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Differential Modulation of 7-Ketocholesterol Toxicity Against PC12 Cells by Calmodulin Antagonists and Ca2+ Channel Blockers

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Abstract

The present study assessed the influence of intracellular Ca2+ and calmodulin against the neurotoxicity of oxysterol 7-ketocholesterol in relation to the mitochondria-mediated cell death process and oxidative stress in PC12 cells. Calmodulin antagonists calmidazolium and W-7 prevented the 7-ketocholesterol-induced mitochondrial damage, leading to caspase-3 activation and cell death, whereas Ca2+ channel blocker nicardipine, mitochondrial Ca2+ uptake inhibitor ruthenium red, and cell permeable Ca2+ chelator BAPTA-AM did not reduce it. Exposure of PC12 cells to 7-ketocholesterol caused elevation of intracellular Ca2+ levels. Unlike cell injury, calmodulin antagonists, nicardipine, and BAPTA-AM prevented the 7-ketocholesterol-induced elevations of intracellular Ca2+ levels. The results show that the cytotoxicity of 7-ketocholesterol seems to be modulated by calmodulin rather than changes in intracellular Ca2+ levels. Calmodulin antagonists may prevent the cytotoxicity of 7-ketocholesterol by suppressing the mitochondrial permeability transition formation, which is associated with the increased formation of reactive oxygen species and the depletion of GSH.

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Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 156-756, South Korea

    Chung Soo Lee & Eun Sook Han

  2. Department of Biochemistry, College of Medicine, Chung-Ang University, Seoul, 156-756, South Korea

    Woo Jae Park

  3. Department of Physiology, College of Medicine, Chung-Ang University, Seoul, 156-756, South Korea

    Hyoweon Bang

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  1. Chung Soo Lee
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  2. Woo Jae Park
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Correspondence to Chung Soo Lee.

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Lee, C.S., Park, W.J., Han, E.S. et al. Differential Modulation of 7-Ketocholesterol Toxicity Against PC12 Cells by Calmodulin Antagonists and Ca2+ Channel Blockers. Neurochem Res 32, 87–98 (2007). https://doi.org/10.1007/s11064-006-9230-8

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