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Ali NH, Al-Kuraishy HM, Al-Gareeb AI, Alnaaim SA, Hetta HF, Saad HM, Batiha GES. A Mutual Nexus Between Epilepsy and α-Synuclein: A Puzzle Pathway. Mol Neurobiol 2024; 61:10198-10215. [PMID: 38703341 DOI: 10.1007/s12035-024-04204-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 04/12/2024] [Indexed: 05/06/2024]
Abstract
Alpha-synuclein (α-Syn) is a specific neuronal protein that regulates neurotransmitter release and trafficking of synaptic vesicles. Exosome-associated α-Syn which is specific to the central nervous system (CNS) is involved in the pathogenesis of epilepsy. Therefore, this review aimed to elucidate the possible link between α-Syn and epilepsy, and how it affects the pathophysiology of epilepsy. A neurodegenerative protein such as α-Syn is implicated in the pathogenesis of epilepsy. Evidence from preclinical and clinical studies revealed that upregulation of α-Syn induces progressive neuronal dysfunctions through induction of oxidative stress, neuroinflammation, and inhibition of autophagy in a vicious cycle with subsequent development of severe epilepsy. In addition, accumulation of α-Syn in epilepsy could be secondary to the different cellular alterations including oxidative stress, neuroinflammation, reduction of brain-derived neurotrophic factor (BDNF) and progranulin (PGN), and failure of the autophagy pathway. However, the mechanism of α-Syn-induced-epileptogenesis is not well elucidated. Therefore, α-Syn could be a secondary consequence of epilepsy. Preclinical and clinical studies are warranted to confirm this causal relationship.
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Affiliation(s)
- Naif H Ali
- Department of Internal Medicine, Medical College, Najran University, Najran, Kingdom of Saudi Arabia
| | - Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, M.B.Ch.B, FRCP, P.O. Box 14132, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Jabir Ibn Hayyan Medical University, Al-Ameer Qu, P.O. Box 13, Kufa, Najaf, Iraq
| | - Saud A Alnaaim
- Clinical Neurosciences Department, College of Medicine, King Faisal University, Hofuf, Saudi Arabia
| | - Helal F Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Hebatallah M Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Matrouh, 51744, Egypt.
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt.
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2
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Sighencea MG, Popescu RȘ, Trifu SC. From Fundamentals to Innovation in Alzheimer's Disease: Molecular Findings and Revolutionary Therapies. Int J Mol Sci 2024; 25:12311. [PMID: 39596378 PMCID: PMC11594972 DOI: 10.3390/ijms252212311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 11/11/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
Alzheimer's disease (AD) is a global health concern and the leading cause of dementia in the elderly. The prevalence of this neurodegenerative condition is projected to increase concomitantly with increased life expectancy, resulting in a significant economic burden. With very few FDA-approved disease-modifying drugs available for AD, there is an urgent need to develop new compounds capable of impeding the progression of the disease. Given the unclear etiopathogenesis of AD, this review emphasizes the underlying mechanisms of this condition. It explores not only well-studied aspects, such as the accumulation of Aβ plaques and neurofibrillary tangles, but also novel areas, including glymphatic and lymphatic pathways, microbiota and the gut-brain axis, serotoninergic and autophagy alterations, vascular dysfunction, the metal hypothesis, the olfactory pathway, and oral health. Furthermore, the potential molecular targets arising from all these mechanisms have been reviewed, along with novel promising approaches such as nanoparticle-based therapy, neural stem cell transplantation, vaccines, and CRISPR-Cas9-mediated genome editing techniques. Taking into account the overlap of these various mechanisms, individual and combination therapies emerge as the future direction in the AD strategy.
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Affiliation(s)
| | - Ramona Ștefania Popescu
- Department of Infectious Diseases, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania;
| | - Simona Corina Trifu
- Department of Psychiatry, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania
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3
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Hu M, Xu F, Liu S, Yao Y, Xia Q, Zhu C, Zhang X, Tang H, Qaiser Z, Liu S, Tang Y. Aging pattern of the brainstem based on volumetric measurement and optimized surface shape analysis. Brain Imaging Behav 2024; 18:396-411. [PMID: 38155336 DOI: 10.1007/s11682-023-00840-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/11/2023] [Indexed: 12/30/2023]
Abstract
The brainstem, a small and crucial structure, is connected to the cerebrum, spinal cord, and cerebellum, playing a vital role in regulating autonomic functions, transmitting motor and sensory information, and modulating cognitive processes, emotions, and consciousness. While previous research has indicated that changes in brainstem anatomy can serve as a biomarker for aging and neurodegenerative diseases, the structural changes that occur in the brainstem during normal aging remain unclear. This study aimed to examine the age- and sex-related differences in the global and local structural measures of the brainstem in 187 healthy adults (ranging in age from 18 to 70 years) using structural magnetic resonance imaging. The findings showed a significant negative age effect on the volume of the two major components of the brainstem: the medulla oblongata and midbrain. The shape analysis revealed that atrophy primarily occurs in specific structures, such as the pyramid, cerebral peduncle, superior and inferior colliculi. Surface area and shape analysis showed a trend of flattening in the aging brainstem. There were no significant differences between the sexes or sex-by-age interactions in brainstem structural measures. These findings provide a systematic description of age associations with brainstem structures in healthy adults and may provide a reference for future research on brain aging and neurodegenerative diseases.
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Affiliation(s)
- Minqi Hu
- Department of Anatomy and Neurobiology, Research Center for Sectional and Imaging Anatomy, Shandong Provincial Key Laboratory of Mental Disorder, Shandong Key Laboratory of Digital Human and Clinical Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China
| | - Feifei Xu
- Department of Anatomy and Neurobiology, Research Center for Sectional and Imaging Anatomy, Shandong Provincial Key Laboratory of Mental Disorder, Shandong Key Laboratory of Digital Human and Clinical Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China
| | - Shizhou Liu
- Department of Anatomy and Neurobiology, Research Center for Sectional and Imaging Anatomy, Shandong Provincial Key Laboratory of Mental Disorder, Shandong Key Laboratory of Digital Human and Clinical Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China
| | - Yuan Yao
- Department of Anatomy and Neurobiology, Research Center for Sectional and Imaging Anatomy, Shandong Provincial Key Laboratory of Mental Disorder, Shandong Key Laboratory of Digital Human and Clinical Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China
| | - Qing Xia
- Department of Anatomy and Neurobiology, Research Center for Sectional and Imaging Anatomy, Shandong Provincial Key Laboratory of Mental Disorder, Shandong Key Laboratory of Digital Human and Clinical Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China
| | - Caiting Zhu
- Department of Anatomy and Neurobiology, Research Center for Sectional and Imaging Anatomy, Shandong Provincial Key Laboratory of Mental Disorder, Shandong Key Laboratory of Digital Human and Clinical Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China
| | - Xinwen Zhang
- Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Haiyan Tang
- Department of Anatomy and Neurobiology, Research Center for Sectional and Imaging Anatomy, Shandong Provincial Key Laboratory of Mental Disorder, Shandong Key Laboratory of Digital Human and Clinical Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China
| | - Zubair Qaiser
- Department of Anatomy and Neurobiology, Research Center for Sectional and Imaging Anatomy, Shandong Provincial Key Laboratory of Mental Disorder, Shandong Key Laboratory of Digital Human and Clinical Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China
| | - Shuwei Liu
- Department of Anatomy and Neurobiology, Research Center for Sectional and Imaging Anatomy, Shandong Provincial Key Laboratory of Mental Disorder, Shandong Key Laboratory of Digital Human and Clinical Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China
| | - Yuchun Tang
- Department of Anatomy and Neurobiology, Research Center for Sectional and Imaging Anatomy, Shandong Provincial Key Laboratory of Mental Disorder, Shandong Key Laboratory of Digital Human and Clinical Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
- Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong, China.
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
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Markussen NB, Knopper RW, Hasselholt S, Skoven CS, Nyengaard JR, Østergaard L, Hansen B. Locus coeruleus ablation in mice: protocol optimization, stereology and behavioral impact. Front Cell Neurosci 2023; 17:1138624. [PMID: 37180952 PMCID: PMC10172584 DOI: 10.3389/fncel.2023.1138624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 04/05/2023] [Indexed: 05/16/2023] Open
Abstract
The Locus Coeruleus (LC) is in the brainstem and supplies key brain structures with noradrenaline, including the forebrain and hippocampus. The LC impacts specific behaviors such as anxiety, fear, and motivation, as well as physiological phenomena that impact brain functions in general, including sleep, blood flow regulation, and capillary permeability. Nevertheless, the short- and long-term consequences of LC dysfunction remain unclear. The LC is among the brain structures first affected in patients suffering from neurodegenerative diseases such as Parkinson's disease and Alzheimer's Disease, hinting that LC dysfunction may play a central role in disease development and progression. Animal models with modified or disrupted LC function are essential to further our understanding of LC function in the normal brain, the consequences of LC dysfunction, and its putative roles in disease development. For this, well-characterized animal models of LC dysfunction are needed. Here, we establish the optimal dose of selective neurotoxin N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP-4) for LC ablation. Using histology and stereology, we compare LC volume and neuron number in LC ablated (LCA) mice and controls to assess the efficacy of LC ablation with different numbers of DSP-4 injections. All LCA groups show a consistent decrease in LC cell count and LC volume. We then proceed to characterize the behavior of LCA mice using a light-dark box test, Barnes maze test, and non-invasive sleep-wakefulness monitoring. Behaviorally, LCA mice differ subtly from control mice, with LCA mice generally being more curious and less anxious compared to controls consistent with known LC function and projections. We note an interesting contrast in that control mice have varying LC size and neuron count but consistent behavior whereas LCA mice (as expected) have consistently sized LC but erratic behavior. Our study provides a thorough characterization of an LC ablation model, firmly consolidating it as a valid model system for the study of LC dysfunction.
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Affiliation(s)
- Nanna Bertin Markussen
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Rasmus West Knopper
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing, China
| | - Stine Hasselholt
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Center for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Christian Stald Skoven
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jens Randel Nyengaard
- Center for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Leif Østergaard
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Brian Hansen
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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5
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Tan Z, Li W, Cheng X, Zhu Q, Zhang X. Non-Coding RNAs in the Regulation of Hippocampal Neurogenesis and Potential Treatment Targets for Related Disorders. Biomolecules 2022; 13:biom13010018. [PMID: 36671403 PMCID: PMC9855933 DOI: 10.3390/biom13010018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/17/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
Non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, circRNAs, and piRNAs, do not encode proteins. Nonetheless, they have critical roles in a variety of cellular activities-such as development, neurogenesis, degeneration, and the response to injury to the nervous system-via protein translation, RNA splicing, gene activation, silencing, modifications, and editing; thus, they may serve as potential targets for disease treatment. The activity of adult neural stem cells (NSCs) in the subgranular zone of the hippocampal dentate gyrus critically influences hippocampal function, including learning, memory, and emotion. ncRNAs have been shown to be involved in the regulation of hippocampal neurogenesis, including proliferation, differentiation, and migration of NSCs and synapse formation. The interaction among ncRNAs is complex and diverse and has become a major topic within the life science. This review outlines advances in research on the roles of ncRNAs in modulating NSC bioactivity in the hippocampus and discusses their potential applications in the treatment of illnesses affecting the hippocampus.
