근위축성측삭경화증 세포모델에서 요산의 항산화 효과 및 PI3K 활성화를 통한 신경보호 효과에 대한 연구

Abstract

Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord. ALS is characterized by wasting and weakness of muscles due to degeneration of upper and lower motor neurons, typically leading to death within 3 to 5 years after the initial onset of symptoms. Several pathogenic mechanisms of ALS have been proposed including genetic factors (mutations in SOD1, FUS, TARDBP, and C9ORF72 gene), oxidative stress, glutamate excitotoxicity, mitochondria dysfunction and abnormal protein aggregation. Uric acid (UA) is the main end product of purine metabolism in humans due to the loss of uricase activity during the evolution of hominoids. UA is an important natural antioxidant that may reduce oxidative stress injury. Our clinical data suggests that UA levels is correlated with survival and prognosis of ALS, however, molecular neuroprotective mechanism of UA in motor neuronal cell death induced by oxidative stress remain poorly understood. This study was designed to evaluate whether the neuroprotective effects of UA mediated through activation of Pi3K-Akt pathway against sodium arsenite induced oxidative stress injury. In this study, UA treatment was resulted in a dose-dependent stepwise increase of viability of motor neuronal cells and decrease production of free radicals in sodium arsenite induced oxidative stress injury. In addition, expression level of p-PI3K, p-Akt, and p-GSK-3β was increased after UA treatment, which was controlled by PI3K inhibitor, LY294002, and confirmed by western blotting. These results suggest that UA mediates neuroprotective effects by reducing ROS, enhancing survival signals through activation of PI3K-Akt pathway, and inhibiting apoptotic signals in motor neurons. Therefore, targeting for increment of UA levels or UA treatment might be important therapeutic modality for preventing motor neuronal cell death in ALS.