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Differential modulation of 7-ketocholesterol toxicity against PC12 cells by calmodulin antagonists and Ca2+ channel

Chung Soo Lee1, Woo Jae Park, Eun Sook Han

  • 1Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea. leecs@cau.ac.kr

Neurochemical Research
|December 8, 2006
PubMed

Insights

Calmodulin, not intracellular calcium, influences neurotoxicity from 7-ketocholesterol in PC12 cells. Calmodulin antagonists protect against cell death by inhibiting mitochondrial damage and reactive oxygen species.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Oxysterols, like 7-ketocholesterol, are implicated in neurodegenerative diseases.
  • Mitochondrial dysfunction and oxidative stress are key mechanisms in neurotoxicity.
  • The roles of intracellular calcium and calmodulin in oxysterol-induced neurotoxicity are not fully understood.

Purpose of the Study:

  • To investigate the influence of intracellular calcium (Ca2+) and calmodulin on 7-ketocholesterol-induced neurotoxicity in PC12 cells.
  • To elucidate the mechanisms underlying 7-ketocholesterol neurotoxicity, focusing on mitochondria-mediated cell death and oxidative stress.

Main Methods:

  • PC12 cells were exposed to 7-ketocholesterol.
  • The effects of calmodulin antagonists (calmidazolium, W-7), Ca2+ channel blocker (nicardipine), mitochondrial Ca2+ uptake inhibitor (ruthenium red), and Ca2+ chelator (BAPTA-AM) were assessed.
  • Intracellular Ca2+ levels, mitochondrial damage, caspase-3 activation, reactive oxygen species (ROS) formation, and glutathione (GSH) levels were measured.

Main Results:

  • Calmodulin antagonists prevented 7-ketocholesterol-induced mitochondrial damage, caspase-3 activation, and cell death.
  • Nicardipine, ruthenium red, and BAPTA-AM did not significantly reduce 7-ketocholesterol-induced cell injury.
  • 7-ketocholesterol exposure elevated intracellular Ca2+ levels, an effect inhibited by calmodulin antagonists, nicardipine, and BAPTA-AM.
  • Calmodulin antagonists suppressed mitochondrial permeability transition, ROS formation, and GSH depletion.

Conclusions:

  • The neurotoxicity of 7-ketocholesterol in PC12 cells is modulated by calmodulin, rather than solely by changes in intracellular Ca2+ levels.
  • Calmodulin antagonists offer a protective effect against 7-ketocholesterol neurotoxicity by mitigating mitochondrial dysfunction and oxidative stress.
  • Targeting calmodulin may represent a therapeutic strategy for conditions involving 7-ketocholesterol-induced neurotoxicity.

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