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Affiliation(s)
- Zhengye Tan
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
| | - Wen Li
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
| | - Xiang Cheng
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
| | - Qing Zhu
- School of Pharmacy, Nantong University, Nantong 226001, China
- Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong 226001, China
| | - Xinhua Zhang
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
- Central Lab, Yancheng Third People’s Hospital, The Sixth Affiliated Hospital of Nantong University, Yancheng 224001, China
- Correspondence:
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Greenfield SA, Ferrati G, Coen CW, Vadisiute A, Molnár Z, Garcia-Rates S, Frautschy S, Cole GM. Characterization of a Bioactive Peptide T14 in the Human and Rodent Substantia Nigra: Implications for Neurodegenerative Disease. Int J Mol Sci 2022; 23:ijms232113119. [PMID: 36361905 PMCID: PMC9654939 DOI: 10.3390/ijms232113119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/20/2022] [Accepted: 10/26/2022] [Indexed: 11/25/2022] Open
Abstract
The substantia nigra is generally considered to show significant cell loss not only in Parkinson's but also in Alzheimer's disease, conditions that share several neuropathological traits. An interesting feature of this nucleus is that the pars compacta dopaminergic neurons contain acetylcholinesterase (AChE). Independent of its enzymatic role, this protein is released from pars reticulata dendrites, with effects that have been observed in vitro, ex vivo and in vivo. The part of the molecule responsible for these actions has been identified as a 14-mer peptide, T14, cleaved from the AChE C-terminus and acting at an allosteric site on alpha-7 nicotinic receptors, with consequences implicated in neurodegeneration. Here, we show that free T14 is co-localized with tyrosine hydroxylase in rodent pars compacta neurons. In brains with Alzheimer's pathology, the T14 immunoreactivity in these neurons increases in density as their number decreases with the progression of the disease. To explore the functional implications of raised T14 levels in the substantia nigra, the effect of exogenous peptide on electrically evoked neuronal activation was tested in rat brain slices using optical imaging with a voltage-sensitive dye (Di-4-ANEPPS). A significant reduction in the activation response was observed; this was blocked by the cyclized variant of T14, NBP14. In contrast, no such effect of the peptide was seen in the striatum, a region lacking the T14 target, alpha-7 receptors. These findings add to the accumulating evidence that T14 is a key signaling molecule in neurodegenerative disorders and that its antagonist NBP14 has therapeutic potential.
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Affiliation(s)
- Susan Adele Greenfield
- Neuro-Bio Ltd., Building F5, Culham Science Centre, Abingdon OX14 3DB, UK
- Correspondence:
| | - Giovanni Ferrati
- Neuro-Bio Ltd., Building F5, Culham Science Centre, Abingdon OX14 3DB, UK
| | - Clive W. Coen
- Faculty of Life Sciences & Medicine, King’s College London, London SE1 1UL, UK
| | - Auguste Vadisiute
- Department Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, UK
| | - Zoltan Molnár
- Department Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, UK
| | - Sara Garcia-Rates
- Neuro-Bio Ltd., Building F5, Culham Science Centre, Abingdon OX14 3DB, UK
| | - Sally Frautschy
- Department of Neurology & Medicine, David Geffen School of Medicine at UCLA and Veterans Affairs Healthcare System, Los Angeles, CA 90095, USA
| | - Gregory M. Cole
- Department of Neurology & Medicine, David Geffen School of Medicine at UCLA and Veterans Affairs Healthcare System, Los Angeles, CA 90095, USA
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Bojja SL, Singh N, Kolathur KK, Rao CM. What is the Role of Lithium in Epilepsy? Curr Neuropharmacol 2022; 20:1850-1864. [PMID: 35410603 PMCID: PMC9886805 DOI: 10.2174/1570159x20666220411081728] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 02/26/2022] [Accepted: 04/01/2022] [Indexed: 11/22/2022] Open
Abstract
Lithium is a well-known FDA-approved treatment for bipolar and mood disorders. Lithium has been an enigmatic drug with multifaceted actions involving various neurotransmitters and intricate cell signalling cascades. Recent studies highlight the neuroprotective and neurotrophic actions of lithium in amyotrophic lateral sclerosis, Alzheimer's disease, intracerebral hemorrhage, and epilepsy. Of note, lithium holds a significant interest in epilepsy, where the past reports expose its non-specific proconvulsant action, followed lately by numerous studies for anti-convulsant action. However, the exact mechanism of action of lithium for any of its effects is still largely unknown. The present review integrates findings from several reports and provides detailed possible mechanisms of how a single molecule exhibits marked pro-epileptogenic as well as anti-convulsant action. This review also provides clarity regarding the safety of lithium therapy in epileptic patients.
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Affiliation(s)
| | | | | | - Chamallamudi Mallikarjuna Rao
- Address correspondence to this author at the Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka-576104, India; E-mails: ,
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Baytas O, Kauer JA, Morrow EM. Loss of mitochondrial enzyme GPT2 causes early neurodegeneration in locus coeruleus. Neurobiol Dis 2022; 173:105831. [PMID: 35908744 PMCID: PMC9669404 DOI: 10.1016/j.nbd.2022.105831] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 07/06/2022] [Accepted: 07/20/2022] [Indexed: 12/02/2022] Open
Abstract
Locus coeruleus (LC) is among the first brain areas to degenerate in Alzheimer’s disease and Parkinson’s disease; however, the underlying causes for the vulnerability of LC neurons are not well defined. Here we report a novel mechanism of degeneration of LC neurons caused by loss of the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). GPT2 Deficiency is a newly-recognized childhood neurometabolic disorder. The GPT2 enzyme regulates cell growth through replenishment of tricarboxylic acid (TCA) cycle intermediates and modulation of amino acid metabolism. In Gpt2-null mice, we observe an early loss of tyrosine hydroxylase (TH)-positive neurons in LC and reduced soma size at postnatal day 18. Gpt2-null LC shows selective positive Fluoro-Jade C staining. Neuron loss is accompanied by selective, prominent microgliosis and astrogliosis in LC. We observe reduced noradrenergic projections to and norepinephrine levels in hippocampus and spinal cord. Whole cell recordings in Gpt2-null LC slices show reduced soma size and abnormal action potentials with altered firing kinetics. Strikingly, we observe early decreases in phosphorylated S6 in Gpt2-null LC, preceding prominent p62 aggregation, increased LC3B-II to LC3B-I ratio, and neuronal loss. These data are consistent with a possible mechanism involving deficiency in protein synthesis and cell growth, associated subsequently with abnormal autophagy and neurodegeneration. As compared to the few genetic animal models with LC degeneration, loss of LC neurons in Gpt2-null mice is developmentally the earliest. Early neuron loss in LC in a model of human neurometabolic disease provides important clues regarding the metabolic vulnerability of LC and may lead to new therapeutic targets.
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Affiliation(s)
- Ozan Baytas
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA; Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University, Providence, RI 02912, USA; Neuroscience Graduate Program, Brown University, Providence, RI 02912, USA
| | - Julie A Kauer
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94035, USA
| | - Eric M Morrow
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA; Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University, Providence, RI 02912, USA.
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9
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Zhang D, Chen S, Xu S, Wu J, Zhuang Y, Cao W, Chen X, Li X. The clinical correlation between Alzheimer's disease and epilepsy. Front Neurol 2022; 13:922535. [PMID: 35937069 PMCID: PMC9352925 DOI: 10.3389/fneur.2022.922535] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/30/2022] [Indexed: 11/17/2022] Open
Abstract
Alzheimer's disease and epilepsy are common nervous system diseases in older adults, and their incidence rates tend to increase with age. Patients with mild cognitive impairment and Alzheimer's disease are more prone to have seizures. In patients older than 65 years, neurodegenerative conditions accounted for ~10% of all late-onset epilepsy cases, most of which are Alzheimer's disease. Epilepsy and seizure can occur in the early and late stages of Alzheimer's disease, leading to functional deterioration and behavioral alterations. Seizures promote amyloid-β and tau deposits, leading to neurodegenerative processes. Thus, there is a bi-directional association between Alzheimer's disease and epilepsy. Epilepsy is a risk factor for Alzheimer's disease and, in turn, Alzheimer's disease is an independent risk factor for developing epilepsy in old age. Many studies have evaluated the shared pathogenesis and clinical relevance of Alzheimer's disease and epilepsy. In this review, we discuss the clinical associations between Alzheimer's disease and epilepsy, including their incidence, clinical features, and electroencephalogram abnormalities. Clinical studies of the two disorders in recent years are summarized, and new antiepileptic drugs used for treating Alzheimer's disease are reviewed.
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Gu L, Yu Q, Shen Y, Wang Y, Xu Q, Zhang H. The role of monoaminergic neurons in modulating respiration during sleep and the connection with SUDEP. Biomed Pharmacother 2022; 150:112983. [PMID: 35453009 DOI: 10.1016/j.biopha.2022.112983] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/04/2022] [Accepted: 04/14/2022] [Indexed: 11/25/2022] Open
Abstract
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death among epilepsy patients, occurring even more frequently in cases with anti-epileptic drug resistance. Despite some advancements in characterizing SUDEP, the underlying mechanism remains incompletely understood. This review summarizes the latest advances in our understanding of the pathogenic mechanisms of SUDEP, in order to identify possible targets for the development of new strategies to prevent SUDEP. Based on our previous research along with the current literature, we focus on the role of sleep-disordered breathing (SDB) and its related neural mechanisms to consider the possible roles of monoaminergic neurons in the modulation of respiration during sleep and the occurrence of SUDEP. Overall, this review suggests that targeting the monoaminergic neurons is a promising approach to preventing SUDEP. The proposed roles of SDB and related monoaminergic neural mechanisms in SUDEP provide new insights for explaining the pathogenesis of SUDEP.
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Affiliation(s)
- LeYuan Gu
- Department of Anesthesiology, The Fourth Clinical School of Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China; Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qian Yu
- Department of Anesthesiology, The Fourth Clinical School of Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China; Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yue Shen
- Department of Anesthesiology, The Fourth Clinical School of Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China; Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - YuLing Wang
- Department of Anesthesiology, The Fourth Clinical School of Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China; Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qing Xu
- Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - HongHai Zhang
- Department of Anesthesiology, The Fourth Clinical School of Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China; Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310006, China.
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B. Szabo A, Cretin B, Gérard F, Curot J, J. Barbeau E, Pariente J, Dahan L, Valton L. Sleep: The Tip of the Iceberg in the Bidirectional Link Between Alzheimer's Disease and Epilepsy. Front Neurol 2022; 13:836292. [PMID: 35481265 PMCID: PMC9035794 DOI: 10.3389/fneur.2022.836292] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/14/2022] [Indexed: 11/13/2022] Open
Abstract
The observation that a pathophysiological link might exist between Alzheimer's disease (AD) and epilepsy dates back to the identification of the first cases of the pathology itself and is now strongly supported by an ever-increasing mountain of literature. An overwhelming majority of data suggests not only a higher prevalence of epilepsy in Alzheimer's disease compared to healthy aging, but also that AD patients with a comorbid epileptic syndrome, even subclinical, have a steeper cognitive decline. Moreover, clinical and preclinical investigations have revealed a marked sleep-related increase in the frequency of epileptic activities. This characteristic might provide clues to the pathophysiological pathways underlying this comorbidity. Furthermore, the preferential sleep-related occurrence of epileptic events opens up the possibility that they might hasten cognitive decline by interfering with the delicately orchestrated synchrony of oscillatory activities implicated in sleep-related memory consolidation. Therefore, we scrutinized the literature for mechanisms that might promote sleep-related epileptic activity in AD and, possibly dementia onset in epilepsy, and we also aimed to determine to what degree and through which processes such events might alter the progression of AD. Finally, we discuss the implications for patient care and try to identify a common basis for methodological considerations for future research and clinical practice.
