopamine depletion in the striatum, promotes the primary motor symptoms of resting tremor, bradykinesia, muscle rigidity, and postural instability. The risk factors of PD comprise environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular injury, aging, and hereditary defects. The pathologic features of PD include impaired protein homeostasis, mitochondrial dysfunction, nitric oxide, and neuroinflammation, but the interaction of these factors contributing to PD is not fully understood. In neurotoxin-induced PD models, neurotoxins, for instance, 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-Methyl-4-phenylpyridinium (MPP+), paraquat, rotenone, and permethrin mainly impair the mitochondrial respiratory chain, activate microglia, and generate reactive oxygen species to induce autooxidation and dopaminergic neuronal apoptosis. Since no current treatment can cure PD, using a suitable PD animal model to evaluate PD motor symptoms' treatment efficacy and identify therapeutic targets and drugs are still needed. Hence, the present review focuses on the latest scientific developments in different neurotoxin-induced PD animal models with their mechanisms of pathogenesis and evaluation methods of PD motor symptoms.
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Affiliation(s)
- E. Maruthi Prasad
- Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan;
| | - Shih-Ya Hung
- Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan;
- Department of Medical Research, China Medical University Hospital, No. 2, Yude Road, Taichung 40447, Taiwan
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13
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Yan J, Liu A, Fan H, Qiao L, Wu J, Shen M, Lai X, Huang J. Simvastatin Improves Behavioral Disorders and Hippocampal Inflammatory Reaction by NMDA-Mediated Anti-inflammatory Function in MPTP-Treated Mice. Cell Mol Neurobiol 2020; 40:1155-1164. [PMID: 32016638 PMCID: PMC11448790 DOI: 10.1007/s10571-020-00804-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 01/28/2020] [Indexed: 01/10/2023]
Abstract
The cognitive function impairment may be related to the inflammation of the hippocampus in Parkinson's disease. Simvastatin can play a positive role in Parkinson's disease. The purpose of this study was to investigate whether simvastatin could improve behavioral disorders, especially depression, anxiety and cognitive function in mouse PD models, and further explore the molecular mechanism. In the present study, C57BL-6 mice underwent intraperitoneal injection of MPTP (30 mg/kg) once a day for 5 consecutive days. At the same time, simvastatin (10 mg/kg) was pretreated for 2 days before the Parkinson's disease model was established, and then continued for 5 days, and the control group underwent intraperitoneal injection of MK801 (dizocilpine, 0.2 mg/kg) and saline solution. Depression status was tested by a tail suspension test and a sucrose splash test, followed by an open-field test and an elevated plus maze test to determine anxiety levels. Spatial behavior and muscle status were measured with a water maze and a rotarod test. The expression of RNA and protein of N-methyl-D-aspartate receptor subtype 2B (NMDAR2B), nerve growth factor IB (Nur77), cyclooxygenase-2 (COX-2), and tumor necrosis factor (TNF) α were assayed by real-time polymerase chain reaction and Western blot. Our results showed that simvastatin can improve the cognitive function, anxiety, and depression of PD mice with MPTP injury. Simvastatin reversed the NMDAR2B increase, restored Nur77 downward, and reduced the expression of COX-2 and TNF-α in MPTP-treated mice. This role of simvastatin was consistent with MK801 in increasing the expression of Nur77 and inhibiting NMDAR2B and cytokines in MPTP-lesioned PD mice. These findings suggest that reversed the NMDAR2B increase, restored Nur77 downward, and reduced the expression of COX-2 and TNF-α in MPTP-treated mice may be one of the mechanisms that simvastatin improves cognitive functions, depression, and anxiety in MPTP-lesioned mice.
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Affiliation(s)
- Junqiang Yan
- The First Affiliated Hospital, Neurological Diseases Institute, College of Clinical Medicine of Henan University of Science and Technology, Jinghua Road 24, Luoyang, 471003, Henan, People's Republic of China.
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, People's Republic of China.
| | - Anran Liu
- The First Affiliated Hospital, Neurological Diseases Institute, College of Clinical Medicine of Henan University of Science and Technology, Jinghua Road 24, Luoyang, 471003, Henan, People's Republic of China
| | - Hua Fan
- Department of Pharmacy, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, People's Republic of China
| | - Liang Qiao
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, People's Republic of China
| | - Jiannan Wu
- The First Affiliated Hospital, Neurological Diseases Institute, College of Clinical Medicine of Henan University of Science and Technology, Jinghua Road 24, Luoyang, 471003, Henan, People's Republic of China
| | - Mengmeng Shen
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, People's Republic of China
| | - Xiaoyi Lai
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, People's Republic of China
| | - Jiarui Huang
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, People's Republic of China
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14
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Neuroprotective effects of melatonin against neurotoxicity induced by intranasal sodium dimethyldithiocarbamate administration in mice. Neurotoxicology 2020; 80:144-154. [PMID: 32738267 DOI: 10.1016/j.neuro.2020.07.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 06/30/2020] [Accepted: 07/22/2020] [Indexed: 12/14/2022]
Abstract
Exposure to fungicide ziram (zinc dimethyldithiocarbamate) has been associated with increased incidence of Parkinson's disease (PD). We recently demonstrated that the intranasal (i.n.) administration of sodium dimethyldithiocarbamate (NaDMDC, a more soluble salt than ziram) induces PD-like behavioral and neurochemical alterations in mice. We now investigated the putative neuroprotective effects of melatonin on behavioral dificits and neurochemical alterations induced by i.n. NaDMDC. Melatonin treatment (3, 10 or 30 mg/kg, i.p.) was given 1 h before NaDMDC administration (1 mg/nostril) during 4 consecutive days and we evaluated early (up to 7 days) and late (up to 35 days) NaDMDC-induced behavioral and neurochemical alterations. Melatonin treatment protected against early motor and general neurological impairments observed in the open field and neurological score of severity, respectively, and late deficits in rotarod test. Melatonin prevented the NaDMDC-induced alterations in the striatal tyrosine hydroxylase immunocontent. Melatonin also protected against increased levels of oxidative stress markers (4-hydroxynonenal and 3-nitrotyrosine) in the striatum, as well as the NaDMDC-induced increase of 4-hydroxynonenal and TNF, markers of oxidative stress and inflammation, respectively, in the olfactory bulb. These results further detail the mechanisms underlying NaDMDC toxicity and demonstrate the neuroprotective effects of melatonin against the neuronal damage induced by NaDMDC.
