Different dependence of lithium and valproate on PI3K/PKB pathway.
OBJECTIVE
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.


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.
Departamento de Bioquímica y Biología Molecular, Facultad de Veterinaria, Universidad de Extremadura, Avda. de la Universidad s/n. 10071, Cáceres, Spain. almoraco@unex.es
Alfonso
A
Mora
Guadalupe
G
Sabio
Juan C
JC
Alonso
Germán
G
Soler
Francisco
F
Centeno
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D000831:Animals, Newborn; D018692:Antimanic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011188:Potassium / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000494:pharmacology*
D064413:3-Phosphoinositide-Dependent Protein Kinases; D018692:Antimanic Agents; D061945:Caspase Inhibitors; D020169:Caspases; D002518:Ceramides; D004792:Enzyme Precursors; D008094:Lithium; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D011188:Potassium; D017346:Protein Serine-Threonine Kinases; D014635:Valproic Acid