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PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats

Journal of Pharmaceutical Analysis 2023年第2期13卷 187-200页

作者： Ya Zhao Yanwei Wang Yuying Wu Cimin Tao Rui Xu Yong Chen Linghui Qian Tengfei Xu Xiaoyuan Lian College of Pharmaceutical Sciences Zhejiang UniversityHangzhou310058China

Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease(PD).However,the mechanisms underlying this association remain *** the present study,we found that high glucose(HG)levels in the cerebrospinal fluid(CSF)of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine(6-OHDA)on the development of motor disorders,and the damage to the nigrostriatal dopaminergic neuronal *** vitro,HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor(NGF)(NGF-PC12).Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle(TCA cycle)activity,which was closely related to abnormal mitochondrial fusion,thus resulting in mitochondrial ***,HG-induced upregulation of pyruvate kinase M2(PKM2)combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 *** addition,we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HGþ***,we found that shikonin(SK),an inhibitor of PKM2,restored the mitochondrial number,promoted TCA cycle activity,reversed hyperglycolysis,enhanced the tolerance of cultured neurons to 6-OHDA,and reduced the risk of PD in diabetic ***,our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upregulation of PKM2,leading to an increase in the vulnerability of dopaminergic neurons to ***,the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.

关键词： Type 1 diabetes mellitus hyperglycolysis Mitochondrial fusion PKM2 Neuronal vulnerability Parkinson's disease

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Nicotinamide adenine dinucleotide phosphate oxidase activation and neuronal death after ischemic stroke

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Neural Regeneration Research 2019年第6期14卷 948-953页

作者： Jiamei Shen Radhika Rastogi Xiaokun Geng Yuchuan Ding China-America Institute of Neuroscience Beijing Luhe HospitalCapital Medical University Department of Neurosurgery Wayne State University School of Medicine Department of Neurology Beijing Luhe HospitalCapital Medical University

Nicotinamide adenine dinucleotide phosphate oxidase(NOX) is a multisubunit enzyme complex that utilizes nicotinamide adenine dinucleotide phosphate to produce superoxide anions and other reactive oxygen species. Under normal circumstances, reactive oxygen species mediate a number of important cellular functions, including the facilitation of adaptive immunity. In pathogenic circumstances, however,excess reactive oxygen species generated by NOX promotes apoptotic cell death. In ischemic stroke, in particular, it has been shown that both NOX activation and derangements in glucose metabolism result in increased apoptosis. Moreover, recent studies have established that glucose, as a NOX substrate, plays a vital role in the pathogenesis of reperfusion injury. Thus, NOX inhibition has the potential to mitigate the deleterious impact of hyperglycemia on stroke. In this paper, we provide an overview of this research,coupled with a discussion of its implications for the development of NOX inhibition as a strategy for the treatment of ischemic stroke. Both inhibition using apocynin, as well as the prospect of developing more specific inhibitors based on what is now understood of the biology of NOX assembly and activation, will be highlighted in the course of our discussion.

关键词： nicotinamide adenine dinucleotide phosphate oxidase stroke nicotinamide adenine dinucleotide phosphate oxidase inhibitors reactive oxygen species ischemia/reperfusion neuroprotection hyperglycolysis NADPH NOX

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