Neurotrophic effects of a @entity10502 dye via the PI3K- @entity2308 pathway: attenuation of motor discoordination and XXXX in an ataxic animal model.

@entity137 @entity274 @entity2308 @entity2137 @entity3249 @entity2306 @entity273 @entity10502 @entity179 @entity76 @entity2955 @entity4357
BACKGROUND: Neurotrophic factors may be future therapeutic agents for @entity179 . In the screening of biologically active molecules for neurotrophic potency, we found that a photosensitizing @entity10502 dye, NK-4, had remarkable neurotrophic activities and was a potent radical scavenger. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we evaluated the effect of NK-4 on the protection of neurons against oxidative damage and investigated the associated intracellular signaling pathways. Subsequently, we evaluated the effect of NK-4 in an animal model of @entity179 . In vitro, NK-4 showed dose-dependent protection of PC12 cells from @entity137 induced by oxidative stress caused by @entity273 ( @entity274 ) or @entity2955 ( @entity2955 ). Comparison of extracellular signal-regulated kinase signaling pathways between treatment with NK-4 and @entity2137 ( @entity2137 ) using K252a, an inhibitor of the @entity2137 receptor @entity3249 , revealed that NK-4 activity occurs independently of @entity2137 receptors. @entity2306 , a @entity4357 3-kinase (PI3K) inhibitor, blocked the protective effect of NK-4, and NK-4 caused activation of @entity2308 /protein kinase B, a downstream effector of PI3K. These results suggest that the neuroprotective effects of NK-4 are mediated by the PI3K- @entity2308 signaling pathway. NK-4 treatment also attenuated stress-induced activation of SAPK/JNK, which suggests that NK-4 activates a survival signaling pathway and inhibits stress-activated apoptotic pathways independently of the @entity3249 receptor in neuronal cells. In vivo, administration of NK-4 improved motor coordination in genetic ataxic hamsters, as assessed by rota-rod testing. Histological analysis showed that @entity76 was significantly attenuated by NK-4 treatment. Notably, the Purkinje cell count in the treated group was threefold higher than that in the vehicle group. CONCLUSIONS/SIGNIFICANCE: These results suggest that NK-4 is a potential agent for therapy for @entity179 based on the activation of survival signaling pathways.
