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Homotaurine, a safe blood-brain barrier permeable GABAA-R-specific agonist, ameliorates disease in mouse models of multiple sclerosis
- Source :
- Scientific reports, vol 8, iss 1, Scientific Reports, Scientific Reports, Vol 8, Iss 1, Pp 1-8 (2018)
- Publication Year :
- 2018
- Publisher :
- eScholarship, University of California, 2018.
-
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.
- Subjects :
- 0301 basic medicine
Taurine
T-Lymphocytes
lcsh:Medicine
Administration, Oral
Pharmacology
Neurodegenerative
Inbred C57BL
T-Lymphocytes, Regulatory
chemistry.chemical_compound
Mice
2.1 Biological and endogenous factors
Aetiology
lcsh:Science
Multidisciplinary
GABAA receptor
Experimental autoimmune encephalomyelitis
FOXP3
Regulatory
3. Good health
medicine.anatomical_structure
Homotaurine
Blood-Brain Barrier
Administration
Neurological
medicine.symptom
Agonist
Oral
Multiple Sclerosis
medicine.drug_class
Inflammation
Blood–brain barrier
Autoimmune Disease
Article
03 medical and health sciences
medicine
Animals
GABA Agonists
business.industry
Animal
Multiple sclerosis
Inflammatory and immune system
lcsh:R
Neurosciences
Th1 Cells
medicine.disease
Brain Disorders
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
chemistry
nervous system
Disease Models
Th17 Cells
lcsh:Q
business
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Scientific reports, vol 8, iss 1, Scientific Reports, Scientific Reports, Vol 8, Iss 1, Pp 1-8 (2018)
- Accession number :
- edsair.doi.dedup.....dd7233a1ec690be437b803c0c0d18f90