Progressive phases of multiple sclerosis are associated with inhibited differentiation of progenitor cells that generate the mature oligodendrocytes required for remyelination and disease remission. In this paper, Deshmukh and colleagues identified benztropine, a drug already used for treatment of Parkinson’s disease, as having significant clinical potential for treatment of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and associated experiments indicated that the observed efficacy of benzotropine results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. Since benztropine and other anti-muscarinics have significant dose-dependent neurological and psychiatric side-effects, these studies should facilitate the search for new drug variants that maintain benzotropine’s myelin-repairing activity and its ability to cross the blood-brain-barrier for the treatment of multiple sclerosis yet minimize its other undesirable properties.
Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ, Padmanabhan K, Swoboda JG, Ahmad I, Kondo T, Gage FH, Theofilopoulos AN, Lawson BR, Schultz PG, Lairson LL: A regenerative approach to the treatment of multiple sclerosis. Nature [Epub ahead of print, October 9, 2013; doi: 10.1038/nature12647].