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 Ca²⁺ as well as phosphoinositide 3-kinase (PI3-K) would mediate the neuroprotective effect of Li⁺. Cortical neurons treated with Li⁺ showed marked increase in [Ca²⁺]_i within 2 min. Addition of BAPTA-acetoxymethyl ester, a selective Ca²⁺ chelator, abrogated the antiapoptotic effect of Li⁺. PI3-K was activated rapidly within 1 min after exposure to Li⁺, which mediated Ca²⁺-dependent neuroprotective effects of Li⁺. Activated PI3-K seemed to increase [Ca²⁺]_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 [Ca²⁺]_i through activation of PI3-K and PLCγ pathways.