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 (MT₂ ) plays a critical role in circadian rhythm disorders, Alzheimer's disease and other neurological disorders. A melatonin replacement strategy has been tested previously, and MT₂ 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 MT₂ 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 MT₂ 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 MT₂ antagonist, blocked the protective effects of melatonin on isoflurane-induced decreases in both hippocampal MT₂ 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 MT₂ -CREB signalling, which could be a potential therapeutic target for anaesthetic-induced cognitive impairment.