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15
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Dafre AL, Rosa JM, Rodrigues ALS, Cunha MP. Multiple cellular targets involved in the antidepressant-like effect of glutathione. Chem Biol Interact 2020; 328:109195. [PMID: 32707044 DOI: 10.1016/j.cbi.2020.109195] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 06/30/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023]
Abstract
A previous study demonstrated that glutathione (GSH) produces specific antidepressant-like effect in the forced swimming test (FST), a predictive test of antidepressant activity. The present study investigated the involvement of multiple cellular targets implicated in the antidepressant-like effect of GSH in the FST. The antidepressant-like effect of GSH (300 nmol/site, icv) lasted up to 3 h when mice were submitted to FST. The central administration of oxidized GSH (GSSG, 3-300 nmol/site) did not alter the behavior of mice submitted to the FST. Furthermore, the combined treatment of sub-effective doses of GSH (100 nmol/site, icv) with a sub-effective dose of classical antidepressants (fluoxetine 10 mg/kg, and imipramine 5 mg/kg, ip) presented synergistic effect by decreasing the immobility time in the FST. The antidepressant-like effect of GSH was abolished by prazosin (1 mg/kg, ip, α1-adrenoceptor antagonist), baclofen (1 mg/kg, ip, GABAB receptor agonist), bicuculline (1 mg/kg, ip, GABAA receptor antagonist), l-arginine (750 mg/kg, ip, NO precursor), SNAP (25 μg/site, icv, NO donor), but not by yohimbine (1 mg/kg, ip, α2-adrenoceptor antagonist). The NMDA receptor antagonists, MK-801(0.001 mg/kg, ip) or GMP (0.5 mg/kg, ip), potentiated the effect of a sub-effective dose of GSH in the FST. These results suggest that the antidepressant-like effect induced by GSH is connected to the activation of α1 adrenergic and GABAA receptors, as well as the inhibition of GABAB and NMDA receptors and NO biosyntesis. We speculate that redox-mediated signaling on the extracelular portion of cell membrane receptors would be a common mechanism of action of GSH.
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Affiliation(s)
- Alcir Luiz Dafre
- Department of Biochemistry, Federal University of Santa Catarina, 88040-900, Florianópolis, SC, Brazil
| | - Juliana M Rosa
- Department of Biochemistry, Federal University of Santa Catarina, 88040-900, Florianópolis, SC, Brazil
| | | | - Mauricio Peña Cunha
- Department of Biochemistry, Federal University of Santa Catarina, 88040-900, Florianópolis, SC, Brazil.
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16
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The involvement of GABAergic system in the antidepressant-like effect of agmatine. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:1931-1939. [DOI: 10.1007/s00210-020-01910-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 05/13/2020] [Indexed: 12/15/2022]
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17
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Olescowicz G, Sampaio TB, de Paula Nascimento-Castro C, Brocardo PS, Gil-Mohapel J, Rodrigues ALS. Protective Effects of Agmatine Against Corticosterone-Induced Impairment on Hippocampal mTOR Signaling and Cell Death. Neurotox Res 2020; 38:319-329. [DOI: 10.1007/s12640-020-00212-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 04/06/2020] [Accepted: 04/22/2020] [Indexed: 12/23/2022]
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18
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Kotagale N, Deshmukh R, Dixit M, Fating R, Umekar M, Taksande B. Agmatine ameliorates manifestation of depression-like behavior and hippocampal neuroinflammation in mouse model of Alzheimer's disease. Brain Res Bull 2020; 160:56-64. [PMID: 32344125 DOI: 10.1016/j.brainresbull.2020.04.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 04/13/2020] [Accepted: 04/19/2020] [Indexed: 12/14/2022]
Abstract
Extensive clinical and experimental studies established that depression and mood disorders are highly prevalent neuropsychiatric conditions in Alzheimer's disease (AD). However, its neurochemical basis is not clearly understood. Thus, understanding the neural mechanisms involved in mediating the co-morbidity of depression and AD may be crucial in exploring new pharmacological treatments for this condition. The present study investigated the role of the agmatinergic system in β-amyloid (Aββ1-42) peptide-induced depression using forced swim test (FST) in mice. Following the 28th days of its administration, Aβ1-42 peptide produced depression-like behavior in mice as evidenced by increased immobility time in FST and increased expression of pro-inflammatory cytokines like IL-6 and TNF-α compared to the control animals. The Aβ1-42 peptide-induced depression and neuroinflammatory markers were significantly inhibited by agmatine -, moxonidine, 2-BFI and l-arginine by once-daily administration during day 8-27 of the protocol. The antidepressant-like effect of agmatine in Aβ1-42 peptide in mice was potentiated by imidazoline receptor I1 agonist, moxonidine and imidazoline receptor I2 agonist 2-BFI at their sub-effective doses. On the other hand, it was completely blocked by imidazoline receptor I1 antagonist, efaroxan and imidazoline receptor I2 antagonist, idazoxan Also, agmatine levels were significantly reduced in brain samples of β-amyloid injected mice as compared to the control animals. In conclusion, the present study suggests the importance of endogenous agmatinergic system and imidazoline receptors system in β-amyloid induced a depressive-like behavior in mice. The data projects agmatine as a potential therapeutic target for the AD-associated depression and comorbidities.
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Affiliation(s)
- Nandkishor Kotagale
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, Maharashtra 441 002, India; Government College of Pharmacy, Amravati, Maharashtra 444 604, India
| | - Rupali Deshmukh
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, Maharashtra 441 002, India
| | - Madhura Dixit
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, Maharashtra 441 002, India
| | - Rajshree Fating
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, Maharashtra 441 002, India
| | - Milind Umekar
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, Maharashtra 441 002, India
| | - Brijesh Taksande
- Division of Neuroscience, Department of Pharmacology, Smt. Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur, Maharashtra 441 002, India.