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Affiliation(s)
- Anna B. Szabo
- Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France
- Centre de Recherche Cerveau & Cognition (CerCo), UMR 5549, CNRS-UPS, Toulouse, France
- *Correspondence: Anna B. Szabo
| | - Benjamin Cretin
- Clinical Neuropsychology Unit, Neurology Department, CM2R (Memory Resource and Research Centre), University Hospital of Strasbourg, Strasbourg, France
- CNRS, ICube Laboratory, UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), Team IMIS, University of Strasbourg, Strasbourg, France
- CMRR d'Alsace, Service de Neurologie des Hôpitaux Universitaires de Strasbourg, Pôle Tête et Cou, Strasbourg, France
| | - Fleur Gérard
- Centre de Recherche Cerveau & Cognition (CerCo), UMR 5549, CNRS-UPS, Toulouse, France
- Neurology Department, Hôpital Purpan Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Jonathan Curot
- Centre de Recherche Cerveau & Cognition (CerCo), UMR 5549, CNRS-UPS, Toulouse, France
- Neurology Department, Hôpital Purpan Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Emmanuel J. Barbeau
- Centre de Recherche Cerveau & Cognition (CerCo), UMR 5549, CNRS-UPS, Toulouse, France
| | - Jérémie Pariente
- Neurology Department, Hôpital Purpan Centre Hospitalier Universitaire de Toulouse, Toulouse, France
- Toulouse NeuroImaging Center (ToNIC), INSERM-University of Toulouse Paul Sabatier, Toulouse, France
| | - Lionel Dahan
- Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Luc Valton
- Centre de Recherche Cerveau & Cognition (CerCo), UMR 5549, CNRS-UPS, Toulouse, France
- Neurology Department, Hôpital Purpan Centre Hospitalier Universitaire de Toulouse, Toulouse, France
- Luc Valton
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12
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Ebrahimnejad M, Azizi P, Alipour V, Zarrindast MR, Vaseghi S. Complicated Role of Exercise in Modulating Memory: A Discussion of the Mechanisms Involved. Neurochem Res 2022; 47:1477-1490. [PMID: 35195832 DOI: 10.1007/s11064-022-03552-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 02/03/2022] [Accepted: 02/05/2022] [Indexed: 12/15/2022]
Abstract
Evidence has shown the beneficial effects of exercise on learning and memory. However, many studies have reported controversial results, indicating that exercise can impair learning and memory. In this article, we aimed to review basic studies reporting inconsistent complicated effects of exercise on memory in rodents. Also, we discussed the mechanisms involved in the effects of exercise on memory processes. In addition, we tried to find scientific answers to justify the inconsistent results. In this article, the role of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (involved in synaptic plasticity and neurogenesis), and vascular endothelial growth factor, nerve growth factor, insulin-like growth factor 1, inflammatory markers, apoptotic factors, and antioxidant system was discussed in the modulation of exercise effects on memory. The role of intensity and duration of exercise, and type of memory task was also investigated. We also mentioned to the interaction of exercise with the function of neurotransmitter systems, which complicates the prediction of exercise effect via altering the level of BDNF. Eventually, we suggested that changes in the function of neurotransmitter systems following different types of exercise (depending on exercise intensity or age of onset) should be investigated in further studies. It seems that exercise-induced changes in the function of neurotransmitter systems may have a stronger role than age, type of memory task, or exercise intensity in modulating memory. Importantly, high levels of interactions between neurotransmitter systems and BDNF play a critical role in the modulation of exercise effects on memory performance.
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Affiliation(s)
- Mahshid Ebrahimnejad
- Department of Physiology, Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Paniz Azizi
- School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Vahide Alipour
- Department of Physical Education and Sport Sciences, Faculty of Humanities, Rasht Branch, Islamic Azad University, Rasht, Iran
| | - Mohammad-Reza Zarrindast
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Salar Vaseghi
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, P.O. Box: 1419815477, Karaj, Iran.
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13
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Fernandes C, Macedo I, Barbosa F, Marques-Teixeira J. Economic decision-making in the continuum between healthy aging and Alzheimer's Disease: A systematic review of 20 years of research. Neurosci Biobehav Rev 2021; 131:1243-1263. [PMID: 34715151 DOI: 10.1016/j.neubiorev.2021.10.030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 09/23/2021] [Accepted: 10/23/2021] [Indexed: 01/21/2023]
Abstract
The effect of pathological aging on economic decision-making is a topic of major relevance as impairments in this domain place older adults at increased risk for financial abuse. This review aims to characterize decision-making across the continuum that goes from healthy aging to Alzheimer's Dementia. We included 42 studies comparing patients with Mild Cognitive Impairment (MCI) and healthy older adults, patients with Alzheimer's Disease (AD) and healthy older adults, and patients with MCI and patients with AD. Substantial evidence emerged suggesting that both MCI as AD affect economic decision-making. However, a non-negligible number of behavioural tasks failed to find significant differences between patients and controls, and no differences were reported between patients with MCI and AD. On the contrary, measures of financial capacity reached more robust findings, showing that healthy older adults had better performance than patients, while MCI patients showed better performance than AD patients. This review presents the main conclusions that may be drawn from significant findings, as well as the hypotheses and recommendations for future research.
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Affiliation(s)
- Carina Fernandes
- Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, Portugal.
| | - Inês Macedo
- Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, Portugal
| | - Fernando Barbosa
- Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, Portugal
| | - João Marques-Teixeira
- Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, Portugal
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14
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Cano A, Fonseca E, Ettcheto M, Sánchez-López E, de Rojas I, Alonso-Lana S, Morató X, Souto EB, Toledo M, Boada M, Marquié M, Ruíz A. Epilepsy in Neurodegenerative Diseases: Related Drugs and Molecular Pathways. Pharmaceuticals (Basel) 2021; 14:1057. [PMID: 34681281 PMCID: PMC8538968 DOI: 10.3390/ph14101057] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/14/2021] [Accepted: 10/14/2021] [Indexed: 12/17/2022] Open
Abstract
Epilepsy is a chronic disease of the central nervous system characterized by an electrical imbalance in neurons. It is the second most prevalent neurological disease, with 50 million people affected around the world, and 30% of all epilepsies do not respond to available treatments. Currently, the main hypothesis about the molecular processes that trigger epileptic seizures and promote the neurotoxic effects that lead to cell death focuses on the exacerbation of the glutamate pathway and the massive influx of Ca2+ into neurons by different factors. However, other mechanisms have been proposed, and most of them have also been described in other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or multiple sclerosis. Interestingly, and mainly because of these common molecular links and the lack of effective treatments for these diseases, some antiseizure drugs have been investigated to evaluate their therapeutic potential in these pathologies. Therefore, in this review, we thoroughly investigate the common molecular pathways between epilepsy and the major neurodegenerative diseases, examine the incidence of epilepsy in these populations, and explore the use of current and innovative antiseizure drugs in the treatment of refractory epilepsy and other neurodegenerative diseases.
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Affiliation(s)
- Amanda Cano
- Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08029 Barcelona, Spain; (I.d.R.); (S.A.-L.); (X.M.); (M.B.); (M.M.); (A.R.)
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain; (M.E.); (E.S.-L.)
- Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
- Institute of Nanoscience and Nanotechnology (IN2UB), 08028 Barcelona, Spain
| | - Elena Fonseca
- Epilepsy Unit, Neurology Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (E.F.); (M.T.)
- Research Group on Status Epilepticus and Acute Seizures, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Miren Ettcheto
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain; (M.E.); (E.S.-L.)
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
- Institute of Neurosciences (UBNeuro), University of Barcelona, 08007 Barcelona, Spain
| | - Elena Sánchez-López
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain; (M.E.); (E.S.-L.)
- Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
- Institute of Nanoscience and Nanotechnology (IN2UB), 08028 Barcelona, Spain
| | - Itziar de Rojas
- Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08029 Barcelona, Spain; (I.d.R.); (S.A.-L.); (X.M.); (M.B.); (M.M.); (A.R.)
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain; (M.E.); (E.S.-L.)
| | - Silvia Alonso-Lana
- Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08029 Barcelona, Spain; (I.d.R.); (S.A.-L.); (X.M.); (M.B.); (M.M.); (A.R.)
| | - Xavier Morató
- Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08029 Barcelona, Spain; (I.d.R.); (S.A.-L.); (X.M.); (M.B.); (M.M.); (A.R.)
| | - Eliana B. Souto
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3004-531 Coimbra, Portugal;
- Centre of Biological Engineering (CEB), University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
| | - Manuel Toledo
- Epilepsy Unit, Neurology Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (E.F.); (M.T.)
- Research Group on Status Epilepticus and Acute Seizures, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Mercè Boada
- Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08029 Barcelona, Spain; (I.d.R.); (S.A.-L.); (X.M.); (M.B.); (M.M.); (A.R.)
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain; (M.E.); (E.S.-L.)
| | - Marta Marquié
- Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08029 Barcelona, Spain; (I.d.R.); (S.A.-L.); (X.M.); (M.B.); (M.M.); (A.R.)
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain; (M.E.); (E.S.-L.)
| | - Agustín Ruíz
- Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08029 Barcelona, Spain; (I.d.R.); (S.A.-L.); (X.M.); (M.B.); (M.M.); (A.R.)
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28031 Madrid, Spain; (M.E.); (E.S.-L.)
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15
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Gulyaeva NV. Stress-Associated Molecular and Cellular Hippocampal Mechanisms Common for Epilepsy and Comorbid Depressive Disorders. BIOCHEMISTRY (MOSCOW) 2021; 86:641-656. [PMID: 34225588 DOI: 10.1134/s0006297921060031] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The review discusses molecular and cellular mechanisms common to the temporal lobe epileptogenesis/epilepsy and depressive disorders. Comorbid temporal lobe epilepsy and depression are associated with dysfunction of the hypothalamic-pituitary-adrenocortical axis. Excessive glucocorticoids disrupt the function and impair the structure of the hippocampus, a brain region key to learning, memory, and emotions. Selective vulnerability of the hippocampus to stress, mediated by the reception of glucocorticoid hormones secreted during stress, is the price of the high functional plasticity and pleiotropy of this limbic structure. Common molecular and cellular mechanisms include the dysfunction of glucocorticoid receptors, neurotransmitters, and neurotrophic factors, development of neuroinflammation, leading to neurodegeneration and loss of hippocampal neurons, as well as disturbances in neurogenesis in the subgranular neurogenic niche and formation of aberrant neural networks. These glucocorticoid-dependent processes underlie altered stress response and the development of chronic stress-induced comorbid pathologies, in particular, temporal lobe epilepsy and depressive disorders.
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Affiliation(s)
- Natalia V Gulyaeva
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, 117485, Russia. .,Research and Clinical Center for Neuropsychiatry of Moscow Healthcare Department, Moscow, 115419, Russia
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16
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Elusiyan CA, Faria ALG, Mendes AEQ, Silva IO, Martins JLR, Rosa DA, Pedrino GR, Costa EA, Ibrahim MA, Zjawiony JK, Fajemiroye JO. Involvement of the Benzodiazepine Site in the Anticonvulsant Activity of Tapinanthus globiferus against Pentylenetetrazole-induced Seizures in Mice. PLANTA MEDICA 2020; 86:1204-1215. [PMID: 32668477 DOI: 10.1055/a-1209-1254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Tapinanthus globiferus is often referred to as an all-purpose herb for the treatment of stroke and epilepsy. The present study investigates the anticonvulsant effect of methanolic leaf extract, active fractions, and lupeol (isolate) of Tapinanthus globiferus in mice as well as the underlying mechanisms. Following phytochemical studies of T. globiferus, preliminary assays were performed to evaluate MLE-induced toxic effect and behavioral changes. The pentylenetetrazol (70 mg/kg, i. p.)-induced seizure was evaluated in mice that were pretreated orally with vehicle 10 mL/kg, MLE (4, 20, or 100 mg/kg), fractions (F1 to F6), lupeol 10 mg/kg or diazepam (3 mg/kg). Methanolic leaf extract preserved neuron viability as well as the relative organ weight, and hematological and biochemical parameters. The behavioral endpoints, neuromuscular coordination, and sensory response parameters revealed a dose-dependent effect of methanolic leaf extract. This extract, active fractions, lupeol, and diazepam potentiated the hypno-sedative effect of the barbiturate and attenuated PTZ-induced acute seizure. This antiseizure effect was completely reversed by flumazenil 2 mg/kg (benzodiazepine site antagonist). Altogether, the benzodiazepine site-mediated anticonvulsant effects of methanolic leaf extract, active fractions, and lupeol corroborate traditional application of T. globiferus against epilepsy.
