Effect of T-588, a novel cognitive enhancer, on NGF-induced neurite outgrowth in PC12 cells

• Published in: Japanese Journal of Pharmacology Vol. 73; no. suppl.2; p. 280
• Main Authors: Hidetoshi Yamaguchi, Satoshi Ono, Kazunari Hirata, Hirokazu Narita
• Format: Journal Article
• Language: Japanese
• Published: The Japanese Pharmacological Society 1997
• ISSN: 0021-5198; 1347-3506

We have previously demonstrated that T-588 improved the learning and memory deficits in animal amnesia models, and stimulated phosphoinositide hydrolysis and cAMP formation in rat cortical and hippocampal slices. It is well known that NGF is involved in cell survival and rearrangement of neural network in CNS cholinergic neurons. In the present study, we investigated the interaction between T-588 and NGF on the neurite outgrowth in PC12 cells. T-588 (1-100 μM) significantly potentiated NGF-dependent neurite outgrowth in a concentration dependent manner, while T-588 alone did not induce morphological change. To investigate the mechanism of T-588 on the enhancement of NGF-dependent differentiation, we examined the effect of protein kinase inhibitors. The potentiating effect of T-588 (10 μM) is significantly reduced by KN-62, a Ca^2+ /calmodulin-dependent protein kinase II inhibitor, and calphostin C, a protein kinase C inhibitor, but not H-89, a protein kinase A inhibitor. The potentiating effects of PMA (1 nM) and dibutyryl-cAMP (10 μM) was significantly inhibited by calphostin C and H-89, respectively. These results suggest that the potentiating effect of T-588 on NGF-induced neurite outgrowth is mediated by stimulating Ca^2+ / kinase II and PKC signal transduction pathway.