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19
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Di T, Wang Y, Zhang Y, Sha S, Zeng Y, Chen L. Dopaminergic afferents from midbrain to dorsolateral bed nucleus of stria terminalis inhibit release and expression of corticotropin-releasing hormone in paraventricular nucleus. J Neurochem 2020; 154:218-234. [PMID: 32096869 DOI: 10.1111/jnc.14992] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 02/07/2020] [Accepted: 02/21/2020] [Indexed: 01/21/2023]
Abstract
Dopaminergic (DAergic) neurons of the midbrain ventral tegmental area (VTA) are known to regulate the hypothalamic-pituitary-adrenal (HPA) axis but have no direct projections to the paraventricular nucleus (PVN) of the hypothalamus. This study investigated whether VTA DAergic afferents modulate glutamatergic transmission-dependent GABAergic neurons in dorsolateral bed nucleus of stria terminalis (dlBNST) to affect the activity of the HPA-axis. Herein, we demonstrate that systemic administration of the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or the VTA-injection of 1-methyl-4-phenylpyridinium ion (MPP+) in male mice (MPTP-mice and MPP+mice) caused a decline of tyrosine hydroxylase positive (TH+) cells in VTA with a reduction in TH+fibers in the dlBNST. MPTP-mice and MPP+mice displayed a clear increase in serum levels of corticosterone (CORT) and adrenocorticotropic hormone, corticotropin-releasing hormone (CRH) expression, and CRH neuron activity in PVN. The presynaptic glutamate release, glutamatergic synaptic transmission and induction of long-term potentiation in dlBNST of MPTP-mice were suppressed, and these effects were rescued by a D1-like DAergic receptor (D1R) agonist and mimicked in control dlBNST by blockade of D1R. MPTP-mice exhibited low expression of glutamic acid decarboxylase and dysfunction of the excitatory-dependent GABAergic circuit in dlBNST, and these effects were recovered by the administration of D1R agonist. Furthermore, either dlBNST-injection of D1R agonist or PVN-injection of GABAA receptor (GABAA R) agonist could correct the increased secretion and expression of CRH in MPTP-mice. The results indicate that the DAergic afferents from VTA enhance excitatory-dependent activation of GABAergic neurons in dlBNST, which suppress the activity of the HPA-axis.
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Affiliation(s)
- Tingting Di
- State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Ya Wang
- Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Yajie Zhang
- Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Sha Sha
- Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Yanying Zeng
- Department of Gerontology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ling Chen
- State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Department of Physiology, Nanjing Medical University, Nanjing, China
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20
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Neuroprotective Role of Dietary Supplementation with Omega-3 Fatty Acids in the Presence of Basal Forebrain Cholinergic Neurons Degeneration in Aged Mice. Int J Mol Sci 2020; 21:ijms21051741. [PMID: 32143275 PMCID: PMC7084583 DOI: 10.3390/ijms21051741] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 02/24/2020] [Accepted: 03/01/2020] [Indexed: 01/05/2023] Open
Abstract
As major components of neuronal membranes, omega-3 polyunsaturated fatty acids (n-3 PUFA) exhibit a wide range of regulatory functions. Recent human and animal studies indicate that n-3 PUFA may exert beneficial effects on aging processes. Here we analyzed the neuroprotective influence of n-3 PUFA supplementation on behavioral deficits, hippocampal neurogenesis, volume loss, and astrogliosis in aged mice that underwent a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valid model to mimic a key component of the cognitive deficits associated with dementia. Aged mice were supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks and then cholinergically depleted with mu-p75-saporin immunotoxin. Two weeks after lesioning, mice were behaviorally tested to assess anxious, motivational, social, mnesic, and depressive-like behaviors. Subsequently, morphological and biochemical analyses were performed. In lesioned aged mice the n-3 PUFA pre-treatment preserved explorative skills and associative retention memory, enhanced neurogenesis in the dentate gyrus, and reduced volume and VAChT levels loss as well as astrogliosis in hippocampus. The present findings demonstrating that n-3 PUFA supplementation before cholinergic depletion can counteract behavioral deficits and hippocampal neurodegeneration in aged mice advance a low-cost, non-invasive preventive tool to enhance life quality during aging.
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21
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Pisella LI, Gaiarsa JL, Diabira D, Zhang J, Khalilov I, Duan J, Kahle KT, Medina I. Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology. Sci Signal 2019; 12:eaay0300. [PMID: 31615899 PMCID: PMC7192243 DOI: 10.1126/scisignal.aay0300] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
KCC2 is a vital neuronal K+/Cl- cotransporter that is implicated in the etiology of numerous neurological diseases. In normal cells, KCC2 undergoes developmental dephosphorylation at Thr906 and Thr1007 We engineered mice with heterozygous phosphomimetic mutations T906E and T1007E (KCC2E/+ ) to prevent the normal developmental dephosphorylation of these sites. Immature (postnatal day 15) but not juvenile (postnatal day 30) KCC2E/+ mice exhibited altered GABAergic inhibition, an increased glutamate/GABA synaptic ratio, and greater susceptibility to seizure. KCC2E/+ mice also had abnormal ultrasonic vocalizations at postnatal days 10 to 12 and impaired social behavior at postnatal day 60. Postnatal bumetanide treatment restored network activity by postnatal day 15 but failed to restore social behavior by postnatal day 60. Our data indicate that posttranslational KCC2 regulation controls the GABAergic developmental sequence in vivo, indicating that deregulation of KCC2 could be a risk factor for the emergence of neurological pathology.
