Regulation of Melatonin on AQP4 Expression in Brain of SD Newborn Rats with Bilirubin Encephalopathy and Protection Mechanism

Bilirubin encephalopathy (BE) is a neurological disorder caused by the accumulation of unconjugated bilirubin (UCB) in the brain of newborns, resulting in various degrees of neuronal impairment. BE is characterized by cytotoxic edema and neuronal Apoptosis. Aquaporin-4 (AQP4), a water channel abundantly expressed in the central nervous system, plays a critical role in maintaining water homeostasis. Dysregulation of AQP4 expression or trafficking is closely associated with brain edema, suggesting that modulation of AQP4 may offer a potential therapeutic approach for BE. Previous studies have indicated that melatonin (MT) possesses neuroprotective and therapeutic potential against BE; however, its precise mechanisms remain unclear. In this study, we optimized rat BE model to investigate the therapeutic effects of melatonin on AQP4 expression, trafficking, and Apoptosis in parietal cortical neurons. Furthermore, we explored the molecular mechanisms underlying melatonin's neuroprotective actions, including the regulation mechanism of AQP4 expression, brain edema formation, and Apoptosis induced by UCB accumulation. The results indicate that in the BE model, pathological injury of parietal cortex was significantly aggravated and AQP4's expression peaked at 24 h after BE modeling. MT activated PI3K/Akt signaling pathway in rat parietal cortex to downregulate AQP4 expression, Apoptosis related proteins, and decreased SNX27's expression to promote the internalization of AQP4, reducing bilirubin induced cytotoxic edema and cortical Apoptosis. This data suggest that MT has a neuroprotective role in BE, by potentially delaying its progression.

Aquaporin 4; Bilirubin encephalopathy; Cytotoxic edema; apoptosis; Internalization; Melatonin; PI3K/AKT pathway.