Homotaurine, a safe blood-brain barrier permeable GABA(A)-R-specific agonist, ameliorates disease in mouse models of multiple sclerosis

There is a need for treatments that can safely promote regulatory lymphocyte responses. T cells express GABA receptors (GABA(A)-Rs) and GABA administration can inhibit Th1-mediated processes such as type 1 diabetes and rheumatoid arthritis in mouse models. Whether GABA(A)-R agonists can also inhibit Th17-driven processes such as experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is an open question. GABA does not pass through the blood-brain barrier (BBB) making it ill-suited to inhibit the spreading of autoreactivity within the CNS. Homotaurine is a BBB-permeable amino acid that antagonizes amyloid fibril formation and was found to be safe but ineffective in long-term Alzheimer’s disease clinical trials. Homotaurine also acts as GABA(A)-R agonist with better pharmacokinetics than that of GABA. Working with both monophasic and relapsing-remitting mouse models of EAE, we show that oral administration of homotaurine can (1) enhance CD8(+)CD122(+)PD-1(+) and CD4(+)Foxp3(+) Treg, but not Breg, responses, (2) inhibit autoreactive Th17 and Th1 responses, and (3) effectively ameliorate ongoing disease. These observations demonstrate the potential of BBB-permeable GABA(A)-R agonists as a new class of treatment to enhance CD8(+) and CD4(+) Treg responses and limit Th17 and Th1-medaited inflammation in the CNS.