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Affiliation(s)
- Lucie I Pisella
- Aix-Marseille University, UMR 1249, INSERM (Institut National de la Santé et de la Recherche Médicale) Unité 1249, INMED (Institut de Neurobiologie de la Méditerranée), Marseille, France
| | - Jean-Luc Gaiarsa
- Aix-Marseille University, UMR 1249, INSERM (Institut National de la Santé et de la Recherche Médicale) Unité 1249, INMED (Institut de Neurobiologie de la Méditerranée), Marseille, France
| | - Diabé Diabira
- Aix-Marseille University, UMR 1249, INSERM (Institut National de la Santé et de la Recherche Médicale) Unité 1249, INMED (Institut de Neurobiologie de la Méditerranée), Marseille, France
| | - Jinwei Zhang
- Institute of Biomedical and Clinical Sciences, College of Medicine and Health, University of Exeter Medical School, Hatherly Laboratories, Exeter EX4 4PS, UK
| | - Ilgam Khalilov
- Aix-Marseille University, UMR 1249, INSERM (Institut National de la Santé et de la Recherche Médicale) Unité 1249, INMED (Institut de Neurobiologie de la Méditerranée), Marseille, France
- Laboratory of Neurobiology, Kazan Federal University, Kazan 420008, Russia
| | - JingJing Duan
- Department of Neurobiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA
- Departments of Neurosurgery, Pediatrics, and Cellular and Molecular Physiology and Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT 06510, USA
| | - Kristopher T Kahle
- Departments of Neurosurgery, Pediatrics, and Cellular and Molecular Physiology and Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT 06510, USA.
| | - Igor Medina
- Aix-Marseille University, UMR 1249, INSERM (Institut National de la Santé et de la Recherche Médicale) Unité 1249, INMED (Institut de Neurobiologie de la Méditerranée), Marseille, France.
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22
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Bergin DH, Jing Y, Williams G, Mockett BG, Zhang H, Abraham WC, Liu P. Safety and neurochemical profiles of acute and sub-chronic oral treatment with agmatine sulfate. Sci Rep 2019; 9:12669. [PMID: 31481723 PMCID: PMC6722093 DOI: 10.1038/s41598-019-49078-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 08/19/2019] [Indexed: 01/25/2023] Open
Abstract
Agmatine (decarboxylated arginine) exerts numerous central nervous system (CNS) dependent pharmacological effects and may potentially modulate altered neurochemistry seen in neurological disorders. In preclinical studies, injection has been the predominant route of systemic administration. However, a significant translational step would be the use of oral agmatine treatment at therapeutic doses and better understanding of L-arginine metabolic profiles in the CNS post-treatment. The present study systematically investigated the tolerability, safety and brain-plasma neurochemistry following daily oral agmatine sulfate treatment (via gavage) to wild-type (WT) mice up to 900 mg/kg for one week (Experiment 1) or WT and APPswe/PS1ΔE9 transgenic (Tg) mice at 300 mg/kg for fifteen weeks (Experiment 2). Agmatine treatment in both experiments was well tolerated with no marked behavioural impairments, and gross necropsy and organ histology revealed no pathological alterations after 15-week dosing. Moreover, oral treatment increased agmatine levels in the hippocampus and plasma of WT mice (Experiment 1), and in 6 brain regions examined (but not plasma) of WT and Tg mice (Experiment 2), at 30 minutes or 24 hours post-treatment respectively. This study provides fundamental pre-clinical evidence that daily oral delivery of agmatine sulfate to both WT and Tg mice is safe and well tolerated. Exogenous agmatine passes through the blood brain barrier and accumulates in the brain to a greater extent in Tg mice. Furthermore exogenous agmatine has differential actions in the brain and periphery, and its effect on brain putrescine appears to be dependent on the time post-treatment.
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Affiliation(s)
- David H Bergin
- Department of Anatomy, School of Biomedical Sciences, Brain Health Research Centre, Brain Research New Zealand, University of Otago, Dunedin, New Zealand.,School of Pharmacy, Brain Health Research Centre, Brain Research New Zealand, University of Otago, Dunedin, New Zealand
| | - Yu Jing
- Department of Anatomy, School of Biomedical Sciences, Brain Health Research Centre, Brain Research New Zealand, University of Otago, Dunedin, New Zealand
| | - Gail Williams
- Department of Pathology, University of Otago, Dunedin, New Zealand
| | - Bruce G Mockett
- Department of Psychology, Brain Health Research Centre, Brain Research New Zealand, University of Otago, Dunedin, New Zealand
| | - Hu Zhang
- School of Pharmacy, Brain Health Research Centre, Brain Research New Zealand, University of Otago, Dunedin, New Zealand
| | - Wickliffe C Abraham
- Department of Psychology, Brain Health Research Centre, Brain Research New Zealand, University of Otago, Dunedin, New Zealand
| | - Ping Liu
- Department of Anatomy, School of Biomedical Sciences, Brain Health Research Centre, Brain Research New Zealand, University of Otago, Dunedin, New Zealand.
