Molecular Cell Biological Study on Neuronal Apoptosis in Cerebellar Graneul Cells

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We analyzed the mechanism underlying cell death using cultured rat cerebellar granule and cerebral cortical neurons, because of their abundance and homogeneity. Cerebellar granule neurons maintained in medium containing 26 mM potassium or in medium (5 mM potassium) with 50 ng/ml BDNF undergo an apoptoic cell death when exposed to 10 μ M LY294002, an inhibitor of PI3-kinase. To investigate the intracellular signaling mechanism of LY294002-induced apoptosis, the activities of Akt and c-Jun N-terminal kinase (JNK) were measured in cells in HKィイD1+ィエD1 (26 mM potassium) or LKィイD1+ィエD1 (5 mM potassium) medium containing BDNF, with or without 10 μ M LY294002. Akt activity decreased following the addition of 10 μ M LY294002. In addition, we found that LY294002 increased the JNK activity, which is known to mediate some types of cell death in PNS neurons. We also observed elevated expression of c-Jun by LY294002 in HKィイD1+ィエD1 +BDNF. These findings demonstrated that apoptosis induced by inhibition of PI3-kinase activity involves suppression of the Akt activity and elevation of the JNK activity in cerebellar granule neurons. Our results suggested that the PI3-kinase-Akt pathway suppresses the activation of JNK and c-Jun expression, and as a result prevents the neuronal cell death in cerebellar granule neurons.