المؤلفون: Corey Fee, Daniel E. Knutson, Keith A. Misquitta, James M. Cook, Guanguan Li, Mounira Banasr, Etienne Sibille, Prithu Mondal, Thomas D. Prevot

المصدر: International Journal of Neuropsychopharmacology

مصطلحات موضوعية: endocrine system, AcademicSubjects/MED00415, Gabra5, GABA Agents, GABRA5, Genetic Vectors, Behavioral Symptoms, Regular Research Articles, gamma-Aminobutyric acid, 03 medical and health sciences, GABA, Mice, 0302 clinical medicine, Interneurons, parasitic diseases, medicine, Animals, Pharmacology (medical), GABAergic Neurons, Receptor, 030304 developmental biology, Pharmacology, 0303 health sciences, antidepressant, biology, Behavior, Animal, GABAA receptor, AcademicSubjects/SCI01870, fungi, Long-term potentiation, medicine.disease, Receptors, GABA-A, Mice, Inbred C57BL, Psychiatry and Mental health, Disease Models, Animal, medicine.anatomical_structure, Mood disorders, Genetic Techniques, depression, biology.protein, Antidepressant, Neuron, Somatostatin, Neuroscience, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, medicine.drug

الوصف: Introduction Deficits in somatostatin-positive gamma-aminobutyric acid interneurons (SST+ GABA cells) are commonly reported in human studies of mood and anxiety disorder patients. A causal link between SST+ cell dysfunction and symptom-related behaviors has been proposed based on rodent studies showing that chronic stress, a major risk factor for mood and anxiety disorders, induces a low SST+ GABA cellular phenotype across corticolimbic brain regions; that lowering Sst, SST+ cell, or GABA functions induces depressive-/anxiety-like behaviors (a rodent behavioral construct collectively defined as “behavioral emotionality”); and that disinhibiting SST+ cells has antidepressant-like effects. Recent studies found that compounds preferentially potentiating receptors mediating SST+ cell functions, α5-GABAA receptor positive allosteric modulators (α5-PAMs), achieved antidepressant-like effects. Together, the evidence suggests that SST+ cells regulate mood and cognitive functions that are disrupted in mood disorders and that rescuing SST+ cell function via α5-PAM may represent a targeted therapeutic strategy. Methods We developed a mouse model allowing chemogenetic manipulation of brain-wide SST+ cells and employed behavioral characterization 30 minutes after repeated acute silencing to identify contributions to symptom-related behaviors. We then assessed whether an α5-PAM, GL-II-73, could rescue behavioral deficits. Results Brain-wide SST+ cell silencing induced features of stress-related illnesses, including elevated neuronal activity and plasma corticosterone levels, increased anxiety- and anhedonia-like behaviors, and impaired short-term memory. GL-II-73 led to antidepressant- and anxiolytic-like improvements among behavioral deficits induced by brain-wide SST+ cell silencing. Conclusion Our data validate SST+ cells as regulators of mood and cognitive functions and demonstrate that bypassing low SST+ cell function via α5-PAM represents a targeted therapeutic strategy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7b39e914e4e66b48e6c06e8ec35da05fTest
http://europepmc.org/articles/PMC8278801Test

المؤلفون: Marcel A. Kopp, Orpheus Mach, Jacquelyn J. Cragg, Benedikt Mach, Catherine R. Jutzeler, John L.K. Kramer, Lukas Grassner, Freda M. Warner, Doris Maier, Jan M. Schwab

المصدر: Neurology

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, GABA Agents, Severity of Illness Index, Article, Longitudinal model, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Outcome Assessment, Health Care, Humans, Medicine, Longitudinal Studies, Spinal cord injury, Spinal Cord Injuries, business.industry, Recovery of Function, Middle Aged, Spinal cord, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, chemistry, Anesthesia, Cohort, Acute spinal cord injury, Anticonvulsants, Female, Observational study, Motor recovery, Neurology (clinical), business, 030217 neurology & neurosurgery, Gabapentinoid

