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GSK-3? Inhibitor Alsterpaullone Attenuates MPP+-Induced Cell Damage in a c-Myc-Dependent Manner in SH-SY5Y Cells.

ABSTRACT: Mitochondrial dysfunction plays significant roles in the pathogenesis of Parkinson's Disease (PD). The inactivation of c-Myc, a down-stream gene of Wnt/?-catenin signaling, may contribute to the mitochondria dysfunction. Inhibition of glycogen synthase kinase 3? (GSK-3?) with Alsterpaullone (Als) can activate the down-stream events of Wnt signaling. Here, we investigated the protective roles of Als against MPP+-induced cell apoptosis in SH-SY5Y cells. The data showed that Als effectively rescued c-Myc from the MPP+-induced decline via Wnt signaling. Furthermore, Als protected SH-SY5Y cells from the MPP+-induced mitochondrial fission and cell apoptosis. However, the protective roles of Als were lost under ?-catenin-deficient conditions. These findings indicate that Als, a GSK-3? inhibitor, attenuated the MPP+-induced mitochondria-dependent apoptotic via up-regulation of the Wnt signaling.

SUBMITTER: Wang J

PROVIDER: S-EPMC6127625 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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GSK-3β Inhibitor Alsterpaullone Attenuates MPP<sup>+</sup>-Induced Cell Damage in a c-Myc-Dependent Manner in SH-SY5Y Cells.

Wang Jiancai J Li Yuqian Y Gao Li L Yan Fengqi F Gao Guodong G Li Lihong L

Frontiers in cellular neuroscience 20180830

Mitochondrial dysfunction plays significant roles in the pathogenesis of Parkinson's Disease (PD). The inactivation of c-Myc, a down-stream gene of Wnt/β-catenin signaling, may contribute to the mitochondria dysfunction. Inhibition of glycogen synthase kinase 3β (GSK-3β) with Alsterpaullone (Als) can activate the down-stream events of Wnt signaling. Here, we investigated the protective roles of Als against MPP<sup>+</sup>-induced cell apoptosis in SH-SY5Y cells. The data showed that Als effectiv ...[more]

PMID: 30233322

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Project description:Complex pathophysiology of Parkinson's disease involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in Parkinson's disease and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. To unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes, respectively, and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP(+) and rotenone. SNJ-1945, a cell-permeable calpain inhibitor was tested for its neuroprotective efficacy. MPP(+) and rotenone dose-dependently elevated the levels of intracellular free Ca(2+) and induced a concomitant rise in the levels of active calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP(+) and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators cyclooxygenase-2 (Cox-2 and cleaved p10 fragment of caspase-1) were up-regulated in the cholinergic phenotype, which could be dose-dependently attenuated by the calpain inhibitor. Overall, SNJ-1945 was efficacious against MPP(+) or rotenone-induced reactive oxygen species generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with calpain inhibitor administration 1-3 h after exposure to MPP(+) or rotenone. Taken together, these results indicate that calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious calpain inhibitor in this context. SH-SY5Y cells, differentiated as dopaminergic (TH positive) and cholinergic (ChAT positive), were used as in vitro models for Parkinson's disease. MPP+ and rotenone induced up-regulation of calpain, expression, and activity as a common mechanism of neurodegeneration. SNJ-1945, a novel calpain inhibitor, protected both the cell phenotypes against MPP+ and rotenone.

Project description:Phosphodiesterase 4 (PDE4) is a promising target for the treatment of Parkinson's disease (PD). However, the underlying mechanism has not yet been well elucidated. Additionally, most of current PDE4 inhibitors produce severe nausea and vomiting response in patients, which limit their clinical application. FCPR16 is a novel PDE4 inhibitor with little emetic potential. In the present study, the neuroprotective effect and underlying mechanism of FCPR16 against cellular apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+) were examined in SH-SY5Y cells. FCPR16 (12.5-50??M) dose-dependently reduced MPP+-induced loss of cell viability, accompanied by reductions in nuclear condensation and lactate dehydrogenase release. The level of cleaved caspase 3 and the ratio of Bax/Bcl-2 were also decreased after treatment with FCPR16 in MPP+-treated cells. Furthermore, FCPR16 (25??M) significantly suppressed the accumulation of reactive oxygen species (ROS), prevented the decline of mitochondrial membrane potential (??m) and attenuated the expression of malonaldehyde level. Further studies disclosed that FCPR16 enhanced the levels of cAMP and the exchange protein directly activated by cAMP (Epac) in SH-SY5Y cells. Western blotting analysis revealed that FCPR16 increased the phosphorylation of cAMP response element-binding protein (CREB) and protein kinase B (Akt) down-regulated by MPP+ in SH-SY5Y cells. Moreover, the inhibitory effects of FCPR16 on the production of ROS and ??m loss could be blocked by PKA inhibitor H-89 and Akt inhibitor KRX-0401. Collectively, these results suggest that FCPR16 attenuates MPP+-induced dopaminergic degeneration via lowering ROS and preventing the loss of ??m in SH-SY5Y cells. Mechanistically, cAMP/PKA/CREB and Epac/Akt signaling pathways are involved in these processes. Our findings indicate that FCPR16 is a promising pre-clinical candidate for the treatment of PD and possibly other oxidative stress-related neuronal diseases.

Dataset Information

GSK-3? Inhibitor Alsterpaullone Attenuates MPP+-Induced Cell Damage in a c-Myc-Dependent Manner in SH-SY5Y Cells.

Publications

GSK-3β Inhibitor Alsterpaullone Attenuates MPP<sup>+</sup>-Induced Cell Damage in a c-Myc-Dependent Manner in SH-SY5Y Cells.

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