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Affiliation(s)
- Christianah A Elusiyan
- Drug Research and Production Unit, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
| | | | | | | | | | - Daniel Alves Rosa
- Department of Physiological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil
| | - Gustavo Rodrigues Pedrino
- Department of Physiological Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil
| | - Elson Alves Costa
- Department of Pharmacology Sciences, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil
| | - Mohamed Ali Ibrahim
- National Center for Natural Products Research, University of Mississippi, University, Mississippi, United States
| | - Jordan K Zjawiony
- National Center for Natural Products Research, University of Mississippi, University, Mississippi, United States
- Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi, United States
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17
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Hira S, Saleem U, Anwar F, Raza Z, Rehman AU, Ahmad B. In Silico Study and Pharmacological Evaluation of Eplerinone as an Anti-Alzheimer's Drug in STZ-Induced Alzheimer's Disease Model. ACS OMEGA 2020; 5:13973-13983. [PMID: 32566864 PMCID: PMC7301577 DOI: 10.1021/acsomega.0c01381] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 05/15/2020] [Indexed: 05/21/2023]
Abstract
UNLABELLED Alzheimer's disease (AD) is the neurodegenerative disorder characterized by impairment of higher intellectual dysfunctions associated with changes in the cognitive, behavioral, and social activities. AIM OF THE STUDY The current study was designed to evaluate the potential of aldosterone antagonist in the treatment of AD. METHODOLOGY The study was conducted on albino mice of either sex (n = 60). Mice were subcategorized into six groups, each group having 10 mice. Group I-normal control (CMC 1 mL/kg), group II-diseased [streptozotocin (STZ), 3 mg/kg, intracerebroventricular (i.c.v.)], group III-standard (piracetam, 200 mg/kg, i.p.), and groups IV-VI designated as the treatment group (eplerinone at dose levels of 4, 8, and 16 mg/kg, orally), respectively. The study was carried out for 14 consecutive days. STZ was administered through the i.c.v. route on first and third days of the study for memory impairment. The molecular docking was performed to investigate the chemical behavior of compounds to inhibit the AChE. Anti-Alzheimer's effect was assessed by using the behavioral paradigms such as passive avoidance, elevated plus maze, Morris water maze, open field, and balance beam. Various endogenous antioxidants such as SOD, GSH, nitrite, MDA, CAT, and AChE were identified in brain tissues of treated mice to assess the oxidative stress index. Biochemical markers for AD such as norepinephrine, dopamine, and serotonin, Aβ 1-40, Aβ 1-42, NF-κB, and tumor necrosis factor alpha were analyzed in brain tissues of mice. Expression of beta amyloid was observed by PCR. RESULTS The in silico study indicated the distinct mechanism of eplerinone to inhibit the AChE. The outcomes of the in vivo study manifested that eplerinone at the highest dose was found to be more effective in the treatment of AD. CONCLUSION It may be concluded from the research work that eplerinone can be effective for cognitive improvement which proposes its therapeutic effect in many neurodegenerative disorders such as AD.
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Affiliation(s)
- Sundas Hira
- Riphah
Institute of Pharmaceutical Sciences, Riphah
International University, Lahore Campus, Lahore 54000, Pakistan
| | - Uzma Saleem
- Faculty
of Pharmaceutical Sciences, GC University, Faisalabad 38000, Pakistan
| | - Fareeha Anwar
- Riphah
Institute of Pharmaceutical Sciences, Riphah
International University, Lahore Campus, Lahore 54000, Pakistan
| | - Zohaib Raza
- Faculty
of Pharmaceutical Sciences, GC University, Faisalabad 38000, Pakistan
| | - Atta Ur Rehman
- Department
of Pharmacy, Faculty of Natural Sciences, Forman Christian College (a Chartered University), Ferozpur Road, Lahore 54600, Pakistan
| | - Bashir Ahmad
- Riphah
Institute of Pharmaceutical Sciences, Riphah
International University, Lahore Campus, Lahore 54000, Pakistan
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18
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The environmental toxicant ziram enhances neurotransmitter release and increases neuronal excitability via the EAG family of potassium channels. Neurobiol Dis 2020; 143:104977. [PMID: 32553709 DOI: 10.1016/j.nbd.2020.104977] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 06/11/2020] [Accepted: 06/13/2020] [Indexed: 12/21/2022] Open
Abstract
Environmental toxicants have the potential to contribute to the pathophysiology of multiple complex diseases, but the underlying mechanisms remain obscure. One such toxicant is the widely used fungicide ziram, a dithiocarbamate known to have neurotoxic effects and to increase the risk of Parkinson's disease. We have used Drosophila melanogaster as an unbiased discovery tool to identify novel molecular pathways by which ziram may disrupt neuronal function. Consistent with previous results in mammalian cells, we find that ziram increases the probability of synaptic vesicle release by dysregulation of the ubiquitin signaling system. In addition, we find that ziram increases neuronal excitability. Using a combination of live imaging and electrophysiology, we find that ziram increases excitability in both aminergic and glutamatergic neurons. This increased excitability is phenocopied and occluded by null mutant animals of the ether a-go-go (eag) potassium channel. A pharmacological inhibitor of the temperature sensitive hERG (human ether-a-go-go related gene) phenocopies the excitability effects of ziram but only at elevated temperatures. seizure (sei), a fly ortholog of hERG, is thus another candidate target of ziram. Taken together, the eag family of potassium channels emerges as a candidate for mediating some of the toxic effects of ziram. We propose that ziram may contribute to the risk of complex human diseases by blockade of human eag and sei orthologs, such as hERG.
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19
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Janitzky K. Impaired Phasic Discharge of Locus Coeruleus Neurons Based on Persistent High Tonic Discharge-A New Hypothesis With Potential Implications for Neurodegenerative Diseases. Front Neurol 2020; 11:371. [PMID: 32477246 PMCID: PMC7235306 DOI: 10.3389/fneur.2020.00371] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 04/14/2020] [Indexed: 12/21/2022] Open
Abstract
The locus coeruleus (LC) is a small brainstem nucleus with widely distributed noradrenergic projections to the whole brain, and loss of LC neurons is a prominent feature of age-related neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). This article discusses the hypothesis that in early stages of neurodegenerative diseases, the discharge mode of LC neurons could be changed to a persistent high tonic discharge, which in turn might impair phasic discharge. Since phasic discharge of LC neurons is required for the release of high amounts of norepinephrine (NE) in the brain to promote anti-inflammatory and neuroprotective effects, persistent high tonic discharge of LC neurons could be a key factor in the progression of neurodegenerative diseases. Transcutaneous vagal stimulation (t-VNS), a non-invasive technique that potentially increases phasic discharge of LC neurons, could therefore provide a non-pharmacological treatment approach in specific disease stages. This article focuses on LC vulnerability in neurodegenerative diseases, discusses the hypothesis that a persistent high tonic discharge of LC neurons might affect neurodegenerative processes, and finally reflects on t-VNS as a potentially useful clinical tool in specific stages of AD and PD.
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Affiliation(s)
- Kathrin Janitzky
- Department of Neurology, Carl von Ossietzky University Oldenburg, Oldenburg, Germany
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20
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Parthimos TP, Schulpis KH, Loukas YL, Dotsikas Y. Increased blood concentrations of neurotransmission amino acids and modulation of specific enzyme activities after resistance and endurance exercise. SPORT SCIENCES FOR HEALTH 2020. [DOI: 10.1007/s11332-020-00648-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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21
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Song NN, Ma P, Zhang Q, Zhang L, Wang H, Zhang L, Zhu L, He CH, Mao B, Ding YQ. Rnf220/Zc4h2-mediated monoubiquitylation of Phox2 is required for noradrenergic neuron development. Development 2020; 147:dev185199. [PMID: 32094113 DOI: 10.1242/dev.185199] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 02/11/2020] [Indexed: 11/20/2022]
Abstract
Noradrenaline belongs to the monoamine system and is involved in cognition and emotional behaviors. Phox2a and Phox2b play essential but non-redundant roles during development of the locus coeruleus (LC), the main noradrenergic (NA) neuron center in the mammalian brain. The ubiquitin E3 ligase Rnf220 and its cofactor Zc4h2 participate in ventral neural tube patterning by modulating Shh/Gli signaling, and ZC4H2 mutation is associated with intellectual disability, although the mechanisms for this remain poorly understood. Here, we report that Zc4h2 and Rnf220 are required for the development of central NA neurons in the mouse brain. Both Zc4h2 and Rnf220 are expressed in developing LC-NA neurons. Although properly initiated at E10.5, the expression of genes associated with LC-NA neurons is not maintained at the later embryonic stages in mice with a deficiency of either Rnf220 or Zc4h2 In addition, we show that the Rnf220/Zc4h2 complex monoubiquitylates Phox2a/Phox2b, a process required for the full transcriptional activity of Phox2a/Phox2b. Our work reveals a role for Rnf220/Zc4h2 in regulating LC-NA neuron development, and this finding may be helpful for understanding the pathogenesis of ZC4H2 mutation-associated intellectual disability.
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Affiliation(s)
- Ning-Ning Song
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Pengcheng Ma
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
| | - Qiong Zhang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Lei Zhang
- Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China
| | - Huishan Wang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650203, China
| | - Longlong Zhang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650203, China
| | - Liang Zhu
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650203, China
| | - Chun-Hui He
- Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China
| | - Bingyu Mao
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China
| | - Yu-Qiang Ding
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
- Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China
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22
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Fast Localization and Sectioning of Mouse Locus Coeruleus. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4860735. [PMID: 32190666 PMCID: PMC7071797 DOI: 10.1155/2020/4860735] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 02/15/2020] [Indexed: 01/29/2023]
Abstract
The locus nucleus (LC) is a multifunctional nucleus which is also the source of norepinephrine in the brain. To date, there is no simple and easy method to locate the small LC in brain sectioning. Here we report a fast, accurate, and easy-to-follow protocol for the localization of mice LC in frozen sectioning. After fixation and dehydration, the intact brains of adult mice were placed on a horizontal surface and vertically cut along the posterior margin of the bilateral cerebral cortex. In the coronal cutting plane, the aqueduct of midbrain can be seen easily with the naked eyes. After embedding the cerebellum part with optimal cutting temperature (OCT) compound, coronal brain slices were cut from the cutting plane, within 1 mm, the aqueduct of midbrain disappeared and the fourth ventricle appeared, then the brain slices contained LC and were collected. From the first collection, at ~200 μm, the noradrenergic neurons' most enriched brain slices can be collected. The tyrosine hydroxylase immunofluorescence staining confirmed that the localization of LC with this method is accurate and the noradrenergic neuron most abundant slices can be determined with this method.
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23
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Dyer-Reaves K, Goodman AM, Nelson AR, McMahon LL. Alpha1-Adrenergic Receptor Mediated Long-Term Depression at CA3-CA1 Synapses Can Be Induced via Accumulation of Endogenous Norepinephrine and Is Preserved Following Noradrenergic Denervation. Front Synaptic Neurosci 2019; 11:27. [PMID: 31649525 PMCID: PMC6794465 DOI: 10.3389/fnsyn.2019.00027] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 09/20/2019] [Indexed: 12/27/2022] Open
Abstract
Locus coeruleus (LC) provides the sole source of noradrenergic (NA) innervation to hippocampus, and it undergoes significant degeneration early in Alzheimer's disease (AD). Norepinephrine (NE) modulates synaptic transmission and plasticity at hippocampal synapses which likely contributes to hippocampus-dependent learning and memory. We previously reported that pharmacological activation of α1 adrenergic receptors (α1ARs) induces long-term depression (LTD) at CA3-CA1 synapses. Here, we investigated whether accumulation of endogenous NE via pharmacological blockade of norepinephrine transporters (NETs) and the NE degradative enzyme, monoamine oxidase (MAO), can induce α1AR LTD, as these inhibitors are used clinically. Further, we sought to determine how degeneration of hippocampal NA innervation, as occurs in AD, impacts α1AR function and α1AR LTD. Bath application of NET and MAO inhibitors in slices from control rats reliably induced α1AR LTD when β adrenergic receptors were inhibited. To induce degeneration of LC-NA innervation, rats were treated with the specific NA neurotoxin DSP-4 and recordings performed 1-3 weeks later when NA axon degeneration had stabilized. Even with 85% loss of hippocampal NA innervation, α1AR LTD was successfully induced using either the α1AR agonist phenylephrine or the combined NET and MAO inhibitors, and importantly, the LTD magnitude was not different from saline-treated control. These data suggest that despite significant decreases in NA input to hippocampus, the mechanisms necessary for the induction of α1AR LTD remain functional. Furthermore, we posit that α1AR activation could be a viable therapeutic target for pharmacological intervention in AD and other diseases involving malfunctions of NA neurotransmission.
