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J Pharmacol Exp Ther. 2017 Sep;362(3):413-423. doi: 10.1124/jpet.117.241653. Epub 2017 Jun 22.

Sembragiline: A Novel, Selective Monoamine Oxidase Type B Inhibitor for the Treatment of Alzheimer's Disease.

Author information

1
Roche Innovation Center Basel, Pharma Research and Early Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland (E.B., B.B., F.G., E.P., S.N., H.L., J.M., A.P., and R.W.); Buck Institute for Research on Aging, Novato, California (S.C., S.R., A.R., A.S., and J.A.); and Evotec International GmbH, Hamburg, Germany (A.M.C. and B.E.) edilio.borroni@roche.com.
2
Roche Innovation Center Basel, Pharma Research and Early Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland (E.B., B.B., F.G., E.P., S.N., H.L., J.M., A.P., and R.W.); Buck Institute for Research on Aging, Novato, California (S.C., S.R., A.R., A.S., and J.A.); and Evotec International GmbH, Hamburg, Germany (A.M.C. and B.E.).

Abstract

Monoamine oxidase B (MAO-B) has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Increased MAO-B expression in astroglia has been observed adjacent to amyloid plaques in AD patient brains. This phenomenon is hypothesized to lead to increased production of hydrogen peroxide and reactive oxygen species (ROS), thereby contributing to AD pathology. Therefore, reduction of ROS-induced oxidative stress via inhibition of MAO-B activity may delay the progression of the disease. In the present study we report the pharmacological properties of sembragiline, a novel selective MAO-B inhibitor specifically developed for the treatment of AD, and on its effect on ROS-mediated neuronal injury and astrogliosis in MAO-B transgenic animals. Sembragiline showed potent and long-lasting MAO-B-selective inhibition and did not inhibit MAO-A at doses where full inhibition of MAO-B was observed. Such selectivity should translate into a favorable clinical safety profile. Indeed, sembragiline neither induced the serotonin syndrome when administered together with the serotonin precursor l-5-hydroxytryptophan in combination with antidepressants such as fluoxetine, nor potentiated the pressor effect of tyramine. Additionally, in experiments using a transgenic animal model conditionally overexpressing MAO-B in astroglia, sembragiline protected against neuronal loss and reduced both ROS formation and reactive astrogliosis. Taken together, these findings warrant further investigation of the potential therapeutic benefit of MAO-B inhibitors in patients with AD and other neurologic disorders.

PMID:
28642233
DOI:
10.1124/jpet.117.241653
[Indexed for MEDLINE]
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