الوصف: ObjectiveTo explore the hypothesis that earlier administration of acute gabapentinoids is beneficial to motor recovery after spinal cord injury in humans.MethodsThis is an observational study using a cohort from the European Multi-Centre Study about Spinal Cord Injury. Patient charts were reviewed to extract information regarding the administration and timing of gabapentinoid anticonvulsants. The primary outcome measure was motor scores, as measured by the International Standards for Neurological Classification of Spinal Cord Injury, collected longitudinally in the first year after injury. Sensory scores (light touch and pinprick) and functional measures (Spinal Cord Independence Measure) were secondary outcomes. Linear mixed effects regression models included a drug-by-time interaction to determine whether exposure to gabapentinoids altered recovery of muscle strength in the first year after injury.ResultsA total of 201 participants were included in the study and had a median age of 46 and baseline motor score of 50. Participants were mostly men (85%) with sensory and motor complete injuries (50%). Seventy individuals (35%) were administered gabapentinoids within the first 30 days after injury, and presented with similar demographics. In the longitudinal model, the administration of gabapentinoids within 30 days after injury was associated with improved motor recovery when compared to those who did not receive gabapentinoids during this time (3.69 additional motor points from 4 to 48 weeks after injury; p = 0.03). This effect size increased as administration occurred earlier after injury (i.e., a benefit of 4.68 points when administered within 5 days).ConclusionsThis retrospective, observational study provided evidence of the beneficial effect of gabapentinoid anticonvulsants on motor recovery after spinal cord injury. More critically, it highlighted a potential time dependence, suggesting that earlier intervention is associated with better outcomes.Classification of evidence:This study provides Class IV evidence that gabapentinoids improve motor recovery for individuals with acute spinal cord injury.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0eb25fd84214fb72683fd64c4e32456bTest
https://doi.org/10.1212/wnl.0000000000010950Test

المؤلفون: Daniele Ferrante, Cosimo Prestigio, Antonella Marte, Franco Onofri, Pietro Baldelli, Alessandra Romei, Fabio Benfenati, Gabriele Lignani, Pierluigi Valente

المصدر: eLife, Vol 10 (2021)
eLife

مصطلحات موضوعية: Mouse, Postsynaptic Current, Tropomyosin receptor kinase B, Hippocampal formation, Hippocampus, REST/NRSF, Homeostatic plasticity, NRSF, Transcriptional regulation, Homeostasis, Premovement neuronal activity, synaptic homeostasis, Biology (General), Cells, Cultured, Neurons, REST, General Neuroscience, GABAergic synapses, General Medicine, BDNF, neural hyperactivity, homeostatic plasticity, NPAS4, medicine.anatomical_structure, Excitatory postsynaptic potential, Medicine, Research Article, GABA Agents, QH301-705.5, Science, Green Fluorescent Proteins, Biology, Inhibitory postsynaptic potential, General Biochemistry, Genetics and Molecular Biology, Glutamatergic, medicine, Animals, Receptor, trkB, General Immunology and Microbiology, Mice, Inbred C57BL, Repressor Proteins, Inhibitory Postsynaptic Potentials, Synapses, Neuron, Neuroscience, Transcription Factors

الوصف: The repressor-element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) controls hundreds of neuron specific genes. We showed that REST/NRSF downregulates glutamatergic transmission in response to hyperactivity, thus contributing to neuronal homeostasis. However, whether GABAergic transmission is also implicated in the homeostatic action of REST/NRSF is unknown. Here, we show that hyperactivity-induced REST/NRSF activation triggers a homeostatic enhancement of GABAergic inhibition, with increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and amplitude of evoked IPSCs. Notably, this effect was only observed at inhibitory-onto-excitatory neuron synapses, whose density increased at perisomatic sites, demonstrating a strict target-selectivity. These effects were occluded by TrkB receptor inhibition and resulted from a coordinated and sequential activation of the Npas4 and BDNF gene programs. The findings highlight the central role of REST/NRSF in the complex transcriptional responses aimed at preserving physiological levels of neuronal activity in front of the ever-changing environment.Impact StatementThis work elucidates the mechanisms by which the transcriptional regulator REST/NRSF selectively upregulates GABAergic transmission onto excitatory neurons in response to hyperactivity to rescue neuronal homeostasis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::96904b2bae7f412da40fe628ff8703eeTest
https://doi.org/10.7554/elife.69058Test

