Prophylactic Melatonin Attenuates Isoflurane‐Induced Cognitive Impairment in Aged Rats through Hippocampal Melatonin Receptor 2 – cAMP Response Element Binding Signalling

Abstract Melatonin exerts many physiological effects via melatonin receptors, among which the melatonin‐2 receptor ( MT 2 ) plays a critical role in circadian rhythm disorders, Alzheimer's disease and other neurological disorders. A melatonin replacement strategy has been tested previously, and MT 2 was a critical target during the process. cAMP response element binding ( CREB ) is an essential transcription factor for memory formation and could be involved in MT 2 signalling. Therefore, the present study was designed to investigate the effects of prophylactic melatonin on inhaled anaesthetic isoflurane‐induced cognitive impairment, and to determine whether the protective effects of melatonin are dependent on MT 2 and downstream CREB signalling in the hippocampus of aged rats. The results showed that prophylactic melatonin attenuated isoflurane‐induced decreases in plasma/hippocampal melatonin levels and cognitive impairment in aged rats. Furthermore, 4P‐ PDOT , a selective MT 2 antagonist, blocked the protective effects of melatonin on isoflurane‐induced decreases in both hippocampal MT 2 expression and downstream CREB phosphorylation. And 4P‐ PDOT blocked the attenuation of melatonin on isoflurane‐induced memory impairment. Collectively, the results suggest that the protective effects of prophylactic melatonin are dependent on hippocampal MT 2 ‐ CREB signalling, which could be a potential therapeutic target for anaesthetic‐induced cognitive impairment.