Distinct mechanisms of neurodegeneration induced by chronic complex I inhibition in dopaminergic and non-dopaminergic cells.
ABSTRACT Chronic mitochondrial dysfunction, in particular of complex I, has been strongly implicated in the dopaminergic neurodegeneration in Parkinson's disease. To elucidate the mechanisms of chronic complex I disruption-induced neurodegeneration, we induced differentiation of immortalized midbrain dopaminergic (MN9D) and non-dopaminergic (MN9X) neuronal cells, to maintain them in culture without significant cell proliferation and compared their survivals following chronic exposure to nanomolar rotenone, an irreversible complex I inhibitor. Rotenone killed more dopaminergic MN9D cells than non-dopaminergic MN9X cells. Oxidative stress played an important role in rotenone-induced neurodegeneration of MN9X cells, but not MN9D cells: rotenone oxidatively modified proteins more in MN9X cells than in MN9D cells and antioxidants decreased rotenone toxicity only in MN9X cells. MN9X cells were also more sensitive to exogenous oxidants than MN9D cells. In contrast, disruption of bioenergetics played a more important role in MN9D cells: rotenone decreased mitochondrial membrane protential and ATP levels in MN9D cells more than in MN9X cells. Supplementation of cellular energy with a ketone body, D-beta-hydroxybutyrate, decreased rotenone toxicity in MN9D cells, but not in MN9X cells. MN9D cells were also more susceptible to disruption of oxidative phosphorylation or glycolysis than MN9X cells. These findings indicate that, during chronic rotenone exposure, MN9D cells die primarily through mitochondrial energy disruption, whereas MN9X cells die primarily via oxidative stress. Thus, intrinsic properties of individual cell types play important roles in determining the predominant mechanism of complex I inhibition-induced neurodegeneration.
- SourceAvailable from: Ahmed Abdel Moneim[Show abstract] [Hide abstract]
ABSTRACT: The principal goal of the current work was to investigate the protective effect of Ginkgo biloba extract and pumpkin seed oil in separate against rotenone induced neurotoxicity in male rats. Adult male albino rats were orally treated with Ginkgo biloba extract (EGb) at a dose of 150 mg/kg body weight or with pumpkin seed oil (PSO) at a dose of 40 mg/kg body weight once a day for 70 days and on the 21st day, rotenone (2.5 mg/kg body weight) was given orally for 50 days. Dopamine "DA" and norepinephrine "NE" contents in striatum, cerebellum and cerebral cortex were determined on 40, 55 and 70 days of treatment. Also, the striatum Na /K -ATPase activity, serum and striatum l + + ipid peroxidation, nitric oxide (NO), reduced glutathione (GSH), total antioxidant capacity (TAC), and serum testosterone level were evaluated with histological investigation of striatum. Results revealed that rotenone administration for 50 days produced significant increase in striatum and serum lipid peroxidation and NO levels, while, significant decrease in DA in striatum and cerebral cortex was detected. Also, striatum Na+/K+-ATPase activity, serum and striatum GSH, TAC levels and serum testosterone level were significantly decreased as a result of rotenone administration. On the other hand, the administration of EGb or PSO resulted in marked improvement in the all studied parameters. Noteworthy, EGb produced more pronounced protective effect against rotenone-induced neurotoxicity than PSO. In conclusion, the present study provided clear evidence that EGb possesses a promising activity against rotenone-induced neurodegeneration. Thus, it may be useful against neurotoxicity induced by environmental neurotoxins. Our study also suggested the possibility of PSO usefulness in limiting toxicant-induced oxidative stress.Journal of Applied Sciences Research 01/2009; 5(6):622-635.
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ABSTRACT: In the present study, using a human neuroblastoma SK-N-SH cells, we explored antioxidant, mitochondrial protective and antiapoptotic properties of mangiferin against rotenone-mediated cytotoxicity. SK-N-SH cells are divided into four experimental groups based on 3-(4,5-dimethyl2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay-untreated cells, cells incubated with rotenone (100 nM), cells treated with mangiferin (20 μg) (pretreatment 4 h before) + rotenone (100 nM) and mangiferin alone treated. 24 h after treatment with rotenone and 28 h after treatment with mangiferin, levels of ATP thiobarbituricacid reactive substances and reduced glutathione and activities of enzymatic antioxidants including superoxide dismutase, catalase and glutathione peroxidise were measured. Finally mitochondrial transmembrane potential and expressions of apoptotic protein were also analysed. Pre-treatment with mangiferin significantly enhanced cell viability, ameliorated decrease in mitochondrial membrane potential and decreased rotenone-induced apoptosis in the cellular model of Parkinson's disease. Moreover oxidative imbalance induced by rotenone was partially rectified by mangiferin. Our results indicated that anti-apoptotic properties of this natural compound due to its antioxidant and mitochondrial protective function protect rotenone induced cytotoxicity.Neurochemical Research 02/2014; · 2.55 Impact Factor
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ABSTRACT: Parkinson's disease (PD) has multiple proposed etiologies with implication of abnormalities in cellular homeostasis ranging from proteostasis to mitochondrial dynamics to energy metabolism. PINK1 mutations are associated with familial PD and here we discover a novel PINK1 mechanism in cellular stress response. Using hypoxia as a physiological trigger of oxidative stress and disruption in energy metabolism, we demonstrate that PINK1(-/-) mouse cells exhibited significantly reduced induction of HIF-1α protein, HIF-1α transcriptional activity, and hypoxia-responsive gene upregulation. Loss of PINK1 impairs both hypoxia-induced 4E-BP1 dephosphorylation and increase in the ratio of internal ribosomal entry site (IRES)-dependent to cap-dependent translation. These data suggest that PINK1 mediates adaptive responses by activating IRES-dependent translation, and the impairments in translation and the HIF-1α pathway may contribute to PINK1-associated PD pathogenesis that manifests under cellular stress.Journal of Neuroscience 02/2014; 34(8):3079-3089. · 6.75 Impact Factor