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Galts CP, Bettio LE, Jewett DC, Yang CC, Brocardo PS, Rodrigues ALS, Thacker JS, Gil-Mohapel J. Depression in neurodegenerative diseases: Common mechanisms and current treatment options. Neurosci Biobehav Rev 2019; 102:56-84. [DOI: 10.1016/j.neubiorev.2019.04.002] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 02/22/2019] [Accepted: 04/02/2019] [Indexed: 12/19/2022]
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The therapeutic and nutraceutical potential of agmatine, and its enhanced production using Aspergillus oryzae. Amino Acids 2019; 52:181-197. [DOI: 10.1007/s00726-019-02720-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 03/05/2019] [Indexed: 12/30/2022]
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25
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Watts D, Pfaffenseller B, Wollenhaupt-Aguiar B, Paul Géa L, Cardoso TDA, Kapczinski F. Agmatine as a potential therapeutic intervention in bipolar depression: the preclinical landscape. Expert Opin Ther Targets 2019; 23:327-339. [DOI: 10.1080/14728222.2019.1581764] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Devon Watts
- Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada
| | - Bianca Pfaffenseller
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
| | | | - Luiza Paul Géa
- Graduate Program in Biological Sciences, Pharmacology and Therapeutics, Federal University of Rio Grande do Sul, UFRGS, Porto Alegre, Brazil
- Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
| | | | - Flavio Kapczinski
- Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
- Graduate Program in Psychiatry and Behavioral Sciences, Federal University of Rio Grande do Sul, UFRGS, Porto Alegre, Brazil
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Guerra de Souza AC, Gonçalves CL, de Souza V, Hartwig JM, Farina M, Prediger RD. Agmatine attenuates depressive-like behavior and hippocampal oxidative stress following amyloid β (Aβ1-40) administration in mice. Behav Brain Res 2018; 353:51-56. [DOI: 10.1016/j.bbr.2018.06.032] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 06/18/2018] [Accepted: 06/27/2018] [Indexed: 01/16/2023]
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27
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Neis VB, Bettio LB, Moretti M, Rosa PB, Olescowicz G, Fraga DB, Gonçalves FM, Freitas AE, Heinrich IA, Lopes MW, Leal RB, Rodrigues ALS. Single administration of agmatine reverses the depressive-like behavior induced by corticosterone in mice: Comparison with ketamine and fluoxetine. Pharmacol Biochem Behav 2018; 173:44-50. [DOI: 10.1016/j.pbb.2018.08.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 08/11/2018] [Accepted: 08/15/2018] [Indexed: 12/12/2022]
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28
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Tavares MK, dos Reis S, Platt N, Heinrich IA, Wolin IA, Leal RB, Kaster MP, Rodrigues ALS, Freitas AE. Agmatine potentiates neuroprotective effects of subthreshold concentrations of ketamine via mTOR/S6 kinase signaling pathway. Neurochem Int 2018; 118:275-285. [DOI: 10.1016/j.neuint.2018.05.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 05/08/2018] [Accepted: 05/11/2018] [Indexed: 12/24/2022]
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29
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The Gender-Biased Effects of Intranasal MPTP Administration on Anhedonic- and Depressive-Like Behaviors in C57BL/6 Mice: the Role of Neurotrophic Factors. Neurotox Res 2018; 34:808-819. [DOI: 10.1007/s12640-018-9912-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 04/24/2018] [Accepted: 05/16/2018] [Indexed: 01/10/2023]
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30
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Mnatsakanyan LA, Balashova TV, Sosin AA, Shumatov VB, Dyuizen IV. The Involvement of Agmatine in Individual Pain Sensitivity. NEUROCHEM J+ 2018. [DOI: 10.1134/s1819712418010117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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31
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Mack JM, Moura TM, Lanznaster D, Bobinski F, Massari CM, Sampaio TB, Schmitz AE, Souza LF, Walz R, Tasca CI, Poli A, Doty RL, Dafre AL, Prediger RD. Intranasal administration of sodium dimethyldithiocarbamate induces motor deficits and dopaminergic dysfunction in mice. Neurotoxicology 2018; 66:107-120. [PMID: 29605442 DOI: 10.1016/j.neuro.2018.03.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 03/27/2018] [Accepted: 03/28/2018] [Indexed: 01/26/2023]
Abstract
The primary etiology of Parkinson's disease (PD) remains unclear, but likely reflects a combination of genetic and environmental factors. Exposure to some pesticides, including ziram (zinc dimethyldithiocarbamate), is a relevant risk factor for PD. Like some other environmental neurotoxicants, we hypothesized that ziram can enter the central nervous system from the nasal mucosa via the olfactory nerves. To address this issue, we evaluated the effects of 1, 2 or 4 days of intranasal (i.n., 1 mg/nostril/day) infusions of sodium dimethyldithiocarbamate (NaDMDC), a dimethyldithiocarbamate more soluble than ziram, on locomotor activity in the open field, neurological severity score and rotarod performance. We also addressed the effects of four daily i.n. NaDMDC infusions on olfactory bulb (OB) and striatal measures of cell death, reactive oxygen species (ROS), tyrosine hydroxylase, and the levels of dopamine, noradrenaline, serotonin, and their metabolites. A single i.n. administration of NaDMDC did not significantly alter the behavioral measures. Two consecutive days of i.n. NaDMDC administrations led to a transient neurological deficit that spontaneously resolved within a week. However, the i.n. infusions of NaDMDC for 4 consecutive days induced motor and neurological deficits for up to 7 days after the last NaDMDC administration and increased striatal TH immunocontent and dopamine degradation within a day of the last infusion. Pharmacological treatment with the anti-parkinsonian drugs l-DOPA and apomorphine improved the NaDMDC-induced locomotor deficits. NaDMDC increased serotonin levels and noradrenaline metabolism in the OB 24 h after the last NaDMDC infusion, ROS levels in the OB 2 h after the last infusion, and striatum 2 and 24 h after the last infusion. These results demonstrate, for the first time, that i.n. NaDMDC administration induces neurobehavioral and neurochemical impairments in mice. This accords with evidence that dimethyldithio-carbamate exposure increases the risk of PD and highlights the possibility that olfactory system could be a major route for NaDMDC entry to central nervous system.
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Affiliation(s)
- Josiel M Mack
- Department of Pharmacology, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Tainara M Moura
- Department of Pharmacology, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Débora Lanznaster
- Department of Biochemistry, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Franciane Bobinski
- Experimental Neuroscience Laboratory (LANEX), Graduate Program in Health Sciences, University of Southern of Santa Catarina (UNISUL), Palhoça, SC, Brazil
| | - Caio M Massari
- Department of Biochemistry, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Tuane B Sampaio
- Department of Pharmacology, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Ariana E Schmitz
- Department of Biochemistry, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Luiz F Souza
- Department of Biochemistry, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Roger Walz
- Department of Clinical Medical, Center of Health Sciences, University Hospital, Federal University of Santa Catarina (UFSC), Florianópolis, SC, Brazil
| | - Carla I Tasca
- Department of Biochemistry, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Anicleto Poli
- Department of Pharmacology, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Richard L Doty
- Smell & Taste Center, Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine, Philadelphia, PA 19104 USA
| | - Alcir L Dafre
- Department of Biochemistry, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Rui D Prediger
- Department of Pharmacology, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil.
