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

Jide Tian,Richard Olsen,Daniel L Kaufman,Hoa Dang,Martin Wallner

doi:10.1038/s41598-018-32733-3

Jide Tian, Richard Olsen + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-32733-3

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Abstract

There is a need for treatments that can safely promote regulatory lymphocyte responses. T cells express GABA receptors (GABAA-Rs) and GABA administration can inhibit Th1-mediated processes such as type 1 diabetes and rheumatoid arthritis in mouse models. Whether GABAA-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 GABAA-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 GABAA-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.

Highlights

This is especially true for T-cell mediated autoimmune disorders such as type 1 diabetes (T1D), rheumatoid arthritis (RA), and multiple sclerosis (MS) in which inhibiting established autoimmune responses against the target tissue may require life-time treatment
While delayed type hypersensitivity (DTH), T1D, and RA are mediated by peripheral autoimmune T cell responses, disease relapses in EAE and MS are thought be due to the spreading of T cell autoreactivity within the CNS17–19
After finding homotaurine was effective in two different murine EAE models, we studied the treatment’s potential therapeutic mechanisms and observed, for the first time, that in addition to promoting CD4+Foxp3+ Treg responses, GABAA-R activation enhances CD8+CD122+PD-1+ Treg responses and inhibits the frequency of PLP139–151-reactive IL-17A (Th17) responses

Summary

Introduction

After finding homotaurine was effective in two different murine EAE models, we studied the treatment’s potential therapeutic mechanisms and observed, for the first time, that in addition to promoting CD4+Foxp3+ Treg responses, GABAA-R activation enhances CD8+CD122+PD-1+ Treg responses and inhibits Th17 responses. We tested homotaurine treatment in a relapsing-remitting model of EAE that was induced by immunizing SJL mice with a proteolipid protein peptide (PLP139–151)[36].

Results

Conclusion