title: Systemic treatment with the inhibitory neurotransmitter γ-aminobutyric acid aggravates experimental autoimmune encephalomyelitis by affecting proinflammatory immune responses.
abstract: 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 (200mg/kg) from day 3 onwards significantly augmented disease severity, which was associated with increased CNS mRNA expression levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6. GABA-treated mice showed enhanced MOG-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 (0.03-0.3mM). In sharp contrast to exogenous GABA administration, endogenous GABA increment by systemic treatment with the GABA-transaminase inhibitor vigabatrin (250mg/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.
authors.affiliation: Hasselt University, Biomedical Research Institute, Agoralaan Building C, B-3590 Diepenbeek, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Carmans
authors.forename: Jerome J A
authors.initials: JJ
authors.lastname: Hendriks
authors.forename: Helena
authors.initials: H
authors.lastname: Slaets
authors.forename: Kristof
authors.initials: K
authors.lastname: Thewissen
authors.forename: Piet
authors.initials: P
authors.lastname: Stinissen
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rigo
authors.forename: Niels
authors.initials: N
authors.lastname: Hellings
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D005260:Female; D018682:GABA Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D009433:Neural Inhibition / Q000187:drug effects* / Q000276:immunology*; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000276:immunology; D012720:Severity of Illness Index; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage* / Q000502:physiology / Q000627:therapeutic use
chemical_list: D018682:GABA Agents; D005680:gamma-Aminobutyric Acid