benztropine and Multiple-Sclerosis

Though promoting remyelination in multiple sclerosis (MS) has emerged as a promising therapeutic strategy, it does not address inflammatory signals that continue to induce neuronal damage and inhibit effectiveness of repair mechanisms. Our lab has previously characterized the immunomodulatory tetrapeptide, tuftsin, which induces an anti-inflammatory shift in microglia and macrophages. This targeted anti-inflammatory agent improves physical deficits in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we sought to determine whether tuftsin is also effective in combination with benztropine, an FDA-approved drug that stimulates remyelination, in both EAE and in the cuprizone model of demyelination. We show that combining these two agents to promote anti-inflammatory and remyelinating mechanisms alleviates symptoms in EAE and lessens pathological hallmarks in both MS models. Importantly, tuftsin is required to transform the inflammatory CNS environment normally present in EAE/MS into one of an anti-inflammatory nature, and benztropine is required in the cuprizone model to improve remyelination. Our data further support tuftsin's beneficial immunomodulatory activity in the context of EAE, and show that when studying remyelination in the absence of an autoimmune insult, tuftsin still activated microglia toward an anti-inflammatory fate, but benztropine was necessary for significant repair of the damaged myelin. Overall, tuftsin effectively combined with benztropine to significantly improve MS-like pathologies in both models.

Topics: Animals; Benztropine; Cuprizone; Disease Models, Animal; Drug Therapy, Combination; Encephalomyelitis, Autoimmune, Experimental; Mice; Multiple Sclerosis; Myelin Sheath; Tuftsin

Topics: Animals; Benztropine; Encephalomyelitis, Autoimmune, Experimental; Female; High-Throughput Screening Assays; Models, Biological; Multiple Sclerosis; Muscarinic Antagonists; Myelin Sheath; Nerve Fibers, Myelinated; Oligodendroglia; Regeneration

Topics: Animals; Benztropine; Encephalomyelitis, Autoimmune, Experimental; Female; Models, Biological; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; Regeneration

Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug 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. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches.

Topics: Animals; Antiparkinson Agents; Benztropine; Cell Differentiation; Coculture Techniques; Cuprizone; Encephalomyelitis, Autoimmune, Experimental; Female; Fingolimod Hydrochloride; Immune System; Mice; Mice, Inbred C57BL; Models, Biological; Multiple Sclerosis; Myelin Proteolipid Protein; Myelin Sheath; Oligodendroglia; Optic Nerve; Propylene Glycols; Rats; Receptor, Muscarinic M1; Receptor, Muscarinic M3; Recurrence; Regeneration; Sphingosine; Stem Cells

Topics: Animals; Benztropine; Encephalomyelitis, Autoimmune, Experimental; Female; Models, Biological; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; Regeneration

Topics: Animals; Benztropine; Encephalomyelitis, Autoimmune, Experimental; Female; Models, Biological; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; Regeneration