Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism.

Abstract

Many studies have shown that mitochondrial aldehyde dehydrogenase 2 (ALDH2) functions as a cellular protector against oxidative stress by detoxification of cytotoxic aldehydes. Within dopaminergic neurons, dopamine is metabolized by monoamine oxidase to yield 3,4-dihydroxyphenylacetaldehyde (DOPAL) then converts to a less toxic acid product by ALDH. The highly toxic and reactive DOPAL has been hypothesized to contribute to the selective neurodegeneration in Parkinson's disease (PD). In this study, we investigated the neuroprotective mechanism and therapeutic effect of ALDH2 in rotenone models for parkinsonism. Overexpression of wild-type ALDH2 gene, but not the enzymatically deficient mutant ALDH2*2 (E504K), reduced rotenone-induced cell death. Application of a potent activator of ALDH2, Alda-1, was effective in protecting against rotenone-induced apoptotic cell death in both SH-SY5Y cells and primary cultured substantia nigra (SN) dopaminergic neurons. In addition, intraperitoneal administration of Alda-1 significantly reduced rotenone- or MPTP-induced death of SN tyrosine hydroxylase (TH)-positive dopaminergic neurons. The attenuation of rotenone-induced apoptosis by Alda-1 resulted from decreasing ROS accumulation, reversal of mitochondrial membrane potential depolarization, and inhibition of activation of proteins related to mitochondrial apoptotic pathway. The present study demonstrates that ALDH2 plays a crucial role in maintaining normal mitochondrial function to protect against neurotoxicity and that Alda-1 is effective in ameliorating mitochondrial dysfunction and inhibiting mitochondria-mediated apoptotic pathway. These results indicate that ALDH2 activation could be a neuroprotective therapy for PD.

• Authors: Ching-Chi Chiu, Tu-Hsueh Yeh, Szu-Chia Lai, Yah-Huei Wu-Chou, Che-Hong Chen, Daria Mochly-Rosen, Yin-Cheng Huang, Yu-Jie Chen, Chao-Lang Chen, Ya-Ming Chang, Hung-Li Wang, Chin-Song Lu
• Journal: Experimental neurology (Exp Neurol) Vol. 263 Pg. 244-53 (Jan 2015) ISSN: 1090-2430 [Electronic] United States
• PMID: 25263579 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Benzamides
• Benzodioxoles
• N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide
• Reactive Oxygen Species
• Uncoupling Agents
• Rotenone
• Aldehyde Dehydrogenase

Topics

• Aldehyde Dehydrogenase (metabolism)
• Animals
• Benzamides (pharmacology)
• Benzodioxoles (pharmacology)
• Cell Line
• Disease Models, Animal
• Enzyme Activation (physiology)
• Enzyme-Linked Immunosorbent Assay
• Humans
• Immunoblotting
• MPTP Poisoning (enzymology, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Mice, Inbred C57BL
• Microscopy, Confocal
• Neurons (drug effects, enzymology, pathology)
• Parkinsonian Disorders
• Rats
• Reactive Oxygen Species (metabolism)
• Rotenone (toxicity)
• Uncoupling Agents (toxicity)