Inhibitory role of diazepam on autoimmune inflammation in rats with experimental autoimmune encephalomyelitis

Abstract Glutamate and GABA are the main excitatory and inhibitory neurotransmitters in the CNS, and both may be involved in the neuronal dysfunction in neurodegenerative conditions. We have recently found that glutamate release was decreased in isolated synaptosomes from the rat cerebral cortex dur...

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Published in:	Neuroscience Vol. 199; pp. 421 - 428
Main Authors:	Bibolini, M.J, Chanaday, N.L, Báez, N.S, Degano, A.L, Monferran, C.G, Roth, G.A
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 29-12-2011 Elsevier
Subjects:	Animal models Animals autoimmunity Autoimmunity - drug effects Autoimmunity - immunology Biological and medical sciences Cerebrospinal fluid. Meninges. Spinal cord diazepam Diazepam - pharmacology Encephalomyelitis, Autoimmune, Experimental - immunology Encephalomyelitis, Autoimmune, Experimental - pathology Fundamental and applied biological sciences. Psychology GABA Agonists - pharmacology GABAergic system Inflammation - immunology Inflammation - pathology Medical sciences multiple sclerosis Nervous system (semeiology, syndromes) Neurology neurotransmitter release Rats Rats, Wistar Synaptic Transmission - drug effects Synaptic Transmission - immunology Synaptosomes - drug effects Synaptosomes - immunology Synaptosomes - pathology Vertebrates: nervous system and sense organs complete Freund's adjuvant MNC stimulation index diazepam concanavalin A phosphate-buffered saline neurotransmitter release mononuclear cells 4-aminopyridine experimental autoimmune encephalomyelitis GABAergic system SI MBP dpi PBS APCs antigen-presenting cells 4AP multiple sclerosis MS Con A EAE days post-induction myelin basic protein delayed-type hypersensitivity autoimmunity DTH CFA Nervous system diseases Encephalomyelitis Rat Rodentia Inflammation Cerebral disorder Vertebrata Mammalia Animal Central nervous system disease Neurotransmitter Spinal cord disease Diazepam Release
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Summary:	Abstract Glutamate and GABA are the main excitatory and inhibitory neurotransmitters in the CNS, and both may be involved in the neuronal dysfunction in neurodegenerative conditions. We have recently found that glutamate release was decreased in isolated synaptosomes from the rat cerebral cortex during the development of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. In contrast to control animals where GABA induced a decrease in the evoked glutamate release, which was abolished by picrotoxin (a GABAA antagonist), synaptosomes from EAE rats showed a loss in the inhibition of the glutamate release mediated by GABA with a concomitant diminution of the flunitrazepam-sensitive GABAA receptor density. We have presently further evaluated the relevance of the GABAergic system in EAE by treating rats challenged for the disease with the GABA agonist diazepam. Administration of diazepam during 6 days starting at day 6 or 11 after EAE active induction led to a marked decrease of the disease incidence and histological signs associated with the disease. Cellular reactivity and antibody responses against the encephalitogenic myelin basic protein were also diminished. Beyond the effects of diazepam on the autoimmune, inflammatory response, we report also a positive effect on neurotransmission. Treatment with diazepam inhibited the previously described reduction in glutamate release in the frontal cortex synaptosomes from EAE animals. These data suggest that an endogenous inhibitory GABAergic system within the immune system is involved in the diazepam effect on EAE and indicate that increasing GABAergic activity potently ameliorates EAE.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0306-4522 1873-7544
DOI:	10.1016/j.neuroscience.2011.08.076