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

Edilio Borroni,Anand Rane,Hansruedi Loetscher,Bart Ellenbroek,Subramanian Rajagopalan,Julie K Andersen,Juerg Messer,Shankar J Chinta,Andrea M Cesura,Axel Pähler,Stephane Nave,Almas Siddiqui,Eric Prinssen,Fiona Grueninger,Rene Wyler,Bernd Bohrmann

doi:10.1124/jpet.117.241653

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.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that currently affects 46 million people worldwide and is projected to affect 131.5 million by 2050 (Alzheimer’s Disease International, 2015)
We report on the pharmacological characterization of sembragiline, a novel oral Monoamine oxidase B (MAO-B) inhibitor, which originated from an AD therapeutics program
Sembragiline is a follow-on from lazabemide, a Monoamine oxidase (MAO)-B inhibitor that showed encouraging data but whose development was halted due to the emergence of adverse events

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that currently affects 46 million people worldwide and is projected to affect 131.5 million by 2050 (Alzheimer’s Disease International, 2015). Daily functioning decreases and neuropsychiatric symptoms increase (Alzheimer’s Disease International, 2013). AD is characterized by the accumulation of extracellular senile plaques containing amyloid-b (Ab) peptides and intracellular neurofibrillary tangles, which, together with cerebral atrophy and neuronal cell death, comprise the hallmark features of the disease (Alzheimer’s Disease International, 2013). The AD brain is characterized by the presence of an “inflammatory” response, even at prodromal stages. These responses result in activation of astroglia and microglia cells, which can activate several signaling pathways (Wyss-Coray, 2006; Avila-Munoz and Arias, 2014) to produce inflammatory signals such as cytokines and reactive oxygen species (ROS), leading to oxidative stress (Sofroniew, 2009; Avila-Munoz and Arias, 2014). Markers of oxidative stress are observed early in AD, indicating that ROS may participate in the cascade of events leading to neuronal dysfunction (MerazRios et al, 2013)

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Results

Conclusion