Systemic treatment with the inhibitory neurotransmitter gamma-aminobutyric acid aggravates experimental autoimmune encephalomyelitis by affecting proinflammatory immune responses

被引:27
作者
Carmans, Sofie [1 ]
Hendriks, Jerome J. A. [1 ]
Slaets, Helena [1 ]
Thewissen, Kristof [1 ]
Stinissen, Piet [1 ]
Rigo, Jean-Michel [1 ]
Hellings, Niels [1 ]
机构
[1] Hasselt Univ, Biomed Res Inst, B-3590 Diepenbeek, Belgium
关键词
Multiple sclerosis; Experimental autoimmune encephalomyelitis; Gamma amino-butyric acid; Vigabatrin; macrophage; T cell; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; NECROSIS-FACTOR-ALPHA; MULTIPLE-SCLEROSIS; CEREBROSPINAL-FLUID; TYROSINE PHOSPHORYLATION; INTERLEUKIN-6; PRODUCTION; PERITONEAL-MACROPHAGES; NEUROLOGIC DISEASE; NEURONAL DAMAGE;
D O I
10.1016/j.jneuroim.2012.11.001
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Transcriptomic and proteomic analyses of multiple sclerosis (MS) lesions indicate alterations in the gamma-aminobutyric acid (GABA) inhibitory system, suggesting its involvement in the disease process. To further elucidate the role of GABA in central nervous system (CNS) inflammation in vivo, the chronic myelin oligodendrocyte glycoprotein (MOG)(35-55) experimental autoimmune encephalomyelitis (EAE) model was used. Daily GABA injections (200 mg/kg) from day 3 onwards significantly augmented disease severity, which was associated with increased CNS mRNA expression levels of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6. GABA-treated mice showed enhanced MUG-dependent proliferation and were skewed towards a T helper 1 phenotype. Moreover, in vitro, the lipopolysaccharide (LPS)-induced increase in interleukin (IL)-6 production by macrophages was enhanced at low GABA concentrations (0.03-0.3 mM). In sharp contrast to exogenous GABA administration, endogenous GABA increment by systemic treatment with the GABA-transaminase inhibitor vigabatrin (250 mg/kg) had prophylactic as well as therapeutic potential in EAE. Together, these results indicate an immune amplifying role of GABA in neuroinflammatory diseases like MS. (C) 2012 Elsevier B.V. All rights reserved.
引用
收藏
页码:45 / 53
页数:9
相关论文
共 69 条
[1]   CEREBROSPINAL-FLUID GAMMA-AMINOBUTYRIC ACID IN NEUROLOGIC DISEASE [J].
ACHAR, VS ;
WELCH, KMA ;
CHABI, E ;
BARTOSH, K ;
MEYER, JS .
NEUROLOGY, 1976, 26 (08) :777-780
[2]   Human peripheral blood mononuclear cells express GABAA receptor subunits [J].
Alam, S ;
Laughton, DL ;
Walding, A ;
Wolstenholme, AJ .
MOLECULAR IMMUNOLOGY, 2006, 43 (09) :1432-1442
[3]   LEVELS OF GAMMA-AMINOBUTYRIC ACID IN CEREBROSPINAL-FLUID IN VARIOUS NEUROLOGIC DISORDERS [J].
BALAMANYAM, NV ;
KATZ, L ;
HARE, TA ;
GERBER, JC ;
GROSSMAN, MH .
ARCHIVES OF NEUROLOGY, 1980, 37 (06) :352-355
[4]   Inhibitory role for GABA in autoimmune inflammation [J].
Bhat, Roopa ;
Axtell, Robert ;
Mitra, Ananya ;
Miranda, Melissa ;
Lock, Christopher ;
Tsien, Richard W. ;
Steinman, Lawrence .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (06) :2580-2585
[5]   INHIBITORY ROLE OF DIAZEPAM ON AUTOIMMUNE INFLAMMATION IN RATS WITH EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS [J].
Bibolini, M. J. ;
Chanaday, N. L. ;
Baez, N. S. ;
Degano, A. L. ;
Monferran, C. G. ;
Roth, G. A. .
NEUROSCIENCE, 2011, 199 :421-428
[6]   GABA, a natural immunomodulator of T lymphocytes [J].
Bjurstrom, Helen ;
Wang, JunYang ;
Ericsson, Ida ;
Bengtsson, Martin ;
Liu, Yawei ;
Kurnar-Mendu, Suresh ;
Issazadeh-Navikas, Shohreh ;
Birnir, Bryndis .
JOURNAL OF NEUROIMMUNOLOGY, 2008, 205 (1-2) :44-50
[7]   NEUROLOGIC DISEASE INDUCED IN TRANSGENIC MICE BY CEREBRAL OVEREXPRESSION OF INTERLEUKIN-6 [J].
CAMPBELL, IL ;
ABRAHAM, CR ;
MASLIAH, E ;
KEMPER, P ;
INGLIS, JD ;
OLDSTONE, MBA ;
MUCKE, L .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (21) :10061-10065
[8]   Coactivation of GABAA and GABAB receptor results in neuroprotection during in vitro ischemia [J].
Costa, C ;
Leone, G ;
Saulle, E ;
Pisani, F ;
Bernardi, G ;
Calabresi, P .
STROKE, 2004, 35 (02) :596-600
[9]  
COX GW, 1992, J IMMUNOL, V149, P3290
[10]  
Demakova E. V., 2003, Klinicheskaya Laboratornaya Diagnostika, P15