Different mechanisms of protection against apoptosis by valproate and Li+

Acute treatment with valproate and Li+ was found to protect cultured cerebe llar granule cells against apoptosis induced by low K+ (5 mM). Because the protection was unaffected by MK801 (N-methyl-D-aspartate receptor inhibitor ), an increase in glutamate release cannot be responsible for the observed neuroprotection. Insulin also protects against low-K+-induced apoptosis of cerebellar granule cells. This protection is totally dependent on LY294002 (a phosphatidylinositol 3-kinase inhibitor). These results suggest a role f or phosphatidyl inositol 3-kinase in the neuroprotection induced by insulin . Likewise, and in contrast with the results observed with Li+, the protect ion induced by valproate is also dependent on insulin and LY294002. Moreove r, valproate (a branched-chain fatty acid) does not change the plasma membr ane microviscosity under physiological conditions. These results suggest th at valproate protects against low-K+-induced apoptosis by acting in the pho sphatidylinositol 3-kinase/protein kinase B pathway. The protection by Lif is independent of this transduction pathway.