Activation of Akt by lithium: Pro-survival pathways in aging

The effects of lithium on senescence were investigated using the senescence-accelerated mouse prone 8 (SAMP8) mice and cultures of aging cerebellar granule cells. Our in vitro findings, using cerebellar granule neurons, demonstrate that lithium (1-10 mM) exerts neuroprotective effects in young cultures (7-8 days) against LY294002-induced Akt inhibition. Furthermore, lithium (10 mM) inhibits GSK-3 beta activity by upregulating p-GSK-3 beta (ser-9) and increases p-FOXO1 (Ser256) suggesting an effective antiapoptotic effect. Our data also showed that lithium in aged cultures exerts anti-apoptotic effects via Akt activation and consequent inhibition of downstream targets regulated by this enzyme. Finally, the administration of lithium to senescence-accelerated mice (SAMP8) and senescence-accelerated resistant mice (SAMR1) at 3 months of age also caused increased Akt activity and p-FoXO-1. These results demonstrate the effectiveness of lithium in preventing age-related neural loss and the potential therapeutic applications of lithium in treatment/prevention of neurological disease. (C) 2009 Elsevier Ireland Ltd. All rights reserved.