المؤلفون: Mikako Sato, Takumi Komaru, Noriyuki Yanaka, Thanutchaporn Kumrungsee, Yasuyuki Oishi, Ai S. Egusa, Takeshi Arima, Kanako Sato

المصدر: Amino Acids. 52:743-753

مصطلحات موضوعية: Male, 0301 basic medicine, medicine.medical_specialty, GABA Agents, Clinical Biochemistry, Anserine, Carnosine, Peptide, Endogeny, Biochemistry, Vigabatrin, Mice, 03 medical and health sciences, GABA transaminase, chemistry.chemical_compound, Internal medicine, medicine, Animals, Muscle, Skeletal, gamma-Aminobutyric Acid, chemistry.chemical_classification, Mice, Inbred ICR, Dipeptide, 030102 biochemistry & molecular biology, Organic Chemistry, Imidazoles, Skeletal muscle, Feeding Behavior, Diet, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, nervous system, chemistry, beta-Alanine, medicine.drug

الوصف: Carnosine (β-alanyl-l-histidine) is an imidazole dipeptide present at high concentrations in skeletal muscles, where it plays a beneficial role. However, oral intake of carnosine or β-alanine to increase skeletal muscle carnosine levels has disadvantages such as low efficiency and side effects. Therefore, we proposed homocarnosine (γ-aminobutyryl-l-histidine) as a novel alternative imidazole peptide for skeletal muscle based on its structural similarity to carnosine. To induce endogenous homocarnosine synthesis in skeletal muscles, mice were fed a basal diet mixed with 0, 0.5, 2, or 5% γ-aminobutyric acid (GABA) for 6 weeks. As expected, in the control group (0% GABA), GABA and homocarnosine were present in trace concentrations. Skeletal muscle homocarnosine levels were significantly increased in the 2% and 5% GABA intake groups (tenfold, P

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e94eca6193ae95e068afdb2d366f3f35Test
https://doi.org/10.1007/s00726-020-02848-xTest

المؤلفون: Qinjin Dai, Jing Xu, Shengping Hou, Suyin Mei, Zongren Xu, Aize Kijlstra, Yike Huang, Juan Wu, Na Li, Peizeng Yang

المساهمون: RS: MHeNs - R3 - Neuroscience, MUMC+: MA Oogheelkunde (9)

المصدر: Current Molecular Medicine, 20(8), 624-632. Bentham Science Publishers Ltd.

مصطلحات موضوعية: GABA Agents, medicine.medical_treatment, Experimental autoimmune uveitis, Intraperitoneal injection, Blood–retinal barrier, T-Lymphocytes, Regulatory, Biochemistry, Autoimmune Diseases, Flow cytometry, Uveitis, T-CELL-ACTIVATION, Mice, chemistry.chemical_compound, medicine, Animals, TRANSCRIPTION, TH17, Eye Proteins, Molecular Biology, Evans Blue, Th17 cell, medicine.diagnostic_test, Chemistry, Th1 cell, Experimental autoimmune encephalomyelitis, NF-kappa B, Aminooxyacetic Acid, FOXP3, aminooxy-acetic acid (AOA), T-Lymphocytes, Helper-Inducer, General Medicine, medicine.disease, Treg cell, Mice, Inbred C57BL, Retinol-Binding Proteins, STAT1 Transcription Factor, Cytokine, medicine.anatomical_structure, DIFFERENTIATION, Immunology, Molecular Medicine, Female, T-Lymphocytes, Cytotoxic

