DANTROLENE IS CYTOPROTECTIVE IN 2 MODELS OF NEURONAL CELL-DEATH

The neuroprotective effects of dantrolene, an inhibitor of calcium rel ease from intracellular stores, were investigated in a model of cell d eath induced by calcium release from endoplasmic reticulum in vitro. T hapsigargin (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 v iability from 94% in control cells to 41% after a 24-h treatment in GT 1-7 hypothalamic neurosecretory cells. Pretreatment with dantrolene fo r 30 min significantly inhibited elevation of cytosolic Ca2+ levels, D NA fragmentation, and GT1-7 cell death induced by thapsigargin in a do se-dependent manner. To determine if dantrolene would also be protecti ve in an in vivo model of neurodegeneration, it was administered intra venously immediately following a 5-min global cerebral ischemia in ger bils, and the number of intact hippocampal CA1 pyramidal neurons was c ounted 7 days later. The effects of dantrolene on brain and rectal tem perature were monitored in a separate experiment. Dantrolene significa ntly increased the number of intact CA1 pyramidal neurons from 40% (un treated 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 chan ges in brain or rectal temperature were detected for 4 h following 50 mg/kg dantrolene, These results suggest that abnormal Ca2+ release fro m intracellular stores can induce neuronal death and that such a mecha nism may contribute to delayed hippocampal neuronal death after cerebr al ischemia. Dantrolene may be a potentially useful drug for neuroprot ection after cerebral ischemia.