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

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Updated: Feb 1, 2026

Oxygen-Glucose Deprivation and Reoxygenation as an In Vitro Ischemia-Reperfusion Injury Model for Studying Blood-Brain Barrier Dysfunction
08:56

Oxygen-Glucose Deprivation and Reoxygenation as an In Vitro Ischemia-Reperfusion Injury Model for Studying Blood-Brain Barrier Dysfunction

Published on: May 7, 2015

18.8K

Hua Liu1, Zhiqing Zhang2, Min Xu3

  • 1Department of Neurosurgery, The First People's Hospital of Kunshan, Jiangsu University, Suzhou, China.

Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology
|December 4, 2018
PubMed
Abstract

Insights

K6PC-5, a novel sphingosine kinase 1 activator, protects neuronal cells from oxygen glucose deprivation/re-oxygenation injury. This neuroprotection is mediated by the sphingosine kinase 1-nuclear factor erythroid 2-related factor 2 signaling pathway.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Neuronal ischemia-reperfusion injuries necessitate novel therapeutic strategies.
  • The sphingosine kinase 1 (SphK1) activator K6PC-5's neuroprotective potential remains unexplored.

Purpose of the Study:

  • To investigate the efficacy of K6PC-5 in protecting neuronal cells against ischemia-reperfusion injury.
  • To elucidate the underlying molecular mechanisms, specifically the involvement of SphK1 and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling.

Main Methods:

  • Cell viability and necrosis assays (Cell Counting Kit-8, lactate dehydrogenase release).
  • Mitochondrial membrane potential assessment (JC-1 dye).
  • Quantitative real-time PCR and Western blotting for Nrf2 pathway components.

Main Results:

  • K6PC-5 demonstrated significant neuroprotection in SH-SY5Y cells and primary neurons against oxygen glucose deprivation/re-oxygenation (OGDR).
  • K6PC-5 activated SphK1, and SphK1 inhibition abrogated its protective effects.
  • K6PC-5 inhibited OGDR-induced programmed necrosis and activated the downstream SphK1-Nrf2 signaling pathway.
  • Nrf2 inhibition abolished K6PC-5-mediated neuroprotection.

Conclusions:

  • K6PC-5 confers neuroprotection against OGDR by activating the SphK1-Nrf2 signaling cascade.
  • K6PC-5 represents a potential therapeutic candidate for mitigating neuronal damage in ischemia-reperfusion injuries.
Keywords:
K6PC-5NeuronNrf2Oxidative stressSphK1

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