Calcium-Dependent Prevention of Neuronal Apoptosis by Lithium Ion: Essential Role of Phosphoinositide 3-Kinase and Phospholipase Cγ

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 C (PLC) pathway. Antiapoptosis action of Li was prevented in the presence of U-73122, a selective phospholipase C inhibitor, and was not observed in PLC1-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 PLC pathways.