Calcium-dependent prevention of neuronal apoptosis by lithium ion: Essential role of phosphoinositide 3-kinase and phospholipase Cγ

Abstract

We examined the possibility that the neuroprotective effects of Li + would depend upon the patterns of neuronal death, apoptosis versus necrosis, and whether Ca 2+ as well as phosphoinositide 3-kinase (PI3-K) would mediate the neuroprotective effect of Li +. Cortical neurons treated with Li + showed marked increase in [Ca 2+] i within 2 min. Addition of BAPTA-acetoxymethyl ester, a selective Ca 2+ chelator, abrogated the antiapoptotic effect of Li +. PI3-K was activated rapidly within 1 min after exposure to Li +, which mediated Ca 2+-dependent neuroprotective effects of Li +. Activated PI3-K seemed to increase [Ca 2+] i via the phospholipase Cγ (PLCγ) pathway. Antiapoptosis action of Li + was prevented in the presence of U-73122, a selective phospholipase C inhibitor, and was not observed in PLCγ1-null fibroblasts. In contrast to antiapoptosis action, administration of Li + did not prevent neuronal cell necrosis by excitotoxicity or free radicals. Li + selectively prevents apoptosis by increasing [Ca 2+] i through activation of PI3-K and PLCγ pathways.