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Olescowicz G, Neis VB, Fraga DB, Rosa PB, Azevedo DP, Melleu FF, Brocardo PS, Gil-Mohapel J, Rodrigues ALS. Antidepressant and pro-neurogenic effects of agmatine in a mouse model of stress induced by chronic exposure to corticosterone. Prog Neuropsychopharmacol Biol Psychiatry 2018; 81:395-407. [PMID: 28842257 DOI: 10.1016/j.pnpbp.2017.08.017] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Revised: 07/27/2017] [Accepted: 08/21/2017] [Indexed: 12/19/2022]
Abstract
Agmatine is an endogenous neuromodulator that has been shown to have beneficial effects in the central nervous system, including antidepressant-like effects in animals. In this study, we investigated the ability of agmatine (0.1mg/kg, p.o.) and the conventional antidepressant fluoxetine (10mg/kg, p.o.) to reverse the behavioral effects and morphological alterations in the hippocampus of mice exposed to chronic corticosterone (20mg/kg, p.o.) treatment for a period of 21days as a model of stress and depressive-like behaviors. Chronic corticosterone treatment increased the immobility time in the tail suspension test (TST), but did not cause anhedonic-like and anxiety-related behaviors, as assessed with the splash test and the open field test (OFT), respectively. Of note, the depressive-like behaviors induced by corticosterone were accompanied by a decrease in hippocampal cell proliferation, although no changes in hippocampal neuronal differentiation were observed. Our findings provide evidence that, similarly to fluoxetine, agmatine was able to reverse the corticosterone-induced depressive-like behaviors in the TST as well as the deficits in hippocampal cell proliferation. Additionally, fluoxetine but not agmatine, increased hippocampal differentiation. Agmatine, similar to fluoxetine, was capable of increasing both dendritic arborization and length in the entire dentate hippocampus, an effect more evident in the ventral portion of the hippocampus, as assessed with the modified Sholl analysis. Altogether, our results suggest that the increase in hippocampal proliferation induced by agmatine may contribute, at least in part, to the antidepressant-like response of this compound in this mouse model of stress induced by chronic exposure to corticosterone.
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Affiliation(s)
- Gislaine Olescowicz
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil
| | - Vivian B Neis
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil
| | - Daiane B Fraga
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil
| | - Priscila B Rosa
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil
| | - Dayane P Azevedo
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil
| | - Fernando Falkenburger Melleu
- Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil
| | - Patricia S Brocardo
- Department of Morphological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil
| | - Joana Gil-Mohapel
- Division of Medical Sciences, UBC Island Medical Program, University of Victoria, Victoria, British Columbia, Canada
| | - Ana Lúcia S Rodrigues
- Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
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Melatonin Augments the Effects of Fluoxetine on Depression-Like Behavior and Hippocampal BDNF-TrkB Signaling. Neurosci Bull 2017; 34:303-311. [PMID: 29086908 DOI: 10.1007/s12264-017-0189-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 09/14/2017] [Indexed: 12/23/2022] Open
Abstract
Depression is a debilitating psychiatric disorder with a huge socioeconomic burden, and its treatment relies on antidepressants including selective serotonin reuptake inhibitors (SSRIs). Recently, the melatonergic system that is closely associated with the serotonergic system has been implicated in the pathophysiology and treatment of depression. However, it remains unknown whether combined treatment with SSRI and melatonin has synergistic antidepressant effects. In this study, we applied a sub-chronic restraint stress paradigm, and evaluated the potential antidepressant effects of combined fluoxetine and melatonin in adult male mice. Sub-chronic restraint stress (6 h/day for 10 days) induced depression-like behavior as shown by deteriorated fur state, increased latency to groom in the splash test, and increased immobility time in the forced-swim test. Repeated administration of either fluoxetine or melatonin at 10 mg/kg during stress exposure failed to prevent depression-like phenotypes. However, combined treatment with fluoxetine and melatonin at the selected dose attenuated stress-induced behavioral abnormalities. Moreover, we found that the antidepressant effects of combined treatment were associated with the normalization of brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the hippocampus, but not in the prefrontal cortex. Our findings suggest that combined fluoxetine and melatonin treatment exerts synergistic antidepressant effects possibly by restoring hippocampal BDNF-TrkB signaling.
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34
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Neis VB, Rosa PB, Olescowicz G, Rodrigues ALS. Therapeutic potential of agmatine for CNS disorders. Neurochem Int 2017; 108:318-331. [DOI: 10.1016/j.neuint.2017.05.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 05/06/2017] [Accepted: 05/12/2017] [Indexed: 12/14/2022]
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35
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Agmatine: multifunctional arginine metabolite and magic bullet in clinical neuroscience? Biochem J 2017; 474:2619-2640. [DOI: 10.1042/bcj20170007] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 05/23/2017] [Accepted: 05/25/2017] [Indexed: 12/12/2022]
Abstract
Agmatine, the decarboxylation product of arginine, was largely neglected as an important player in mammalian metabolism until the mid-1990s, when it was re-discovered as an endogenous ligand of imidazoline and α2-adrenergic receptors. Since then, a wide variety of agmatine-mediated effects have been observed, and consequently agmatine has moved from a wallflower existence into the limelight of clinical neuroscience research. Despite this quantum jump in scientific interest, the understanding of the anabolism and catabolism of this amine is still vague. The purification and biochemical characterization of natural mammalian arginine decarboxylase and agmatinase still are open issues. Nevertheless, the agmatinergic system is currently one of the most promising candidates in order to pharmacologically interfere with some major diseases of the central nervous system, which are summarized in the present review. Particularly with respect to major depression, agmatine, its derivatives, and metabolizing enzymes show great promise for the development of an improved treatment of this common disease.
