A novel evidence of different mechanisms of lithium and valproate neuroprotective action on human SY5Y neuroblastoma cells: caspase-3 dependency

Both lithium and valproate have been used in the treatment of manic-depress ive illness with very limited understanding of their therapeutic mechanism of action. Recent literature suggests that blocking of potassium channels m ay be a common therapeutic mechanism of many antidepressant agents. To dete rmine whether the commonly used antimanic agents could prevent potassium ef flux-induced cell damage and apoptosis and the underlying mechanisms, we tr eated SH-SY5Y human neuroblastoma cells with the potassium ionophore, valin omycin (2-100 muM) and observed cell shrinkage, mitochondria damage, a sign ificant increase in of lactate dehydrogenase (LDH) activity and caspase-3 p rotein expression. Cells treated with lithium (0.5-3 mM) or valproate (0.07 -1.4 mM) alone produced no apoptotic morphological and biochemical changes while both mood stabilizers pretreatment reduced or prevented the apoptotic morphological changes. However, valinomycin-induced caspase-3 elevation wa s only prevented by lithium pretreatment while both lithium and valproate a ttenuated valinomycin-induced LDH release. Our results suggest that lithium and valproate share a common neuroprotective action against potassium effl ux-induced cell apoptosis with different mechanisms, (C) 2000 Elsevier Scie nce Ireland Ltd. All rights reserved.