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Affiliation(s)
- Katie Dyer-Reaves
- Department of Cell, Developmental, and Integrative Biology (CDIB), School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Anthoni M. Goodman
- Department of Cell, Developmental, and Integrative Biology (CDIB), School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Amy R. Nelson
- Department of Cell, Developmental, and Integrative Biology (CDIB), School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Lori L. McMahon
- Department of Cell, Developmental, and Integrative Biology (CDIB), School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
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24
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Regan P, McClean PL, Smyth T, Doherty M. Early Stage Glycosylation Biomarkers in Alzheimer's Disease. MEDICINES 2019; 6:medicines6030092. [PMID: 31484367 PMCID: PMC6789538 DOI: 10.3390/medicines6030092] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 08/29/2019] [Accepted: 08/30/2019] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) is of great cause for concern in our ageing population, which currently lacks diagnostic tools to permit accurate and timely diagnosis for affected individuals. The development of such tools could enable therapeutic interventions earlier in the disease course and thus potentially reducing the debilitating effects of AD. Glycosylation is a common, and important, post translational modification of proteins implicated in a host of disease states resulting in a complex array of glycans being incorporated into biomolecules. Recent investigations of glycan profiles, in a wide range of conditions, has been made possible due to technological advances in the field enabling accurate glycoanalyses. Amyloid beta (Aβ) peptides, tau protein, and other important proteins involved in AD pathogenesis, have altered glycosylation profiles. Crucially, these abnormalities present early in the disease state, are present in the peripheral blood, and help to distinguish AD from other dementias. This review describes the aberrant glycome in AD, focusing on proteins implicated in development and progression, and elucidates the potential of glycome aberrations as early stage biomarkers of AD.
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Affiliation(s)
- Patricia Regan
- Institute of Technology Sligo, Ash Lane, F91 YW50 Sligo, Ireland.
- Cellular Health and Toxicology Research Group, Institute of Technology Sligo, Ash Lane, F91 YW50 Sligo, Ireland.
| | - Paula L McClean
- Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, Clinical Translational Research and Innovation Centre, Altnagelvin Area Hospital, Glenshane Road, Derry BT47 6SB, UK
| | - Thomas Smyth
- Institute of Technology Sligo, Ash Lane, F91 YW50 Sligo, Ireland
- Cellular Health and Toxicology Research Group, Institute of Technology Sligo, Ash Lane, F91 YW50 Sligo, Ireland
| | - Margaret Doherty
- Institute of Technology Sligo, Ash Lane, F91 YW50 Sligo, Ireland
- Cellular Health and Toxicology Research Group, Institute of Technology Sligo, Ash Lane, F91 YW50 Sligo, Ireland
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25
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Monzani E, Nicolis S, Dell'Acqua S, Capucciati A, Bacchella C, Zucca FA, Mosharov EV, Sulzer D, Zecca L, Casella L. Dopamin, oxidativer Stress und Protein‐Chinonmodifikationen bei Parkinson und anderen neurodegenerativen Erkrankungen. Angew Chem Int Ed Engl 2019. [DOI: 10.1002/ange.201811122] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Enrico Monzani
- Department of ChemistryUniversity of Pavia 27100 Pavia Italien
| | | | | | | | | | - Fabio A. Zucca
- Institute of Biomedical TechnologiesNational Research Council of Italy Segrate (Mailand) Italien
| | - Eugene V. Mosharov
- Department of PsychiatryColumbia University Medical CenterNew York State Psychiatric Institute New York NY USA
- Departments Neurology, PharmacologyColumbia University Medical Center New York NY USA
| | - David Sulzer
- Department of PsychiatryColumbia University Medical CenterNew York State Psychiatric Institute New York NY USA
- Departments Neurology, PharmacologyColumbia University Medical Center New York NY USA
| | - Luigi Zecca
- Institute of Biomedical TechnologiesNational Research Council of Italy Segrate (Mailand) Italien
- Department of PsychiatryColumbia University Medical CenterNew York State Psychiatric Institute New York NY USA
| | - Luigi Casella
- Department of ChemistryUniversity of Pavia 27100 Pavia Italien
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26
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Monzani E, Nicolis S, Dell'Acqua S, Capucciati A, Bacchella C, Zucca FA, Mosharov EV, Sulzer D, Zecca L, Casella L. Dopamine, Oxidative Stress and Protein-Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases. Angew Chem Int Ed Engl 2019; 58:6512-6527. [PMID: 30536578 DOI: 10.1002/anie.201811122] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/10/2018] [Indexed: 12/19/2022]
Abstract
Dopamine (DA) is the most important catecholamine in the brain, as it is the most abundant and the precursor of other neurotransmitters. Degeneration of nigrostriatal neurons of substantia nigra pars compacta in Parkinson's disease represents the best-studied link between DA neurotransmission and neuropathology. Catecholamines are reactive molecules that are handled through complex control and transport systems. Under normal conditions, small amounts of cytosolic DA are converted to neuromelanin in a stepwise process involving melanization of peptides and proteins. However, excessive cytosolic or extraneuronal DA can give rise to nonselective protein modifications. These reactions involve DA oxidation to quinone species and depend on the presence of redox-active transition metal ions such as iron and copper. Other oxidized DA metabolites likely participate in post-translational protein modification. Thus, protein-quinone modification is a heterogeneous process involving multiple DA-derived residues that produce structural and conformational changes of proteins and can lead to aggregation and inactivation of the modified proteins.
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Affiliation(s)
- Enrico Monzani
- Department of Chemistry, University of Pavia, 27100, Pavia, Italy
| | - Stefania Nicolis
- Department of Chemistry, University of Pavia, 27100, Pavia, Italy
| | | | | | - Chiara Bacchella
- Department of Chemistry, University of Pavia, 27100, Pavia, Italy
| | - Fabio A Zucca
- Institute of Biomedical Technologies, National Research Council of Italy, Segrate (Milano), Italy
| | - Eugene V Mosharov
- Department of Psychiatry, Columbia University Medical Center, New York State Psychiatric Institute, New York, NY, USA
| | - David Sulzer
- Department of Psychiatry, Columbia University Medical Center, New York State Psychiatric Institute, New York, NY, USA.,Departments of Neurology and Pharmacology, Columbia University Medical Center, New York, NY, USA
| | - Luigi Zecca
- Institute of Biomedical Technologies, National Research Council of Italy, Segrate (Milano), Italy.,Department of Psychiatry, Columbia University Medical Center, New York State Psychiatric Institute, New York, NY, USA
| | - Luigi Casella
- Department of Chemistry, University of Pavia, 27100, Pavia, Italy
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27
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Farfán-García ED, Márquez-Gómez R, Barrón-González M, Pérez-Capistran T, Rosales-Hernández MC, Pinto-Almazán R, Soriano-Ursúa MA. Monoamines and their Derivatives on GPCRs: Potential Therapy for Alzheimer's Disease. Curr Alzheimer Res 2019; 16:871-894. [PMID: 30963972 DOI: 10.2174/1570159x17666190409144558] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 03/18/2019] [Accepted: 04/01/2019] [Indexed: 02/07/2023]
Abstract
Albeit cholinergic depletion remains the key event in Alzheimer's Disease (AD), recent information describes stronger links between monoamines (trace amines, catecholamines, histamine, serotonin, and melatonin) and AD than those known in the past century. Therefore, new drug design strategies focus efforts to translate the scope on these topics and to offer new drugs which can be applied as therapeutic tools in AD. In the present work, we reviewed the state-of-art regarding genetic, neuropathology and neurochemistry of AD involving monoamine systems. Then, we compiled the effects of monoamines found in the brain of mammals as well as the reported effects of their derivatives and some structure-activity relationships. Recent derivatives have triggered exciting effects and pharmacokinetic properties in both murine models and humans. In some cases, the mechanism of action is clear, essentially through the interaction on G-protein-coupled receptors as revised in this manuscript. Additional mechanisms are inhibition of enzymes for their biotransformation, regulation of free-radicals in the central nervous system and others for the effects on Tau phosphorylation or amyloid-beta accumulation. All these data make the monoamines and their derivatives attractive potential elements for AD therapy.
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Affiliation(s)
- Eunice D Farfán-García
- Departamento de Fisiologia y Bioquimica. Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron s/n, 11340, Mexico City, Mexico
| | - Ricardo Márquez-Gómez
- MRC Anatomical Neuropharmacology Unit, Department of Pharmacology, University of Oxford, OX1 3TH, Oxford, United Kingdom
| | - Mónica Barrón-González
- Departamento de Fisiologia y Bioquimica. Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron s/n, 11340, Mexico City, Mexico
| | - Teresa Pérez-Capistran
- Departamento de Fisiologia y Bioquimica. Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron s/n, 11340, Mexico City, Mexico
| | - Martha C Rosales-Hernández
- Laboratorio de Biofisica y Biocatalisis, Seccion de Estudios de Posgrado e Investigacion Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron s/n, 11340, Mexico City, Mexico
| | - Rodolfo Pinto-Almazán
- Unidad de Investigacion Hospital Regional de Alta Especialidad Ixtapaluca, Carretera Federal Mexico-Puebla km 34.5, C.P. 56530. Ixtapaluca, State of Mexico, Mexico
| | - Marvin A Soriano-Ursúa
- Departamento de Fisiologia y Bioquimica. Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron s/n, 11340, Mexico City, Mexico
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28
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Nabavi SF, Sureda A, Dehpour AR, Shirooie S, Silva AS, Devi KP, Ahmed T, Ishaq N, Hashim R, Sobarzo-Sánchez E, Daglia M, Braidy N, Volpicella M, Vacca RA, Nabavi SM. Regulation of autophagy by polyphenols: Paving the road for treatment of neurodegeneration. Biotechnol Adv 2018; 36:1768-1778. [DOI: 10.1016/j.biotechadv.2017.12.001] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 12/01/2017] [Accepted: 12/03/2017] [Indexed: 12/11/2022]
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29
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Nguyen PV, Gelinas JN. Noradrenergic gating of long-lasting synaptic potentiation in the hippocampus: from neurobiology to translational biomedicine. J Neurogenet 2018; 32:171-182. [DOI: 10.1080/01677063.2018.1497630] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- Peter V. Nguyen
- Department of Physiology and Institute of Neuroscience & Mental Health, University of Alberta School of Medicine, Edmonton, Canada
| | - Jennifer N. Gelinas
- Department of Neurology and Institute for Genomic Medicine, College of Physicians & Surgeons of Columbia University, New York, NY,USA
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30
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Peterson AC, Li CSR. Noradrenergic Dysfunction in Alzheimer's and Parkinson's Diseases-An Overview of Imaging Studies. Front Aging Neurosci 2018; 10:127. [PMID: 29765316 PMCID: PMC5938376 DOI: 10.3389/fnagi.2018.00127] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 04/16/2018] [Indexed: 12/31/2022] Open
Abstract
Noradrenergic dysfunction contributes to cognitive impairment in Alzheimer's Disease (AD) and Parkinson's Disease (PD). Conventional therapeutic strategies seek to enhance cholinergic and dopaminergic neurotransmission in AD and PD, respectively, and few studies have examined noradrenergic dysfunction as a target for medication development. We review the literature of noradrenergic dysfunction in AD and PD with a focus on human imaging studies that implicate the locus coeruleus (LC) circuit. The LC sends noradrenergic projections diffusely throughout the cerebral cortex and plays a critical role in attention, learning, working memory, and cognitive control. The LC undergoes considerable degeneration in both AD and PD. Advances in magnetic resonance imaging have facilitated greater understanding of how structural and functional alteration of the LC may contribute to cognitive decline in AD and PD. We discuss the potential roles of the noradrenergic system in the pathogenesis of AD and PD with an emphasis on postmortem anatomical studies, structural MRI studies, and functional MRI studies, where we highlight changes in LC connectivity with the default mode network (DMN). LC degeneration may accompany deficient capacity in suppressing DMN activity and increasing saliency and task control network activities to meet behavioral challenges. We finish by proposing potential and new directions of research to address noradrenergic dysfunction in AD and PD.
