Raloxifene acutely reduces glutamate-induced intracellular calcium increase in cultured rat cortical neurons via inhibition of high-voltage-activated calcium current.
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 (Ca2+) overload in rat cultured cortical neurons. The bulk cytosolic intracellular Ca2+ level was measured by using confocal microscopy with fluorescent Ca2+ probe fluo3. Whole-cell recording technique was used to observe the effects of raloxifene on N-methyl-D-aspartate (NMDA)-evoked and voltage-activated Ca2+ currents in cultured cortical neurons. Pre-exposure of cortical neurons to raloxifene (0.5 microM-10 microM) for 3 min attenuated intracellular Ca2+ increase induced by application of glutamate (300 microM) 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 microM) significantly reduced the amplitude of the high-voltage-activated Ca2+ current but had no effect on NMDA-evoked Ca2+ current. The present study demonstrates that raloxifene acutely reduces glutamate-induced intracellular Ca2+ increase probably via inhibition of high-voltage-activated calcium channels.
Huang
Y
Y
National Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China.
Huang
Y L
YL
Lai
B
B
Zheng
P
P
Zhu
Y C
YC
Yao
T
T
D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers; D015220:Calcium Channels / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D003952:Diagnostic Imaging; D004594:Electrophysiology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists; D000077267:Fulvestrant; D018698:Glutamic Acid / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004965:Estrogen Antagonists; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D000077267:Fulvestrant; D018698:Glutamic Acid; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D016202:N-Methylaspartate; D019284:Thapsigargin; D002118:Calcium