الوصف: Purpose: A small molecular compound, aminooxy-acetic acid (AOA), has been shown to modulate experimental autoimmune encephalomyelitis (EAE). The current study was designed to investigate whether AOA has a similar effect on the development of experimental autoimmune uveitis (EAU) and to further explore underlying mechanisms of this drug. Methods: EAU was induced in C57BL/6J mice by immunization with interphotoreceptor retinoid-binding protein peptide 651-670 (IRBP 651-670). AOA (500μg or 750μg) or vehicle was administered by intraperitoneal injection from day 10 to 14 after EAU induction. The severity was assessed by clinical and histological scores. The integrity of the blood retinal barrier was detected with Evans Blue. Frequencies of splenic Th1, Th17 and Foxp3+ Treg cells were examined by flow cytometry. The production of cytokines was tested by ELISA. The mRNA expression of IL-17, IFN-γ and IL-10 was detected by RT-PCR. The expression of p-Stat1 and NF-κB was detected by Western Blotting. Results: AOA was found to markedly inhibit the severity of EAU, as determined by clinical and histopathological examinations. AOA can relieve the leakage of blood retinal barrier (BRB). Functional studies found a decreased frequency of Th1 and Th17 cells and an increased frequency of Treg cells in EAU mice as compared with controls. Further studies showed that AOA not only downregulated the production of the proinflammatory cytokines including IFN-γ and IL-17 but also upregulated the expression of an anti-inflammatory cytokine such as IL-10, which might be caused by inhibiting the expressions of p-Stat1 and NF-κB. Conclusion: This study shows that AOA inhibits the severity and development of EAU by modulating the balance between regulatory and pathogenic lymphocyte subsets.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::33aab601a8c3b10e8fc242c4f885c777Test
https://doi.org/10.2174/1566524020666200211112219Test

المؤلفون: Melissa J. Green, Suresh Sundram, Matthew R. Hudson, Xin Du, Michael Notaras, Anna Schroeder, Vaidy Swaminathan, Rachel Anne Hill, Jay P. Nakamura, Murray J. Cairns, Brendan Gillespie, Nigel C. Jones, Joshua R. Atkins, Vaughan J. Carr, William R. Reay

المصدر: Brain, Behavior, and Immunity. 81:161-171

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Interneuron, GABA Agents, Immunology, Prefrontal Cortex, Hippocampus, medicine.disease_cause, Mice, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Interneurons, Pregnancy, medicine, Animals, Gamma Rhythm, Humans, Missense mutation, Theta Rhythm, gamma-Aminobutyric Acid, Prepulse inhibition, Homeodomain Proteins, Neurons, Mutation, biology, Endocrine and Autonomic Systems, Brain, Middle Aged, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, Parvalbumins, Poly I-C, 030104 developmental biology, medicine.anatomical_structure, Schizophrenia, Forebrain, biology.protein, Female, Immunity, Maternally-Acquired, Neuroscience, 030217 neurology & neurosurgery, Parvalbumin, Transcription Factors

الوصف: A hallmark feature of schizophrenia is altered high frequency neural oscillations, including reduced auditory-evoked gamma oscillatory power, which is underpinned by parvalbumin (PV) interneuron dysfunction. Maternal immune activation (MIA) in rodents models an environmental risk factor for schizophrenia and recapitulates these PV interneuron changes. This study sought to link reduced PV expression in the MIA model with alterations to auditory-evoked gamma oscillations and transcript expression. We further aligned transcriptional findings from the animal model with human genome sequencing data. We show that MIA, induced by the viral mimetic, poly-I:C in C57Bl/6 mice, caused in adult offspring reduced auditory-evoked gamma and theta oscillatory power paralleled by reduced PV protein levels. We then showed the Arx gene, critical to healthy neurodevelopment of PV interneurons, is reduced in the forebrain of MIA exposed mice. Finally, in a whole-genome sequenced patient cohort, we identified a novel missense mutation of ARX in a patient with schizophrenia and in the Psychiatric Genomics Consortium 2 cohort, a nominal association of proximal ARX SNPs with the disorder. This suggests MIA, as a risk factor for schizophrenia, may be influencing Arx expression to induce the GABAergic dysfunction seen in schizophrenia and that the ARX gene may play a role in the prenatal origins of schizophrenia pathophysiology.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cc3206b6a3f883cd9b3e48fa6f6cd4e2Test
https://doi.org/10.1016/j.bbi.2019.06.009Test