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Affiliation(s)
- Andrew C Peterson
- Frank H. Netter MD School of Medicine, Quinnipiac University, North Haven, CT, United States.,Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
| | - Chiang-Shan R Li
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.,Department of Neuroscience, Yale University School of Medicine, New Haven, CT, United States.,Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, United States
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31
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Sánchez MP, García-Cabrero AM, Sánchez-Elexpuru G, Burgos DF, Serratosa JM. Tau-Induced Pathology in Epilepsy and Dementia: Notions from Patients and Animal Models. Int J Mol Sci 2018; 19:ijms19041092. [PMID: 29621183 PMCID: PMC5979593 DOI: 10.3390/ijms19041092] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 03/23/2018] [Accepted: 04/03/2018] [Indexed: 12/24/2022] Open
Abstract
Patients with dementia present epilepsy more frequently than the general population. Seizures are more common in patients with Alzheimer’s disease (AD), dementia with Lewy bodies (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) than in other dementias. Missense mutations in the microtubule associated protein tau (MAPT) gene have been found to cause familial FTD and PSP, while the P301S mutation in MAPT has been associated with early-onset fast progressive dementia and the presence of seizures. Brains of patients with AD, LBD, FTD and PSP show hyperphosphorylated tau aggregates, amyloid-β plaques and neuropil threads. Increasing evidence suggests the existence of overlapping mechanisms related to the generation of network hyperexcitability and cognitive decline. Neuronal overexpression of tau with various mutations found in FTD with parkinsonism-linked to chromosome 17 (FTDP-17) in mice produces epileptic activity. On the other hand, the use of certain antiepileptic drugs in animal models with AD prevents cognitive impairment. Further efforts should be made to search for plausible common targets for both conditions. Moreover, attempts should also be made to evaluate the use of drugs targeting tau and amyloid-β as suitable pharmacological interventions in epileptic disorders. The diagnosis of dementia and epilepsy in early stages of those diseases may be helpful for the initiation of treatments that could prevent the generation of epileptic activity and cognitive deterioration.
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Affiliation(s)
- Marina P Sánchez
- Laboratory of Neurology, IIS (Instituto Investigación Sanitaria/Health Research Institute)-Jiménez Díaz Foundation, UAM (Universidad Autonoma de Madrid/Autonomous University of Madrid) and Biomedical Research Network Center on Rare Diseases (CIBERER), 28045 Madrid, Spain.
| | - Ana M García-Cabrero
- Laboratory of Neurology, IIS (Instituto Investigación Sanitaria/Health Research Institute)-Jiménez Díaz Foundation, UAM (Universidad Autonoma de Madrid/Autonomous University of Madrid) and Biomedical Research Network Center on Rare Diseases (CIBERER), 28045 Madrid, Spain.
- Department of Immunology and Oncology and Protein Tools Unit, Biotechnology National Center (CNB/CSIC), 28049 Madrid, Spain.
| | - Gentzane Sánchez-Elexpuru
- Laboratory of Neurology, IIS (Instituto Investigación Sanitaria/Health Research Institute)-Jiménez Díaz Foundation, UAM (Universidad Autonoma de Madrid/Autonomous University of Madrid) and Biomedical Research Network Center on Rare Diseases (CIBERER), 28045 Madrid, Spain.
| | - Daniel F Burgos
- Laboratory of Neurology, IIS (Instituto Investigación Sanitaria/Health Research Institute)-Jiménez Díaz Foundation, UAM (Universidad Autonoma de Madrid/Autonomous University of Madrid) and Biomedical Research Network Center on Rare Diseases (CIBERER), 28045 Madrid, Spain.
| | - José M Serratosa
- Laboratory of Neurology, IIS (Instituto Investigación Sanitaria/Health Research Institute)-Jiménez Díaz Foundation, UAM (Universidad Autonoma de Madrid/Autonomous University of Madrid) and Biomedical Research Network Center on Rare Diseases (CIBERER), 28045 Madrid, Spain.
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32
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Moradifard S, Hoseinbeyki M, Ganji SM, Minuchehr Z. Analysis of microRNA and Gene Expression Profiles in Alzheimer's Disease: A Meta-Analysis Approach. Sci Rep 2018; 8:4767. [PMID: 29555910 PMCID: PMC5859169 DOI: 10.1038/s41598-018-20959-0] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 01/24/2018] [Indexed: 12/11/2022] Open
Abstract
Understanding the molecular mechanisms underlying Alzheimer’s disease (AD) is necessary for the diagnosis and treatment of this neurodegenerative disorder. It is therefore important to detect the most important genes and miRNAs, which are associated with molecular events, and studying their interactions for recognition of AD mechanisms. Here we focus on the genes and miRNAs expression profile, which we have detected the miRNA target genes involved in AD. These are the most quintessential to find the most important miRNA, to target genes and their important pathways. A total of 179 differentially expressed miRNAs (DEmiRs) and 1404 differentially expressed genes (DEGs) were obtained from a comprehensive meta-analysis. Also, regions specific genes with their molecular function in AD have been demonstrated. We then focused on miRNAs which regulated most genes in AD, alongside we analyzed their pathways. The miRNA-30a-5p and miRNA-335 elicited a major function in AD after analyzing the regulatory network, we showed they were the most regulatory miRNAs in the AD. In conclusion, we demonstrated the most important genes, miRNAs, miRNA-mRNA interactions and their related pathways in AD using Bioinformatics methods. Accordingly, our defined genes and miRNAs could be used for future molecular studies in the context of AD.
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Affiliation(s)
- Shirin Moradifard
- National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Moslem Hoseinbeyki
- National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | | | - Zarrin Minuchehr
- National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.
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33
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Shared preventive strategies between cardiovascular diseases and neurodegenerative diseases. Eur J Prev Cardiol 2018; 25:881-882. [DOI: 10.1177/2047487318755201] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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34
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Weatherburn CJ, Heath CA, Mercer SW, Guthrie B. Physical and mental health comorbidities of epilepsy: Population-based cross-sectional analysis of 1.5 million people in Scotland. Seizure 2017; 45:125-131. [DOI: 10.1016/j.seizure.2016.11.013] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 11/16/2016] [Accepted: 11/18/2016] [Indexed: 01/18/2023] Open
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35
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Hentschel F, Dressler D, Abele M, Paus S. Impaired heart rate variability in cervical dystonia is associated to depression. J Neural Transm (Vienna) 2016; 124:245-251. [DOI: 10.1007/s00702-016-1639-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 10/28/2016] [Indexed: 12/19/2022]
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36
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Sun JJ, Ray R. Generation of Two Noradrenergic-Specific Dopamine-Beta-Hydroxylase-FLPo Knock-In Mice Using CRISPR/Cas9-Mediated Targeting in Embryonic Stem Cells. PLoS One 2016; 11:e0159474. [PMID: 27441631 PMCID: PMC4956144 DOI: 10.1371/journal.pone.0159474] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 06/09/2016] [Indexed: 12/18/2022] Open
Abstract
CRISPR/Cas9 mediated DNA double strand cutting is emerging as a powerful approach to increase rates of homologous recombination of large targeting vectors, but the optimization of parameters, equipment and expertise required remain barriers to successful mouse generation by single-step zygote injection. Here, we sought to apply CRISPR/Cas9 methods to traditional embryonic stem (ES) cell targeting followed by blastocyst injection to overcome the common issues of difficult vector construction and low targeting efficiency. To facilitate the study of noradrenergic function, which is implicated in myriad behavioral and physiological processes, we generated two different mouse lines that express FLPo recombinase under control of the noradrenergic-specific Dopamine-Beta-Hydroxylase (DBH) gene. We found that by co-electroporating a circular vector expressing Cas9 and a locus-specific sgRNA, we could target FLPo to the DBH locus in ES cells with shortened 1 kb homology arms. Two different sites in the DBH gene were targeted; the translational start codon with 6-8% targeting efficiency, and the translational stop codon with 75% targeting efficiency. Using this approach, we established two mouse lines with DBH-specific expression of FLPo in brainstem catecholaminergic populations that are publically available on MMRRC (MMRRC_041575-UCD and MMRRC_041577-UCD). Altogether, this study supports simplified, high-efficiency Cas9/CRISPR-mediated targeting in embryonic stem cells for production of knock-in mouse lines in a wider variety of contexts than zygote injection alone.
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Affiliation(s)
- Jenny J. Sun
- Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America
| | - Russell Ray
- Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America
- McNair Medical Institute, Baylor College of Medicine, Houston, Texas, United States of America
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37
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Daulatzai MA. Dysfunctional Sensory Modalities, Locus Coeruleus, and Basal Forebrain: Early Determinants that Promote Neuropathogenesis of Cognitive and Memory Decline and Alzheimer’s Disease. Neurotox Res 2016; 30:295-337. [DOI: 10.1007/s12640-016-9643-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 06/08/2016] [Accepted: 06/10/2016] [Indexed: 12/22/2022]
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Feinstein DL, Kalinin S, Braun D. Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: noradrenergic signaling system. J Neurochem 2016; 139 Suppl 2:154-178. [PMID: 26968403 DOI: 10.1111/jnc.13447] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 11/23/2015] [Accepted: 11/24/2015] [Indexed: 12/31/2022]
Abstract
Aside from its roles in as a classical neurotransmitter involved in regulation of behavior, noradrenaline (NA) has other functions in the CNS. This includes restricting the development of neuroinflammatory activation, providing neurotrophic support to neurons, and providing neuroprotection against oxidative stress. In recent years, it has become evident that disruption of physiological NA levels or signaling is a contributing factor to a variety of neurological diseases and conditions including Alzheimer's disease (AD) and Multiple Sclerosis. The basis for dysregulation in these diseases is, in many cases, due to damage occurring to noradrenergic neurons present in the locus coeruleus (LC), the major source of NA in the CNS. LC damage is present in AD, multiple sclerosis, and a large number of other diseases and conditions. Studies using animal models have shown that experimentally induced lesion of LC neurons exacerbates neuropathology while treatments to compensate for NA depletion, or to reduce LC neuronal damage, provide benefit. In this review, we will summarize the anti-inflammatory and neuroprotective actions of NA, summarize examples of how LC damage worsens disease, and discuss several approaches taken to treat or prevent reductions in NA levels and LC neuronal damage. Further understanding of these events will be of value for the development of treatments for AD, multiple sclerosis, and other diseases and conditions having a neuroinflammatory component. The classical neurotransmitter noradrenaline (NA) has critical roles in modulating behaviors including those involved in sleep, anxiety, and depression. However, NA can also elicit anti-inflammatory responses in glial cells, can increase neuronal viability by inducing neurotrophic factor expression, and can reduce neuronal damage due to oxidative stress by scavenging free radicals. NA is primarily produced by tyrosine hydroxylase (TH) expressing neurons in the locus coeruleus (LC), a relatively small brainstem nucleus near the IVth ventricle which sends projections throughout the brain and spinal cord. It has been known for close to 50 years that LC neurons are lost during normal aging, and that loss is exacerbated in neurological diseases including Parkinson's disease and Alzheimer's disease. LC neuronal damage and glial activation has now been documented in a variety of other neurological conditions and diseases, however, the causes of LC damage and cell loss remain largely unknown. A number of approaches have been developed to address the loss of NA and increased inflammation associated with LC damage, and several methods are being explored to directly minimize the extent of LC neuronal cell loss or function. In this review, we will summarize some of the consequences of LC loss, consider several factors that likely contribute to that loss, and discuss various ways that have been used to increase NA or to reduce LC damage. This article is part of the 60th Anniversary special issue.
