α-lipoic acid exerts neuroprotective effects on neuronal cells by upregulating the expression of PCNA via the P53 pathway in neurodegenerative conditions.
Oxidative stress appears to be a central event responsible for the degeneration of dopaminergic neurons in Parkinson's disease (PD). 1-methyl-4‑phenyl-1,2,3,6-tetrahydropyridine or its toxic metabolite 1‑methyl‑4‑phenylpyridinium (MPP+) are classical widely‑used pharmacological and toxic agents to model PD; they cause the production of reactive oxygen species by inhibiting mitochondrial complex I, leading to DNA oxidative damage and subsequent neuronal death. Previous findings have suggested that proliferating cell nuclear antigen (PCNA), a critical regulatory protein for DNA repair, is involved in dopaminergic neuron damage in the MPP+‑induced PD model. The naturally occurring dithiol compound, α‑lipoic acid (ALA) has been reported to provide neuroprotection in in vitro models of PD. The molecular mechanism by which ALA reduces neuronal death in PD remains to be fully elucidated. The present study aimed to analyze the ability of ALA to protect neuronal PC12 cells from the toxicity induced by MPP+, and the molecular mechanism underlying these actions using MTT and lactate dehydrogenase cytotoxicity assays, Hoechst 33258 staining and western blot analysis. The results demonstrated that ALA efficiently increased the production of PCNA in MPP+‑treated PC12 cells. Accordingly, ALA treatment attenuated MPP+‑induced toxicity in the PC12 cells, and reduced cell apoptosis. The increase in the expression levels of PCNA by ALA in the MPP+‑treated PC12 cells appeared to be mediated by repression of the p53 protein, as the expression of p53 was increased by MPP+‑treatment and reduced by ALA. Taken together, these results indicated that ALA protected dopaminergic neurons against MPP+‑induced neurotoxicity through its ability to upregulate the DNA repair protein, PCNA, via the P53 pathway.
Department of Neurology, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China.
Da-Wei
DW
Li
Department of Urinary Surgery, Tumor Hospital of Jilin, Changchun, Jilin 130021, P.R. China.
Ying-Di
YD
Wang
Department of Clinical Medicine, Jilin University, Changchun, Jilin 130021, P.R. China.
Shi-Yao
SY
Zhou
Department of Neurology, Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China.
Wen-Ping
WP
Sun
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D000818:Animals; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020267:MPTP Poisoning; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D008063:Thioctic Acid / Q000008:administration & dosage*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*
D018696:Neuroprotective Agents; D018809:Proliferating Cell Nuclear Antigen; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D008063:Thioctic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D042967:Electron Transport Complex I