المؤلفون: Anna Hoerder-Suabedissen, Yasushi Nakagawa, Andre Marques-Smith, Filippo Ghezzi, Zoltán Molnár, Alexandra Rowett, Simon J. B. Butt, Daniel Lyngholm, Gokul Parameswaran, Paul G. Anastasiades, Cristiana Vagnoni

المصدر: eLife, Vol 10 (2021)
Ghezzi, F, Marques-Smith, A, Anastasiades, P G, Lyngholm, D, Vagnoni, C, Rowett, A, Parameswaran, G, Hoerder-Suabedissen, A, Nakagawa, Y, Molnar, Z & Butt, S J B 2021, ' Non-canonical role for Lpar1-EGFP subplate neurons in early postnatal mouse somatosensory cortex ', eLife, vol. 10, e60810 . https://doi.org/10.7554/eLife.60810Test
eLife

مصطلحات موضوعية: 0301 basic medicine, Mouse, Somatosensory system, neural development, Mice, 0302 clinical medicine, Thalamus, Cortex (anatomy), Subplate, neocortex, Receptors, Lysophosphatidic Acid, Biology (General), neural circuits, Neurons, education.field_of_study, Neocortex, General Neuroscience, General Medicine, medicine.anatomical_structure, Medicine, Neural development, Research Article, GABA Agents, QH301-705.5, Science, Population, Green Fluorescent Proteins, Optogenetics, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Biological neural network, Animals, education, optogenetics, General Immunology and Microbiology, Somatosensory Cortex, Axons, Electric Stimulation, laser scanning photostimulation, 030104 developmental biology, Animals, Newborn, Vibrissae, subplate, Neuroscience, 030217 neurology & neurosurgery

الوصف: Subplate neurons (SPNs) are thought to play a role in nascent sensory processing in neocortex. To better understand how heterogeneity within this population relates to emergent function, we investigated the synaptic connectivity of Lpar1-EGFP SPNs through the first postnatal week in whisker somatosensory cortex (S1BF). These SPNs comprise of two morphological subtypes: fusiform SPNs with local axons and pyramidal SPNs with axons that extend through the marginal zone. The former receive translaminar synaptic input up until the emergence of the whisker barrels, a timepoint coincident with significant cell death. In contrast, pyramidal SPNs receive local input from the subplate at early ages but then – during the later time window – acquire input from overlying cortex. Combined electrical and optogenetic activation of thalamic afferents identified that Lpar1-EGFP SPNs receive sparse thalamic innervation. These data reveal components of the postnatal network that interpret sparse thalamic input to direct the emergent columnar structure of S1BF.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f9154a5386b8c29ca242c6975d50eab5Test
https://elifesciences.org/articles/60810Test

المؤلفون: Clara Ballerini, Elena Bonechi, Giulia Panattoni, Alessandra Aldinucci, Laura Ballerini, Vincenzo Giacco, Manuela Medelin

المصدر: Journal of Neuroinflammation, Vol 16, Iss 1, Pp 1-14 (2019)
Journal of Neuroinflammation

