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Hypoxia/Reoxygenation Stimulates Proliferation Through PKC-Dependent Activation of ERK and Akt in Mouse Neural Progenitor Cells

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Abstract

Cerebral ischemia increases neural progenitor cell proliferation and neurogenesis. However, the precise molecular mechanism is poorly understood. The present study was undertaken to determine roles of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt and their signaling pathways in neural progenitor cells exposed to hypoxia/reoxygenation (H/R), an in vitro model of ischemia/reperfusion. Neural progenitor cells were isolated from postnatal mouse brain. ERK and Akt were transiently activated during the early phase of reoxygenation following 4-h of hypoxia. The ERK activation was inhibited by U0126, a specific inhibitor of MEK, but not by LY294002, a specific inhibitor of PI3K, whereas the Akt activation was blocked by LY294002, but not by U0126. Reoxygenation following 4-h hypoxia stimulated cell proliferation, which was dependent on ERK and Akt activation. Inhibitors of growth factor receptor (AG1478) and Src (PP2) and the antioxidant N-acetylcysteine did not affect activation of ERK and Akt, while the Ras and Raf inhibitors inhibited activation of ERK, but not Akt. PKC inhibitors inhibited both ERK and Akt activation. Taken together, these results suggest that H/R induces activation of MEK/ERK and PI3K/Akt survival signaling pathways through a PKC-dependent mechanism. These pathways may be responsible for the repair process during ischemia/reperfusion.

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Acknowledgment

This study was supported by the MRC program of MOST/KOSEF (R13-2005-009) and the 21st Century Frontier/Stem Cell Research Committee (SC3130) in South Korea.

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Authors and Affiliations

  1. Department of Neurology, College of Medicine, Pusan National University, Pusan, 602-739, South Korea

    Sang Min Sung & Dae Soo Jung

  2. Department of Physiology, College of Medicine, Pusan National University, Pusan, 602-739, South Korea

    Chae Hwa Kwon, Ji Yeon Park, Soo Kyung Kang & Yong Keun Kim

  3. MRC for Ischemic Tissue Regeneration, College of Medicine, Pusan National University, Pusan, 602-739, South Korea

    Yong Keun Kim

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  1. Sang Min Sung
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Correspondence to Yong Keun Kim.

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Sung, S.M., Jung, D.S., Kwon, C.H. et al. Hypoxia/Reoxygenation Stimulates Proliferation Through PKC-Dependent Activation of ERK and Akt in Mouse Neural Progenitor Cells. Neurochem Res 32, 1932–1939 (2007). https://doi.org/10.1007/s11064-007-9390-1

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