Neuroprotective Effects and Mechanisms of Action of Multifunctional Agents Targeting Free Radicals, Monoamine Oxidase B and Cholinesterase in Parkinson's Disease Model.

Abstract

Parkinson's disease (PD) is a complex neurodegenerative disorder with multifactorial pathologies, including progressive loss of dopaminergic (DA) neurons, oxidative stress, mitochondrial dysfunction, and increased monoamine oxidase (MAO) enzyme activity. There are currently only a few agents approved to ameliorate the symptoms of PD; however, no agent is able to reverse the progression of the disease. Due to the multifactorial pathologies, it is necessary to develop multifunctional agents that can affect more than one target involved in the disease pathology. We have designed and synthesized a series of new multifunctional anti-Parkinson's compounds which can protect cerebral granular neurons from 1-methyl-4-phenylpyridinium (MPP+) insult, scavenge free radicals, and inhibit monoamine oxidase (MAO)/cholinesterase (ChE) activities. Among them, MT-20R exhibited the most potent MAO-B inhibition both in vitro and in vivo. We further investigated the neuroprotective effects of MT-20R using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. In vivo, MT-20R alleviated MPTP-induced motor deficits, raised the striatal contents of dopamine and its metabolites, and restored the expression of tyrosine hydroxylase (TH) and the number of TH-positive DA neurons in the substantia nigra. Additionally, MT-20R enhanced the expression of Bcl-2, decreased the expression of Bax and Caspase 3, and activated the AKT/Nrf2/HO-1 signaling pathway. These findings suggest that MT-20R may be a novel therapeutic candidate for treatment of PD.

• Authors: Zheng Liu, Wei Cai, Ming Lang, Ruizuo Yan, Zhenshen Li, Gaoxiao Zhang, Pei Yu, Yuqiang Wang, Yewei Sun, Zaijun Zhang
• Journal: Journal of molecular neuroscience : MN (J Mol Neurosci) Vol. 61 Issue 4 Pg. 498-510 (Apr 2017) ISSN: 1559-1166 [Electronic] United States
• PMID: 28144826 (Publication Type: Journal Article)

Chemical References

• Antiparkinson Agents
• Cholinesterase Inhibitors
• Free Radical Scavengers
• Monoamine Oxidase Inhibitors

Topics

• Animals
• Antiparkinson Agents (chemical synthesis, pharmacology, therapeutic use)
• Apoptosis
• Cells, Cultured
• Cholinesterase Inhibitors (chemical synthesis, pharmacology)
• Cognition
• Dopaminergic Neurons (drug effects, metabolism)
• Free Radical Scavengers (chemical synthesis, pharmacology)
• MPTP Poisoning (drug therapy)
• Monoamine Oxidase Inhibitors (chemical synthesis, pharmacology, therapeutic use)
• Motor Activity
• Rats
• Rats, Sprague-Dawley