A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson’s disease

Wei Liu,Yuqiang Wang,Moussa B H Youdim

doi:10.20517/and.2021.09

Abstract

The current novel therapeutic approach suggests that multi-targeted compounds, with diverse biological activities but a single set of bioavailability and pharmacokinetics, will be significantly more advantageous in the treatment of the complex pathology of Parkinson’s diseases (PD) than traditional therapies. This review introduces a novel cholinesterase (ChE)-monoamine oxidase (MAO) inhibitor, namely MT-031, which was designed by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor and neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the methylamino position of the ChE inhibitor anti-AD drug, rivastigmine. MT-031 possesses neuroprotective, cognition enhancing, anti-depressant, and anti-inflammatory properties both in vitro and in vivo. Altogether, these findings suggest that MT-031 may be a potential treatment for combating PD and associated dementia and depression.

Highlights

With aging and the increasing life span of the population, Parkinson’s disease (PD), an age-related neurodegenerative disorder, is receiving increased attention
Since dementia in both Alzheimer’s disease (AD) and PD patients generally presents with similar features, present treatments for Parkinson’s disease dementia (PDD) are mostly derived from drugs utilized in AD, such as cholinesterase inhibitors (ChEIs) and memantine, which was initially developed for the treatment of AD
MT-031 exerted a significant inhibitory effect on ChE in the hippocampus and frontal cortex of mice[54]. This is an advantageous property of MT-031, as previous data show that, when ChE inhibitors are less effective in the hippocampus, other brain regions may produce insufficient amounts of ACh to displace scopolamine from receptors, which results in dysfunctional mediation of working memory[100]

Summary

Introduction

With aging and the increasing life span of the population, Parkinson’s disease (PD), an age-related neurodegenerative disorder, is receiving increased attention. The underlying principle in the design of ladostigil was to join the carbamate ChE inhibitory moiety of the anti-AD drug, rivastigmine, to the irreversible selective MAO-B inhibitor, rasagiline[24]. Rasagiline (Azilect®) is an anti-Parkinsonian MAO-B inhibitor drug, which presented neuroprotective and neurorescue activities in animal models and neuronal cell models of neurodegeneration[30] and exerted disease-modifying effects in PD patients[30,31,32].

Results

Conclusion