Abstract
The objectives of the study were to explore the mechanism of rotenone-induced cell damage and to examine the protective effects of water-soluble Coenzyme Q10 (CoQ10) on the toxic effects of rotenone. Murine hippocampal HT22 cells were cultured with mitochondrial complex I inhibitor rotenone. Water-soluble CoQ10 was added to the culture media 3 h prior to the rotenone incubation. Cell viability was determined by alamar blue, reactive oxygen species (ROS) production by dihydroethidine (DHE) and mitochondrial membrane potential by tetramethyl rhodamine methyl ester (TMRM). Cytochrome c, caspase-9 and apoptosis-inducing factor (AIF) were measured using Western blotting after 24 h rotenone incubation. Rotenone caused more than 50% of cell death, increased ROS production, AIF nuclear translocation and reduction in mitochondrial membrane potential, but failed to cause mitochondrial cytochrome c release and caspase-9 activation. Pretreatment with water-soluble CoQ10 enhanced cell viability, decreased ROS production, maintained mitochondrial membrane potential and prevented AIF nuclear translocation. The results suggest that rotenone activates a mitochondria-initiated, caspase-independent cell death pathway. Water-soluble CoQ10 reduces ROS accumulation, prevents the fall of mitochondrial membrane potential, and inhibits AIF translocation and subsequent cell death.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disease in the aging population
To define the adequate dosage of rotenone for inducing a targeted ~50% cell death, HT22 cells were incubated with four different concentrations (0.25, 0.5, 1.0, 2.0 μM) of rotenone for 24 h
We have revealed that rotenone induces neuronal death in a dose-dependent manner and water-soluble Coenzyme Q10 (CoQ10) exerts a potent protection against rotenone-induced cell death
Summary
Parkinson’s disease (PD) is a common neurodegenerative disease in the aging population. PD is characterized by the selective death of dopaminergic neurons in the substantia nigra leading to low levels of dopamine in the striatum [1]. Oxidative damage and mitochondrial dysfunction have been proposed to play a major role in the pathogenesis of PD [2]. A widely used pesticide, has been used for many years as a tool to induce PD model in vitro and in vivo [3,4,5] and proven to be reproducible. Its neurotoxicity may be related to the ability of generating reactive oxygen species (ROS) and disrupting mitochondrial oxidative phosphorylation. Elevated ROS levels cause depolarization of the mitochondrial membrane and release of pro-apoptotic factors such as apoptosis inducing factor (AIF), which eventually causes neuronal death [6]
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