Neuroprotection by c-Jun NH2-terminal kinase inhibitor SP600125 against potassium deprivation-induced apoptosis involves the Akt pathway and inhibition of cell cycle reentry

M Yeste-Velasco, J Folch, G Casadesús, M A Smith, M Pallàs, A Camins
Neuroscience 2009 March 31, 159 (3): 1135-47
Increasing evidence implicates the c-Jun NH(2)-terminal kinase (JNK) pathway in the regulation of apoptosis in neurodegenerative diseases. In this study, we examined the neuroprotective effect of SP600125, a selective JNK inhibitor, in cerebellar granule cells (CGNs) deprived of serum and potassium (S/K withdrawal). S/K withdrawal-induced apoptosis occurs via activation of multiple pro-apoptotic pathways, including re-entry into the cell cycle, activation of glycogen synthase kinase-3 beta (GSK-3beta), cyclin-dependent kinase 5 (cdk5/p35) breakdown, formation of cdk5/p25 and JNK activation. Here we demonstrate that SP600125 is able to inhibit all these pro-apoptotic pathways via the inhibition of JNK. Further, we found that JNK inhibition maintains the phosphorylation/activation of Akt after S/K withdrawal. For further confirmation of this result, we studied several targets downstream of Akt including GSK-3beta, p-FOXO1, p-CREB and p35. In addition, the specific PI3K/Akt inhibitor LY294002 greatly diminished the antiapoptotic effects of SP600125 upon S/K withdrawal, confirming that Akt is involved in the neuroprotection achieved by SP600125. These results suggest that the maintenance of the PI3-kinase/Akt pathway by inhibition of JNK contributes to the prevention of apoptosis in rat cerebellar granule neurons mediated by S/K withdrawal. Furthermore, we propose that JNK may regulate the cell cycle re-entry by a novel mechanism that involves Akt, GSK-3beta and Rb phosphorylation.

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