مصطلحات موضوعية: Lipopolysaccharides, 0301 basic medicine, Synaptic Transmission, Settore BIO/09 - Fisiologia, lcsh:RC346-429, Synapse, Mice, 0302 clinical medicine, Neuroinflammation, NKCC1, Spinal circuits, Organotypic spinal slices, General Neuroscience, GABAergic inhibition, GABAergic receptors, 3. Good health, medicine.anatomical_structure, Spinal Cord, Neurology, Excitatory postsynaptic potential, Cytokines, Neuroglia, GABAergic, Synaptopathy, medicine.symptom, Synaptic currents, GABAergic inhibition, GABAergic receptors, Patch-clamp, Resident neuroglia, GABA Agents, Immunology, Central nervous system, Inflammation, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Organ Culture Techniques, medicine, Animals, lcsh:Neurology. Diseases of the nervous system, Spinal circuits, Resident neuroglia, Research, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Neuroscience, 030217 neurology & neurosurgery

الوصف: Background Synaptic dysfunction, named synaptopathy, due to inflammatory status of the central nervous system (CNS) is a recognized factor potentially underlying both motor and cognitive dysfunctions in neurodegenerative diseases. To gain knowledge on the mechanistic interplay between local inflammation and synapse changes, we compared two diverse inflammatory paradigms, a cytokine cocktail (CKs; IL-1β, TNF-α, and GM-CSF) and LPS, and their ability to tune GABAergic current duration in spinal cord cultured circuits. Methods We exploit spinal organotypic cultures, single-cell electrophysiology, immunocytochemistry, and confocal microscopy to explore synaptic currents and resident neuroglia reactivity upon CK or LPS incubation. Results Local inflammation in slice cultures induced by CK or LPS stimulations boosts network activity; however, only CKs specifically reduced GABAergic current duration. We pharmacologically investigated the contribution of GABAAR α-subunits and suggested that a switch of GABAAR α1-subunit might have induced faster GABAAR decay time, weakening the inhibitory transmission. Conclusions Lower GABAergic current duration could contribute to providing an aberrant excitatory transmission critical for pre-motor circuit tasks and represent a specific feature of a CK cocktail able to mimic an inflammatory reaction that spreads in the CNS. Our results describe a selective mechanism that could be triggered during specific inflammatory stress. Electronic supplementary material The online version of this article (10.1186/s12974-019-1519-z) contains supplementary material, which is available to authorized users.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7543ea2bad1f60ef88dadc1af4dc4584Test
http://link.springer.com/article/10.1186/s12974-019-1519-zTest

المؤلفون: Zuhal Keskin Yildirim, Aydemir Kale, Nese Lortlar Ünlü, Necdet Çeviker, Emre Durdag

المصدر: World Neurosurgery. 120:e33-e41

مصطلحات موضوعية: Male, genetic structures, GABA Agents, Ischemia, Nitric Oxide, Neuroprotection, Vigabatrin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Malondialdehyde, medicine, Animals, Spinal cord injury, Spinal Cord Ischemia, business.industry, medicine.disease, Spinal cord, Constriction, Glutathione, Oxidative Stress, Neuroprotective Agents, medicine.anatomical_structure, Advanced Oxidation Protein Products, Spinal Cord, chemistry, Reperfusion Injury, 030220 oncology & carcinogenesis, Anesthesia, Surgery, Rabbits, Neurology (clinical), business, Reperfusion injury, 030217 neurology & neurosurgery, medicine.drug, Abdominal surgery

الوصف: Objective Spinal cord ischemia is a serious and catastrophic clinicopathologic condition. Despite studies reported over the last 20 years, alternative and efficient treatment options remain unclear. We examined the neuroprotective effects of vigabatrin on a spinal ischemia-reperfusion model. Methods We divided 24 New Zealand rabbits into 4 groups (control, ischemia reperfusion, and low-dose and high-dose vigabatrin). The control group underwent only abdominal surgery, whereas an abdominal aortic cross-clamp model of spinal ischemia was performed in the other groups. Clips were removed after 30 minutes and 50 and 150 mg/kg vigabatrin was administered intraperitoneally to the low-dose and high-dose groups, respectively. Neurologic examination was performed for 48 hours, after which the rabbits were sacrificed and a blood sample obtained. Biochemical examination of malondialdehyde, advanced oxidation protein products, total nitric oxide, and glutathione levels and superoxide dismutase activities in plasma and tissue sample, and histopathologic examination of the spinal cord were performed and statistical results compared between the groups. Results Low-dose vigabatrin had statistically significant effects of neuroprotection on spinal ischemia. Although high-dose vigabatrin had similar effects, the results were not statistically significant for all parameters of biochemical analysis. In addition, histopathologic examination showed some toxic effects of high-dose vigabatrin. Conclusions Neuroprotective effects of vigabatrin are shown. For clinical use, further studies are needed.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::adfcfb59216ac4ca25903d7f7cc5fcd7Test
https://doi.org/10.1016/j.wneu.2018.07.103Test

