Dantrolene is cytoprotective in two models of neuronal cell death.
The neuroprotective effects of dantrolene, an inhibitor of calcium release from intracellular stores, were investigated in a model of cell death induced by calcium release from endoplasmic reticulum in vitro. Thapsigargin (50 nM), a selective inhibitor of endoplasmic reticular Ca(2+)-ATPase, significantly increased the cytosolic Ca2+ concentration to 230% over basal levels, induced DNA fragmentation, and reduced cell viability from 94% in control cells to 41% after a 24-h treatment in GT1-7 hypothalamic neurosecretory cells. Pretreatment with dantrolene for 30 min significantly inhibited elevation of cytosolic Ca2+ levels, DNA fragmentation, and GT1-7 cell death induced by thapsigargin in a dose-dependent manner. To determine if dantrolene would also be protective in an in vivo model of neurodegeneration, it was administered intravenously immediately following a 5-min global cerebral ischemia in gerbils, and the number of intact hippocampal CA1 pyramidal neurons was counted 7 days later. The effects of dantrolene on brain and rectal temperature were monitored in a separate experiment. Dantrolene significantly increased the number of intact CA1 pyramidal neurons from 40% (untreated ischemic animals) to 67 (10 mg/kg), 78 (25 mg/kg), or 83% (50 mg/kg) of values in sham controls (all p < 0.001). No significant changes in brain or rectal temperature were detected for 4 h following 50 mg/kg dantrolene. These results suggest that abnormal Ca2+ release from intracellular stores can induce neuronal death and that such a mechanism may contribute to delayed hippocampal neuronal death after cerebral ischemia. Dantrolene may be a potentially useful drug for neuroprotection after cerebral ischemia.
Wei
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Department of Pharmacology, George Washington University Medical Center, Washington D.C. 20037, USA.
Perry
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D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D003620:Dantrolene / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005849:Gerbillinae; D006624:Hippocampus / Q000098:blood supply / Q000166:cytology; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000166:cytology* / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology
D004791:Enzyme Inhibitors; D009125:Muscle Relaxants, Central; D018696:Neuroprotective Agents; D019284:Thapsigargin; D003620:Dantrolene; D002118:Calcium