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Affiliation(s)
- Douglas L Feinstein
- Department of Anesthesiology, University of Illinois, Chicago, IL, USA. .,Jesse Brown VA Medical Center, Chicago, IL, USA.
| | - Sergey Kalinin
- Department of Anesthesiology, University of Illinois, Chicago, IL, USA.,Jesse Brown VA Medical Center, Chicago, IL, USA
| | - David Braun
- Department of Anesthesiology, University of Illinois, Chicago, IL, USA.,Jesse Brown VA Medical Center, Chicago, IL, USA
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Rodrigues RJ, Almeida T, Díaz-Hernández M, Marques JM, Franco R, Solsona C, Miras-Portugal MT, Ciruela F, Cunha RA. Presynaptic P2X1-3 and α3-containing nicotinic receptors assemble into functionally interacting ion channels in the rat hippocampus. Neuropharmacology 2016; 105:241-257. [PMID: 26801076 DOI: 10.1016/j.neuropharm.2016.01.022] [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: 09/14/2015] [Revised: 12/20/2015] [Accepted: 01/18/2016] [Indexed: 01/10/2023]
Abstract
Previous studies documented a cross-talk between purinergic P2X (P2XR) and nicotinic acetylcholine receptors (nAChR) in heterologous expression systems and peripheral preparations. We now investigated if this occurred in native brain preparations and probed its physiological function. We found that P2XR and nAChR were enriched in hippocampal terminals, where both P2X1-3R and α3, but not α4, nAChR subunits were located in the active zone and in dopamine-β-hydroxylase-positive hippocampal terminals. Notably, P2XR ligands displaced nAChR binding and nAChR ligands displaced P2XR binding to hippocampal synaptosomes. In addition, a negative P2XR/nAChR cross-talk was observed in the control of the evoked release of noradrenaline from rat hippocampal synaptosomes, characterized by a less-than-additive facilitatory effect upon co-activation of both receptors. This activity-dependent cross-inhibition was confirmed in Xenopus oocytes transfected with P2X1-3Rs and α3β2 (but not α4β2) nAChR. Besides, P2X2 co-immunoprecipitated α3β2 (but not α4β2) nAChR, both in HEK cells and rat hippocampal membranes indicating that this functional interaction is supported by a physical association between P2XR and nAChR. Moreover, eliminating extracellular ATP with apyrase in hippocampal slices promoted the inhibitory effect of the nAChR antagonist tubocurarine on noradrenaline release induced by high- but not low-frequency stimulation. Overall, these results provide integrated biochemical, pharmacological and functional evidence showing that P2X1-3R and α3β2 nAChR are physically and functionally interconnected at the presynaptic level to control excessive noradrenergic terminal activation upon intense synaptic firing in the hippocampus.
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Affiliation(s)
- Ricardo J Rodrigues
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Portugal.
| | - Teresa Almeida
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Portugal; Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028, Spain; Department of Pathology and Experimental Therapeutics, Faculty of Medicine, IDIBELL, University of Barcelona, 08907, Spain
| | - Miguel Díaz-Hernández
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary, Complutense University of Madrid, 28040, Spain
| | - Joana M Marques
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Portugal
| | - Rafael Franco
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028, Spain; CIBERNED, Centro de Investigación en Red, Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain
| | - Carles Solsona
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine, IDIBELL, University of Barcelona, 08907, Spain
| | - María Teresa Miras-Portugal
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary, Complutense University of Madrid, 28040, Spain
| | - Francisco Ciruela
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine, IDIBELL, University of Barcelona, 08907, Spain; Department of Physiology, Faculty of Sciences, University of Ghent, B-9000, Belgium
| | - Rodrigo A Cunha
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Portugal; Faculty of Medicine, University of Coimbra, 3004-504, Portugal
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Park HE, Kim JS, Oh YS, Park IS, Park JW, Song IU, Lee KS. Autonomic Nervous System Dysfunction in Patients With Parkinson Disease Having Depression. J Geriatr Psychiatry Neurol 2016; 29:11-7. [PMID: 26232405 DOI: 10.1177/0891988715598234] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 05/06/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM Both depression and cardiovascular autonomic dysfunctions, such as orthostatic hypotension, supine hypertension, and the absence of normal nocturnal blood pressure (BP) fall ("nondipping"), occur relatively commonly in Parkinson disease (PD); however, the relationship between depression and cardiovascular autonomic abnormalities has not been established. In this study, we sought to determine whether the cardiovascular autonomic abnormalities found in PD are associated with depression. METHODS Among 129 nondemented, levodopa-naive patients with mild PD, 44 had depression. Orthostatic vital signs and ambulatory 24-hour BP monitoring were recorded, and geriatric depressive scales were obtained in all patients. Associations between orthostatic hypotension, supine hypertension, nocturnal hypertension, nondipping, and depression were analyzed. The ratio of the standard deviation of 24-hour heart rate to that of systolic BP (SBP) was utilized as an index of baroreflex-cardiovagal function. RESULTS Depression was associated with orthostatic hypotension, and patients with depression had higher SBP change during orthostasis and attenuated cardiovagal dysfunction as observed during ambulatory BP monitoring. Across individuals, values for orthostatic changes in BP were correlated with values for geriatric depressive scale. CONCLUSION Depression is associated with neurocirculatory abnormalities-especially orthostatic hypotension-in early PD. Although the association does not imply causation, this result suggests that depression in PD might be associated with functional impairment of the autonomic nervous system and its pathologic substrate.
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Affiliation(s)
- Hyung-Eun Park
- Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Joong-Seok Kim
- Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yoon-Sang Oh
- Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - In-Seok Park
- Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong-Wook Park
- Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - In-Uk Song
- Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kwang-Soo Lee
- Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Martin CA, Myers KM, Chen A, Martin NT, Barajas A, Schweizer FE, Krantz DE. Ziram, a pesticide associated with increased risk for Parkinson's disease, differentially affects the presynaptic function of aminergic and glutamatergic nerve terminals at the Drosophila neuromuscular junction. Exp Neurol 2016; 275 Pt 1:232-41. [PMID: 26439313 PMCID: PMC4688233 DOI: 10.1016/j.expneurol.2015.09.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Revised: 09/04/2015] [Accepted: 09/26/2015] [Indexed: 12/29/2022]
Abstract
Multiple populations of aminergic neurons are affected in Parkinson's disease (PD), with serotonergic and noradrenergic loci responsible for some non-motor symptoms. Environmental toxins, such as the dithiocarbamate fungicide ziram, significantly increase the risk of developing PD and the attendant spectrum of both motor and non-motor symptoms. The mechanisms by which ziram and other environmental toxins increase the risk of PD, and the potential effects of these toxins on aminergic neurons, remain unclear. To determine the relative effects of ziram on the synaptic function of aminergic versus non-aminergic neurons, we used live-imaging at the Drosophila melanogaster larval neuromuscular junction (NMJ). In contrast to nearly all other studies of this model synapse, we imaged presynaptic function at both glutamatergic Type Ib and aminergic Type II boutons, the latter responsible for storage and release of octopamine, the invertebrate equivalent of noradrenalin. To quantify the kinetics of exo- and endo-cytosis, we employed an acid-sensitive form of GFP fused to the Drosophila vesicular monoamine transporter (DVMAT-pHluorin). Additional genetic probes were used to visualize intracellular calcium flux (GCaMP) and voltage changes (ArcLight). We find that at glutamatergic Type Ib terminals, exposure to ziram increases exocytosis and inhibits endocytosis. By contrast, at octopaminergic Type II terminals, ziram has no detectable effect on exocytosis and dramatically inhibits endocytosis. In contrast to other reports on the neuronal effects of ziram, these effects do not appear to result from perturbation of the Ubiquitin Proteasome System (UPS) or calcium homeostasis. Unexpectedly, ziram also caused spontaneous and synchronized bursts of calcium influx (measured by GCaMP) and electrical activity (measured by ArcLight) at aminergic Type II, but not glutamatergic Type Ib, nerve terminals. These events are sensitive to both tetrodotoxin and cadmium chloride, and thus appear to represent spontaneous depolarizations followed by calcium influx into Type II terminals. We speculate that the differential effects of ziram on Type II versus Type Ib terminals may be relevant to the specific sensitivity of aminergic neurons in PD, and suggest that changes in neuronal excitability could contribute to the increased risk for PD caused by exposure to ziram. We also suggest that the fly NMJ will be useful to explore the synaptic effects of other pesticides associated with an increased risk of PD.
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Affiliation(s)
- Ciara A Martin
- Department of Psychiatry and Biobehavioral Sciences, Hatos Center for Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States; UCLA Interdepartmental Program in Molecular Toxicology, Los Angeles, CA 90095, United States.
| | - Katherine M Myers
- Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States; UCLA Interdepartmental Program for Neuroscience, Los Angeles, CA 90095, United States.
| | - Audrey Chen
- Department of Psychiatry and Biobehavioral Sciences, Hatos Center for Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States; Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States.
| | - Nathan T Martin
- UCLA Biomedical Physics Interdepartmental Graduate Program, Los Angeles, CA 90095, United States.
| | - Angel Barajas
- Department of Psychiatry and Biobehavioral Sciences, Hatos Center for Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States.
| | - Felix E Schweizer
- Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States; UCLA Interdepartmental Program for Neuroscience, Los Angeles, CA 90095, United States.
| | - David E Krantz
- Department of Psychiatry and Biobehavioral Sciences, Hatos Center for Neuropharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States; UCLA Interdepartmental Program in Molecular Toxicology, Los Angeles, CA 90095, United States; UCLA Interdepartmental Program for Neuroscience, Los Angeles, CA 90095, United States.
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Pagida MA, Konstantinidou AE, Korelidou A, Katsika D, Tsekoura E, Patsouris E, Panayotacopoulou MT. The Effect of Perinatal Hypoxic/Ischemic Injury on Tyrosine Hydroxylase Expression in the Locus Coeruleus of the Human Neonate. Dev Neurosci 2015; 38:41-53. [DOI: 10.1159/000439270] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 08/08/2015] [Indexed: 11/19/2022] Open
Abstract
We have previously shown that perinatal hypoxic/ischemic injury (HII) may cause selective vulnerability of the mesencephalic dopaminergic neurons of human neonate. In the present study, we investigated the effect of perinatal HII on the noradrenergic neurons of the locus coeruleus (LC) of the same sample. We studied immunohistochemically the expression of tyrosine hydroxylase (TH, first limiting enzyme for catecholamine synthesis) in LC neurons of 15 autopsied infants (brains collected from the Greek Brain Bank) in relation to the neuropathological changes of acute or chronic HII of the neonatal brain. Our results showed that perinatal HII appears to affect the expression of TH and the size of LC neurons of the human neonate. In subjects with neuropathological lesions consistent with abrupt/severe HII, intense TH immunoreactivity was found in almost all neurons of the LC. In most of the neonates with neuropathological changes of prolonged or older injury, however, reduction in cell size and a decrease or absence of TH staining were observed in the LC. Intense TH immunoreactivity was found in the LC of 3 infants of the latter group, who interestingly had a longer survival time and had been treated with anticonvulsant drugs. Based on our observations and in view of experimental evidence indicating that the reduction of TH-immunoreactive neurons occurring in the LC after perinatal hypoxic insults persists into adulthood, we suggest that a dysregulation of monoaminergic neurotransmission in critical periods of brain development in humans is likely to predispose the survivors of perinatal HII, in combination with genetic susceptibility, to psychiatric and/or neurological disorders later in life.
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Boison D, Aronica E. Comorbidities in Neurology: Is adenosine the common link? Neuropharmacology 2015; 97:18-34. [PMID: 25979489 PMCID: PMC4537378 DOI: 10.1016/j.neuropharm.2015.04.031] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Revised: 04/24/2015] [Accepted: 04/27/2015] [Indexed: 12/13/2022]
Abstract
Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression, and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the 'adenosine hypothesis of comorbidities' implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS. We discuss a transgenic 'comorbidity model', in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain co-morbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions.
