K6PC-5 Activates SphK1-Nrf2 Signaling to Protect Neuronal Cells from Oxygen Glucose Deprivation/Re-Oxygenation

K6PC-5 Activates SphK1-Nrf2 Signaling to Protect Neuronal Cells from Oxygen Glucose Deprivation/Re-Oxygenation

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Background/Aims: New strategies are required to combat neuronal ischemia-reperfusion injuries.K6PC-5 is a novel kt196 torque converter sphingosine kinase 1 (SphK1) activator whose potential activity in neuronal cells has not yet been tested.Methods: Cell survival and necrosis were assessed with a Cell Counting Kit-8 assay and lactate dehydrogenase release assay, respectively.

Mitochondrial depolarization was tested by a JC-1 dye assay.Expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling components were examined by quantitative real-timePCR and western blotting.Results: K6PC-5 protected SH-SY5Y neuronal cells and primary murine hippocampal neurons from oxygen glucose deprivation/re-oxygenation (OGDR).

K6PC-5 activated SphK1, and SphK1 knockdown by targeted short hairpin RNA (shRNA) almost completely abolished K6PC-5-induced neuronal cell protection.Further work showed that K6PC-5 inhibited OGDR-induced programmed necrosis in neuronal cells.Importantly, K6PC-5 activated Nrf2 signaling, which is downstream of SphK1.

Silencing of hiboost 4k smart link Nrf2 by targeted shRNA almost completely nullified K6PC-5-mediated neuronal cell protection against OGDR.Conclusion: K6PC-5 activates SphK1-Nrf2 signaling to protect neuronal cells from OGDR.K6PC-5 might be a promising neuroprotective strategy for ischemia-reperfusion injuries.