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Fortuna JTS, Gralle M, Beckman D, Neves FS, Diniz LP, Frost PS, Barros-Aragão F, Santos LE, Gonçalves RA, Romão L, Zamberlan DC, Soares FAA, Braga C, Foguel D, Gomes FCA, De Felice FG, Ferreira ST, Clarke JR, Figueiredo CP. Brain infusion of α-synuclein oligomers induces motor and non-motor Parkinson's disease-like symptoms in mice. Behav Brain Res 2017; 333:150-160. [PMID: 28668282 DOI: 10.1016/j.bbr.2017.06.047] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 06/16/2017] [Accepted: 06/27/2017] [Indexed: 01/05/2023]
Abstract
Parkinson's disease (PD) is characterized by motor dysfunction, which is preceded by a number of non-motor symptoms including olfactory deficits. Aggregation of α-synuclein (α-syn) gives rise to Lewy bodies in dopaminergic neurons and is thought to play a central role in PD pathology. However, whether amyloid fibrils or soluble oligomers of α-syn are the main neurotoxic species in PD remains controversial. Here, we performed a single intracerebroventricular (i.c.v.) infusion of α-syn oligomers (α-SYOs) in mice and evaluated motor and non-motor symptoms. Familiar bedding and vanillin essence discrimination tasks showed that α-SYOs impaired olfactory performance of mice, and decreased TH and dopamine levels in the olfactory bulb early after infusion. The olfactory deficit persisted until 45days post-infusion (dpi). α- SYO-infused mice behaved normally in the object recognition and forced swim tests, but showed increased anxiety-like behavior in the open field and elevated plus maze tests 20 dpi. Finally, administration of α-SYOs induced late motor impairment in the pole test and rotarod paradigms, along with reduced TH and dopamine content in the caudate putamen, 45 dpi. Reduced number of TH-positive cells was also seen in the substantia nigra of α-SYO-injected mice compared to control. In conclusion, i.c.v. infusion of α-SYOs recapitulated some of PD-associated non-motor symptoms, such as increased anxiety and olfactory dysfunction, but failed to recapitulate memory impairment and depressive-like behavior typical of the disease. Moreover, α-SYOs i.c.v. administration induced motor deficits and loss of TH and dopamine levels, key features of PD. Results point to α-syn oligomers as the proximal neurotoxins responsible for early non-motor and motor deficits in PD and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of PD novel therapeutic targets and drug screening.
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Affiliation(s)
- Juliana T S Fortuna
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Matthias Gralle
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Danielle Beckman
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Fernanda S Neves
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Luan P Diniz
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Paula S Frost
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil; Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Fernanda Barros-Aragão
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil; Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Luís E Santos
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil; Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Rafaella A Gonçalves
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Luciana Romão
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil; Campus Xerém, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Daniele C Zamberlan
- Department of Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Felix A A Soares
- Department of Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Carolina Braga
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil; Campus Xerém, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Debora Foguel
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Flávia C A Gomes
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Fernanda G De Felice
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil; Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Sergio T Ferreira
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil; Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil
| | - Julia R Clarke
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil.
| | - Cláudia P Figueiredo
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil.
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37
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Freitas AE, Neis VB, Rodrigues ALS. Agmatine, a potential novel therapeutic strategy for depression. Eur Neuropsychopharmacol 2016; 26:1885-1899. [PMID: 27836390 DOI: 10.1016/j.euroneuro.2016.10.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 10/12/2016] [Accepted: 10/29/2016] [Indexed: 12/19/2022]
Abstract
Major depressive disorder is the most common psychiatric disorder with lifetime prevalence of up to 20% worldwide. It is responsible for more years lost to disability than any other disorder. Despite the fact that current available antidepressant drugs are safe and effective, they are far from ideal. In addition to the need to administer the drugs for weeks or months to obtain clinical benefit, side effects are still a serious problem. Agmatine is an endogenous polyamine synthesized by the enzyme arginine decarboxylase. It modulates several receptors and is considered as a neuromodulator in the brain. In this review, studies demonstrating the antidepressant effects of agmatine are presented and discussed, as well as, the mechanisms of action related to these effects. Also, the potential beneficial effects of agmatine for the treatment of other neurological disorders are presented. In particular, we provide evidence to encourage future clinical studies investigating agmatine as a novel antidepressant drug.
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Affiliation(s)
- Andiara E Freitas
- Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil.
| | - Vivian B Neis
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Ana Lúcia S Rodrigues
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil
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Antidepressant-like effect of pramipexole in an inflammatory model of depression. Behav Brain Res 2016; 320:365-373. [PMID: 27825895 DOI: 10.1016/j.bbr.2016.11.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 10/31/2016] [Accepted: 11/04/2016] [Indexed: 12/13/2022]
Abstract
Pramipexole (PPX), a dopamine D2/3 receptor preferring agonist, is currently in use for the treatment of Parkinson's disease symptoms and restless legs syndrome. Recently, anti-inflammatory properties of PPX have been shown in an autoimmune model of multiple sclerosis, and case reports indicate PPX ameliorates depressive symptoms. Since peripheral inflammation is known to induce depression-like behavior in rodents, we assessed the potential antidepressant effect of PPX in an inflammatory model of depression induced by LPS. Repeated (daily for 7days, 1mg/kg, i.p.), but not acute (1h before LPS) treatment with PPX abolished the depression-like behavior induced by LPS (0.1mg/kg, i.p.) in the forced swim test, and the anhedonic behavior in the splash test. Interestingly, PPX per se decreased interleukin 1β levels and reversed LPS-induced increase in its content in mice hippocampus⋅ Repeated PPX treatment also prevented the increase in hippocampal levels of the 3-nitrotyrosine protein adducts induced by LPS. Haloperidol (0.2mg/kg, i.p.) and sulpiride (50mg/kg, i.p.) were unable to prevent the antidepressant-like effect of PPX in LPS-treated mice. Altogether, these results suggest that the observed antidepressant-like effect of PPX in LPS-treated mice may be dependent on its anti-inflammatory properties and may not be related to dopamine D2 receptor activation.