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Affiliation(s)
- Detlev Boison
- Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR 97232, USA.
| | - Eleonora Aronica
- Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, The Netherlands; Stichting Epilepsie Instellingen (SEIN) Nederland, Heemstede, The Netherlands
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Szot P, Franklin A, Miguelez C, Wang Y, Vidaurrazaga I, Ugedo L, Sikkema C, Wilkinson CW, Raskind MA. Depressive-like behavior observed with a minimal loss of locus coeruleus (LC) neurons following administration of 6-hydroxydopamine is associated with electrophysiological changes and reversed with precursors of norepinephrine. Neuropharmacology 2015; 101:76-86. [PMID: 26362360 DOI: 10.1016/j.neuropharm.2015.09.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 07/01/2015] [Accepted: 09/03/2015] [Indexed: 01/23/2023]
Abstract
Depression is a common co-morbid condition most often observed in subjects with mild cognitive impairment (MCI) and during the early stages of Alzheimer's disease (AD). Dysfunction of the central noradrenergic nervous system is an important component in depression. In AD, locus coeruleus (LC) noradrenergic neurons are significantly reduced pathologically and the reduction of LC neurons is hypothesized to begin very early in the progression of the disorder; however, it is not known if dysfunction of the noradrenergic system due to early LC neuronal loss is involved in mediating depression in early AD. Therefore, the purpose of this study was to determine in an animal model if a loss of noradrenergic LC neurons results in depressive-like behavior. The LC noradrenergic neuronal population was reduced by the bilateral administration of the neurotoxin 6-hydroxydopamine (6-OHDA) directly into the LC. Forced swim test (FST) was performed three weeks after the administration of 6-OHDA (5, 10 and 14 μg/μl), animals administered the 5 μg/μl of 6-OHDA demonstrated a significant increase in immobility, indicating depressive-like behavior. This increase in immobility at the 5 μg/μl dose was observed with a minimal loss of LC noradrenergic neurons as compared to LC neuronal loss observed at 10 and 14 μg/μl dose. A significant positive correlation between the number of surviving LC neurons after 6-OHDA and FST immobile time was observed, suggesting that in animals with a minimal loss of LC neurons (or a greater number of surviving LC neurons) following 6-OHDA demonstrated depressive-like behavior. As the 6-OHDA-induced loss of LC neurons is increased, the time spent immobile is reduced. Depressive-like behavior was also observed with the 5 μg/μl dose of 6-OHDA with a second behavior test, sucrose consumption. FST increased immobility following 6-OHDA (5 μg/μl) was reversed by the administration of a single dose of L-1-3-4-dihydroxyphenylalanine (DOPA) or l-threo-3,4-dihydroxyphenylserine (DOPS) prior to behavioral assessment. Surviving LC neurons 3 weeks after 6-OHDA (5 μg/μl) demonstrated compensatory changes of increased firing frequency, a more irregular firing pattern, and a higher percentage of cells firing in bursts. These results indicate that depressive-like behavior in mice is observed following the administration of 6-OHDA and the loss of LC noradrenergic neurons; however, the depressive-like behavior correlates positively with the number of surviving LC neurons with 6-OHDA administration. This data suggests the depression observed in MCI subjects and in the early stages of AD may due to the hypothesized early, minimal loss of LC neurons with remaining LC neurons being more active than normal.
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Affiliation(s)
- Patricia Szot
- Mental Illness Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
| | - Allyn Franklin
- Mental Illness Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA, USA
| | - Cristina Miguelez
- Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain; Department of Pharmacology, University of the Basque Country, UPV/EHU, Vitoria-Gasteiz, Spain
| | - Yangqing Wang
- Mental Illness Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA, USA
| | - Igor Vidaurrazaga
- Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain
| | - Luisa Ugedo
- Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain
| | - Carl Sikkema
- Geriatric Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA, USA
| | - Charles W Wilkinson
- Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA; Geriatric Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA, USA
| | - Murray A Raskind
- Mental Illness Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA
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Ádori C, Glück L, Barde S, Yoshitake T, Kovacs GG, Mulder J, Maglóczky Z, Havas L, Bölcskei K, Mitsios N, Uhlén M, Szolcsányi J, Kehr J, Rönnbäck A, Schwartz T, Rehfeld JF, Harkany T, Palkovits M, Schulz S, Hökfelt T. Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer's disease. Acta Neuropathol 2015; 129:541-63. [PMID: 25676386 DOI: 10.1007/s00401-015-1394-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 01/23/2015] [Accepted: 01/23/2015] [Indexed: 12/18/2022]
Abstract
Alzheimer's disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is noteworthy since cortical and hypothalamic somatostatin content is reduced in neurodegenerative pathologies. Yet a possible role of a somatostatin signal deficit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometry and mRNA profiling in a cohort of Alzheimer's and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer's disease, we found significantly reduced somatostatin protein expression in the temporal cortex, with aberrant clustering and bulging of tyrosine hydroxylase-immunoreactive afferents. As such, somatostatin receptor 2 (SSTR2) mRNA was highly expressed in the human LC, with its levels significantly decreasing from Braak stages III/IV and onwards, i.e., a process preceding advanced Alzheimer's pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine β-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2(-/-) mice and, unlike in Sstr1(-/-) or Sstr4(-/-) genotypes, they showed selective, global and progressive degeneration of their central noradrenergic projections. However, neuronal perikarya in the LC were found intact until late adulthood (<8 months) in Sstr2(-/-) mice. In contrast, the noradrenergic neurons in the superior cervical ganglion lacked SSTR2 and, as expected, the sympathetic innervation of the head region did not show any signs of degeneration. Our results indicate that SSTR2-mediated signaling is integral to the maintenance of central noradrenergic projections at the system level, and that early loss of somatostatin receptor 2 function may be associated with the selective vulnerability of the noradrenergic system in Alzheimer's disease.
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Affiliation(s)
- Csaba Ádori
- Department of Neuroscience, Retzius Laboratory, Karolinska Institutet, Retzius väg 8, 17177, Stockholm, Sweden,
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Relevance of the glutathione system in temporal lobe epilepsy: evidence in human and experimental models. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:759293. [PMID: 25538816 PMCID: PMC4265701 DOI: 10.1155/2014/759293] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 11/11/2014] [Indexed: 12/14/2022]
Abstract
Oxidative stress, which is a state of imbalance in the production of reactive oxygen species and nitrogen, is induced by a wide variety of factors. This biochemical state is associated with diseases that are systemic as well as diseases that affect the central nervous system. Epilepsy is a chronic neurological disorder, and temporal lobe epilepsy represents an estimated 40% of all epilepsy cases. Currently, evidence from human and experimental models supports the involvement of oxidative stress during seizures and in the epileptogenesis process. Hence, the aim of this review was to provide information that facilitates the processing of this evidence and investigate the therapeutic impact of the biochemical status for this specific pathology.
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Espay AJ, LeWitt PA, Kaufmann H. Norepinephrine deficiency in Parkinson's disease: The case for noradrenergic enhancement. Mov Disord 2014; 29:1710-9. [PMID: 25297066 DOI: 10.1002/mds.26048] [Citation(s) in RCA: 180] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 09/02/2014] [Accepted: 09/11/2014] [Indexed: 12/28/2022] Open
Affiliation(s)
- Alberto J. Espay
- Gardner Family Center for Parkinson's Disease and Movement Disorders; Department of Neurology; University of Cincinnati; Cincinnati Ohio USA
| | - Peter A. LeWitt
- Departments of Neurology; Henry Ford Hospital and Wayne State University School of Medicine; West Bloomfield Michigan USA
| | - Horacio Kaufmann
- Dysautonomia Center; Department of Neurology; NYU School of Medicine; New York New York USA
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Fitzgerald PJ. Noradrenaline transmission reducing drugs may protect against a broad range of diseases. ACTA ACUST UNITED AC 2014; 34:15-26. [PMID: 25271382 DOI: 10.1111/aap.12019] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
1 A growing body of evidence suggests that the signalling molecule, noradrenaline (NA), plays a pathophysiological role in a broad range of psychiatric, neurological and peripheral disorders. Both preclinical and clinical data suggest that elevated NA signalling may be involved in the aetiology of major diseases such as depression, Alzheimer's disease and diabetes mellitus. 2 The molecular pathways by which NA may cause the manifestation of disease remain poorly understood, although they may include G protein-coupled receptor modulation of the Ras/MAP kinase, Stat3 and PI3K pathways, among others. In both individual animals and humans, NA tone may be elevated largely due to genetics, but also because of the exposure to marked psychological stress or trauma, or other environmental factors. 3 As NA is involved in the 'fight or flight' response by the sympathetic nervous system, this transmitter may be elevated in a large number of organisms due to evolutionary selection of enhancing responses to immediate environmental dangers. Likewise, acetylcholine signalling by the parasympathetic ('rest and digest') nervous system may be relatively diminished. This putative autonomic imbalance may result in diminished engagement in homeostatic processes, resulting in the emergence and progression of a number of diseases throughout the body. 4 In this scenario, a large number of individuals may benefit from chronic use of pharmacological agents - such as clonidine, guanfacine, propranolol or prazosin - that diminish NA signalling throughout the body. If so, NA transmission lowering drugs may protect against a wide range of diseases.
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Affiliation(s)
- P J Fitzgerald
- Department of Psychology, Texas A&M University, College Station, Texas, 77843, USA
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Shared mechanisms of neurodegeneration in Alzheimer's disease and Parkinson's disease. BIOMED RESEARCH INTERNATIONAL 2014; 2014:648740. [PMID: 24900975 PMCID: PMC4037122 DOI: 10.1155/2014/648740] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 04/16/2014] [Accepted: 04/20/2014] [Indexed: 12/03/2022]
Abstract
Alzheimer's disease (AD) and Parkinson's disease (PD) have markedly different clinical and pathological features, but these two diseases are the most common neurodegenerative disorders. Previous studies have showed that there are common mechanisms in AD and PD. Several genetic studies have revealed mutations in genes associated with the risk of AD and PD. Circumstantial evidences have shown that dysregulation of brain iron homeostasis leads to abnormal iron accumulation and results in AD as well as PD. α-Synuclein and tau take part in the mechanisms of these diseases by oxidative stress and mitochondrial dysfunction. Some studies indicated that the loss of LC noradrenergic neurons may occur early in the progression of AD and PD. Nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily of pentameric ligand-gated ion channels; some evidence showed that nicotinic receptors may be associated with AD and PD. These experimental and clinical studies may provide a scientific foundation for common shared mechanisms in AD and PD.
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Ma CC, Liu AJ, Liu AH, Zhou XY, Zhou SN. Electroencephalogram global field synchronization analysis: a new method for assessing the progress of cognitive decline in Alzheimer's disease. Clin EEG Neurosci 2014; 45:98-103. [PMID: 23986293 DOI: 10.1177/1550059413489669] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Alzheimer's disease (AD) is the most common cause of dementia. Global field synchronization (GFS) can measure functional synchronization in frequency-domain electroencephalogram (EEG) data. The aim of this study is to explore GFS values and its clinical significance for severity of cognitive decline in AD. EEGs were recorded from 37 AD patients and 37 age-matched healthy individuals. GFS values were calculated in delta, theta, alpha, beta 1, beta 2, beta 3, gamma, and full frequency bands. The Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating scale (CDR) were employed to assess symptom severity in AD patients. Correlation analysis, clustering analysis, and concordance analysis were performed to analyze the relationship between GFS values and MoCA scores in AD patients. GFS values of the beta 1, beta 2, beta 3, and full bands were lower in AD patients than in healthy individuals, and positively correlated with MoCA and CDR scores in the combined group (AD patients and healthy individuals). GFS values were positively correlated with MoCA socres in 3 beta bands and full bands, and with CDR scores in the delta band. There was a good concordance between K-means clustering algorithm calculating of GFS values and MoCA scoring (κ = .913, P < .001). In conclusion, the present results indicated that GFS can serve as an indicator of cognitive decline or impairment in AD patients. Furthermore, the GFS method of EEG holds considerable promise to distinguish mild cognitive impairment from serious cognitive impairment in patients with AD.
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