JAK-STAT Pathway Mediates Anti-oxidative Effects Of GX-50 On Neuron

Alzheimer's disease(AD) is a neurodegenerative disease common in the elderly. The pathogenesis of AD is complex, involving the interaction of multiple intracellular molecular mechanisms and signaling pathways. And it is also closely associated with the complex environmental factors. Present study has still not found effective preventive measures and treatments against Alzheimer's disease. ?-amyloid protein(A?) is the main component of senile plaques, one of the important pathological features of Alzheimer's disease. A? is the main cause of Alzheimer's disease, and it also contributes to the generation of free radicals in the brain, which may cause oxidative damage to a large number of neurons. N-[2-(3, 4-dimethoxyphenyl) ethyl]-3-phenyl-acrylamide(gx-50), a novel compound derived from Zanthoxylum, has been demonstrated by our previous study that it has neuroprotective effects against AD. Therefore, studying effects of gx-50 on development and progression of Alzheimer's disease from the perspective of oxidative stress is of great significance.Research objectMain biological functions of gx-50 are improving the cognitive and memory abilities in dementia mice, protecting primary neurons and inhibiting the release of inflammatory factors in macrophages. Although gx-50 showed positive therapeutic effects against AD, the mechanism of its antioxidant properties is largely unknown. This study focuses on the mechanism and association of its antioxidant properties and neuropretective effect on neurons.MethodsIn this study, we used DCFH-DA fluorescent probe to detect how gx-50 pretreatment influences the level of reactive oxygen species(ROS) in PC12 cells. We investigated the impact of gx-50 on total superoxide dismutase(SOD) activity in PC12 cells by using WST-8 method. We measured the ability of gx-50 to resist oxidation of lipid by detecting the level of malondialdehyde(MDA) in PC12 cells. The expression of p-JAK2 and p-STAT3 and the activation of caspase-3 were detected by Western blot methods. In addition, the activation of JAK-STAT pathway in brains of APP-Tg mice was detected by immunohistochemistry.Results and conclusionData showed that gx-50 reduced the levels of reactive oxygen species(ROS) and malondialdehyde(MDA), and recovered the activity of total intracellular superoxide dismutase(SOD) in neuronal PC12 cells exposed to A?. After gx-50 pretreatment, the levels of p-JAK2 and p-STAT3 both increased in PC12 cells, while they were down-regulated in A?-treated group. In present study, we also found that gx-50 reduced the relative expression level of the activated caspase-3 in PC12 cells by activating JAK-STAT signaling pathway. Results demonstrated that gx-50 reduced oxidative stress induced by amyloid-beta(A?) in neuron-like PC12 cells through enhancing the activation of JAK-STAT signaling pathway. It might help to protect neurons in Alzheimer's disease.