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Fonseca R, Carvalho RA, Lemos C, Sequeira AC, Pita IR, Carvalho F, Silva CD, Prediger RDS, Jarak I, Cunha RA, Fontes Ribeiro CA, Köfalvi A, Pereira FC. Methamphetamine Induces Anhedonic-Like Behavior and Impairs Frontal Cortical Energetics in Mice. CNS Neurosci Ther 2016; 23:119-126. [PMID: 27762079 DOI: 10.1111/cns.12649] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 09/06/2016] [Accepted: 09/07/2016] [Indexed: 01/18/2023] Open
Abstract
INTRODUCTION We recently showed that a single high dose of methamphetamine (METH) induces a persistent frontal cortical monoamine depletion that is accompanied by helpless-like behavior in mice. However, brain metabolic alterations underlying both neurochemical and mood alterations remain unknown. AIMS Herein, we aimed at characterizing frontal cortical metabolic alterations associated with early negative mood behavior triggered by METH. Adult C57BL/6 mice were injected with METH (30 mg/kg, i.p.), and their frontal cortical metabolic status was characterized after probing their mood and anxiety-related phenotypes 3 days postinjection. RESULTS Methamphetamine induced depressive-like behavior, as indicated by the decreased grooming time in the splash test and by a transient decrease in sucrose preference. At this time, METH did not alter anxiety-like behavior or motor functions. Depolarization-induced glucose uptake was reduced in frontocortical slices from METH-treated mice compared to controls. Consistently, astrocytic glucose transporter (GluT1) density was lower in the METH group. A proton high rotation magic angle spinning (HRMAS) spectroscopic approach revealed that METH induced a significant decrease in N-acetyl aspartate (NAA) and glutamate levels, suggesting that METH decreased neuronal glutamatergic function in frontal cortex. CONCLUSIONS We report, for the first time, that a single METH injection triggers early self-care and hedonic deficits and impairs frontal cortical energetics in mice.
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Affiliation(s)
- Raquel Fonseca
- Laboratory of Pharmacology and Experimental Therapeutics/Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Rui A Carvalho
- CNC.IBILI, University of Coimbra, Coimbra, Portugal.,CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal
| | - Cristina Lemos
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Ana C Sequeira
- Laboratory of Pharmacology and Experimental Therapeutics/Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Inês R Pita
- Laboratory of Pharmacology and Experimental Therapeutics/Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Fábio Carvalho
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Carlos D Silva
- Laboratory of Pharmacology and Experimental Therapeutics/Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Rui D S Prediger
- Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, Brazil
| | - Ivana Jarak
- CNC.IBILI, University of Coimbra, Coimbra, Portugal.,CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Rodrigo A Cunha
- CNC.IBILI, University of Coimbra, Coimbra, Portugal.,CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Carlos A Fontes Ribeiro
- Laboratory of Pharmacology and Experimental Therapeutics/Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CNC.IBILI, University of Coimbra, Coimbra, Portugal
| | - Attila Köfalvi
- CNC.IBILI, University of Coimbra, Coimbra, Portugal.,CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Frederico C Pereira
- Laboratory of Pharmacology and Experimental Therapeutics/Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CNC.IBILI, University of Coimbra, Coimbra, Portugal
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Neis VB, Bettio LEB, Moretti M, Rosa PB, Ribeiro CM, Freitas AE, Gonçalves FM, Leal RB, Rodrigues ALS. Acute agmatine administration, similar to ketamine, reverses depressive-like behavior induced by chronic unpredictable stress in mice. Pharmacol Biochem Behav 2016; 150-151:108-114. [PMID: 27743829 DOI: 10.1016/j.pbb.2016.10.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 10/06/2016] [Accepted: 10/10/2016] [Indexed: 01/06/2023]
Abstract
Agmatine is an endogenous neuromodulator that has been shown to have antidepressant-like properties. We have previously demonstrated that it can induce a rapid increase in BDNF levels after acute administration, suggesting that agmatine may be a fast-acting antidepressant. To investigate this hypothesis, the present study evaluated the effects of a single administration of agmatine in mice subjected to chronic unpredictable stress (CUS), a model of depression responsive only to chronic treatment with conventional antidepressants. The ability of agmatine to reverse CUS-induced behavioral and biochemical alterations was evaluated and compared with those elicited by the fast-acting antidepressant (ketamine) and the conventional antidepressant (fluoxetine). After exposed to CUS for 14days, mice received a single oral dose of agmatine (0.1mg/kg), ketamine (1mg/kg) or fluoxetine (10mg/kg), and were submitted to behavioral evaluation after 24h. The exposure to CUS caused an increased immobility time in the tail suspension test (TST) but did not change anhedonic-related parameters in the splash test. Our findings provided evidence that, similarly to ketamine, agmatine is able to reverse CUS-induced depressive-like behavior in the TST. Western blot analyses of prefrontal cortex (PFC) demonstrated that mice exposed to CUS and/or treated with agmatine, fluoxetine or ketamine did not present alterations in the immunocontent of synaptic proteins [i.e. GluA1, postsynaptic density protein 95 (PSD-95) and synapsin]. Altogether, our findings indicate that a single administration of agmatine is able to reverse behavioral alterations induced by CUS in the TST, suggesting that this compound may have fast-acting antidepressant-like properties. However, there was no alteration in the levels of synaptic proteins in the PFC, a result that need to be further investigated in other time points.
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Affiliation(s)
- Vivian B Neis
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Luis E B Bettio
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Morgana Moretti
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil; Post-Graduate Nutrition Program, Center of Health Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Priscila B Rosa
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Camille M Ribeiro
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Andiara E Freitas
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Filipe M Gonçalves
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Rodrigo B Leal
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil
| | - Ana Lúcia S Rodrigues
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil.
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Cunha AS, Matheus FC, Moretti M, Sampaio TB, Poli A, Santos DB, Colle D, Cunha MP, Blum-Silva CH, Sandjo LP, Reginatto FH, Rodrigues ALS, Farina M, Prediger RD. Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors. Behav Brain Res 2016; 312:64-76. [DOI: 10.1016/j.bbr.2016.06.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 06/03/2016] [Accepted: 06/07/2016] [Indexed: 11/29/2022]
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