المؤلفون: Amy W. Lasek, Chang You, Mark S. Brodie, Subhash C. Pandey, Huaibo Zhang, Bertha J. Vandegrift

المصدر: Alcoholism, Clinical and Experimental Research

مصطلحات موضوعية: Male, 0301 basic medicine, GABA Agents, medicine.drug_class, Dopamine, Histone Deacetylase 2, Medicine (miscellaneous), Craving, Pharmacology, Neurotransmission, Toxicology, Aminobutyric acid, Histones, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Animals, gamma-Aminobutyric Acid, Neurons, Vorinostat, Ethanol, Chemistry, GABAA receptor, Histone deacetylase 2, Ventral Tegmental Area, Histone deacetylase inhibitor, SAHA, Epigenetic, Receptors, GABA-A, Diet, Rats, Substance Withdrawal Syndrome, 3. Good health, Histone Deacetylase Inhibitors, Ventral tegmental area, Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, nervous system, Original Article, medicine.symptom, VTA, 030217 neurology & neurosurgery, Neuroscience, medicine.drug

الوصف: Background The ventral tegmental area (VTA) is important for alcohol-related reward and reinforcement. Mouse VTA neurons are hyposensitive to γ-aminobutyric acid (GABA) during ethanol (EtOH) withdrawal, and GABA responsiveness is normalized by in vitro treatment with histone deacetylase inhibitors (HDACi). The present study examined the effect of a systemically administered HDACi, suberanilohydroxamic acid (SAHA) on GABA sensitivity, and related molecular changes in VTA neurons during withdrawal after chronic EtOH intake in rats. Methods Sprague Dawley male adult rats were fed with Lieber-DeCarli diet (9% EtOH or control diet) for 16 days. Experimental groups included control diet-fed and EtOH diet-fed (0- or 24-hour withdrawal) rats treated with either SAHA or vehicle injection. Single-unit recordings were used to measure the response of VTA neurons to GABA. Immunohistochemistry was performed to examine levels of HDAC2, acetylated histone H3 lysine 9 (acH3K9), and GABAA receptor α1 and α5 subunits in the VTA; quantitative polymerase chain reaction was performed to examine the mRNA levels of HDAC2 and GABAA receptor subunits. Results VTA neurons from the withdrawal group exhibited GABA hyposensitivity. In vivo SAHA treatment 2 hours before sacrifice normalized the sensitivity of VTA neurons to GABA. EtOH withdrawal was associated with increased HDAC2 and decreased acH3K9 protein levels; SAHA treatment normalized acH3K9 levels. Interestingly, no significant change was observed in the mRNA levels of HDAC2. The mRNA levels, but not protein levels, of GABAA receptor α1 and α5 subunits were increased during withdrawal. Conclusions Withdrawal from chronic EtOH exposure results in a decrease in GABA-mediated inhibition, and this GABA hyposensitivity is normalized by in vivo SAHA treatment. Disruption of signaling in the VTA produced by alteration of GABA neurotransmission could be 1 neuroadaptive physiological process leading to craving and relapse. These results suggest that HDACi pharmacotherapy with agents like SAHA might be an effective treatment for alcoholism.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::66833036a6a220556bffe1126bee39a6Test
https://doi.org/10.1111/acer.13870Test