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1 Drug restores cells that are missing in MS patients on Sat Nov 30, 2013 12:26 am


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An oligodendrocyte and the myelin it produces.

UC Denver

Multiple sclerosis (MS) is an autoimmune disease in which the immune system destroys the myelin sheaths surrounding neurons. These myelin sheaths are often likened to the insulation surrounding electrical wires; they enable neurons to transmit electrical impulses specifically and efficiently.
Cells called oligodendrocytes make myelin and do so throughout adulthood. People with MS have plenty of oligodendrocyte precursor cells (OPCs), and these cells are able to migrate to sites where myelination is required. The problem is that these precursor cells fail to mature properly into myelin producing cells, and this failure promotes disease progression.
Many current approved therapies for MS are immunosuppressants, but researchers at The Scripps Research Institute tried another tack. They screened 100,000 (or so) structurally diverse molecules to try to find some that would induce OPCs to mature. The researchers identified compounds that could make rodent OPCs mature into oligodendrocytes in a dish.
A thyroid hormone can do this, but it “has several physiological effects that make it unattractive as a therapeutic agent for MS.” Other compounds that work “have limited therapeutic potential due to off-target activities, toxicity, poor brain exposure, and/or demonstrated lack of in vivo efficacy.” But these compounds provided valuable positive controls in the experiment, showing that it was possible to pick out these useful compounds.
One of the most effective inducers of OPC maturation they found is a drug called benztropine, which is already available in oral form as an approved treatment for Parkinson’s disease. Once the researchers homed in on benztropine, they confirmed that the oligodendrocytes it had coaxed into maturity could in fact make myelin when in a dish with neurons. The team then analyzed benztropine’s activity in a mouse model of MS, finding that it diminished the clinical severity of the acute and remission phases of the disease while pretty much eliminating the relapse phase. In this model system, benztropine worked at least as well as the immunosuppressive drugs now in use to treat MS.
Benztropine isn't ideal. Its use is “associated with dose-dependent adverse neurological side effects”—cognitive changes, blurred vision, anorexia, and psychosis. So the authors decided to see if it could be used at a lower dose when combined with other therapies.
Fingolimod is an immunosuppressant that has reduced the relapse rate in relapsing-remitting multiple sclerosis by over half. But its use can lead to a dose-dependent bradycardia—it slows the heart rate. So in the researchers' mouse model, a combination of suboptimal doses of this with benztropine yielded a decrease in clinical severity. The combination of drugs was as good in terms of results as the standard therapeutic dose of Fingolimod.
Since the side effects are dose dependent, reducing the dose of each drug without sacrificing efficacy is a big deal. The authors hope that remyelination enhancers like benztropine might one day become good clinical options to treat MS, and they are now examining other hits from their initial screen to find some more.]

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