Raloxifene acutely reduces glutamate-induced intracellular calcium increase in cultured rat cortical neurons via inhibition of high-voltage-activated calcium current

Abstract

There is increasing evidence indicating that estrogen replacement therapy produces neuroprotective actions but has undesirable side effects on the reproductive system. Raloxifene is a selective estrogen receptor modulator that exerts estrogen agonist action in the brain while acting as an estrogen antagonist in the reproductive system. In the present study, we investigated whether raloxifene affected the glutamate-induced calcium (Ca 2+) overload in rat cultured cortical neurons. The bulk cytosolic intracellular Ca 2+ level was measured by using confocal microscopy with fluorescent Ca 2+ probe fluo3. Whole-cell recording technique was used to observe the effects of raloxifene on N-methyl- d-aspartate (NMDA)-evoked and voltage-activated Ca 2+ currents in cultured cortical neurons. Pre-exposure of cortical neurons to raloxifene (0.5 μM–10 μM) for 3 min attenuated intracellular Ca 2+ increase induced by application of glutamate (300 μM) for 1 min. The action of raloxifene was reversible after washout. ICI 182,780 and thapsigargin did not block the action of raloxifene. In whole-cell recording experiments, raloxifene (10 μM) significantly reduced the amplitude of the high-voltage-activated Ca 2+ current but had no effect on NMDA-evoked Ca 2+ current. The present study demonstrates that raloxifene acutely reduces glutamate-induced intracellular Ca 2+ increase probably via inhibition of high-voltage-activated calcium channels.