The role of Ca2+ channel modulation in the neuroprotective actions of estrogen in β-amyloid protein and 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) cytotoxic models

Physiologically relevant concentrations of 17beta-estradiol (E2) are neuroprotective in both P-amyloid protein 25-35 (Abeta) and 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced cytotoxicity in SK-N-SH cells. MPTP, but not Abeta, induces apoptosis in this cell line. The L-type calcium channel blocker nifedipine or decreased extracellular Ca2+ concentration blocked Abeta-induced cell death, but not MPTP-induced cell death. Other blockers selective for different Ca2+ channel subtypes had no effects on either Abeta or MPTP induced death. Western blot analysis for L-type Ca2+ channel (alpha1 -subunits demonstrated that Abeta increases the expression of the neuronal alpha(1c) and alpha(1D) subunits of L-type channels. Both E2 and nifedipine inhibit the increase in expression of these by Abeta. MPTP also increases expression of (alpha1(C) and alpha1(D), but the increases were not influenced by E2 or nifedipine. These observations suggested that Abeta cytotoxicity in SK-N-SH cells may involve increased availability of calcium to cells, whereas MPTP induced cytotoxicity does not require extracellular Ca2+. Both cytotoxic models were associated with increased expression of Ca2+ channel (alpha I subunits, and neuroprotection associated with inhibition of that increase. These studies reveal that nifedipine, in addition to its direct action of nifedipine on Ca-2+ channels, may also protect neurons from Abeta toxicity through the suppression of the channel protein overexpression. A new action of dihydropyridines (DHPs) may be considered in the regulation of calcium homeostasis. (C) 2004 Elsevier Ltd. All rights reserved.