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

Departments of Neuroscience and Pharmacology, Center for the Interventional Therapy of Stroke and Alzheimer's Disease (H.J.K., B.J.G.), Department of Psychiatry (J.S.N.), Ajou University School of Medicine, Suwon, Kyunggido, Korea; and Center for Cell Signaling Research, Division of Molecular Life Sciences, and Department of Biological Sciences, Ewha Womans University, Seoul, Korea (Y.S.B.).

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 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 [Ca²⁺]_i through activation of PI3-K and PLC pathways.

Address correspondence to: Dr. Byoung Joo Gwag, Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea, 442-749. E-mail: bjgwag{at}madang ajou ac kr

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