• apoptosis;
  • caspase 3;
  • cerebellar granule cells;
  • insulin;
  • lithium;
  • PI3K;
  • PKB;
  • valproate

Objectives: Acute treatment with valproate (VPA) or lithium (Li+) protects cerebellar granule cells (CGC) against apoptosis induced by low potassium (K+) (5 mM). As the protection induced by VPA is absolutely dependent on insulin, in contrast to the observed effects of Li+, we decided to study the different role of the PI3K/PKB pathway in the neuroprotective effects of both drugs. Methods: We have studied the neuroprotection elicited by Li+ or VPA in cultures of rat CGC. We induced the apoptosis by switching to a medium with a low concentration of K+ or by adding C2-ceramide to the cultures. We studied the effect of Li+ and VPA on viability and on the regulation of the PI3K/PKB pathway. Results and conclusions: Insulin also protects against low K+-induced apoptosis in CGC, probably through its interaction with an insulin-like growth factor receptor. Moreover, whereas Li+ protects against the apoptosis induced by C2-ceramide, VPA cannot, probably due to the inhibition of protein kinase B (PKB) caused in this apoptotic stimulus. These results suggest that VPA protects against low K+-induced apoptosis by acting on the PI3K/PKB pathway; however, VPA does not affect the increase of PKB activity caused by insulin in these cells. The protection by Li+ is independent of this transduction pathway. Moreover, Li+ blocks the caspase 3 activation induced by low K+, whereas neither VPA nor insulin affects this activation.