TABLE 1.

Summary of experiments related to melatonin for the prevention and treatment of postoperative cognitive dysfunction.

Mechanism of action	Study	Anesthetic drugs	Dose and timing of melatonin administration	Results
Adjusting circadian rhythms	Song et al., 2018	Isoflurane	Gavage at 10 mg/kg daily for 7 consecutive days before anesthesia	Melatonin could restore the desynchronization of clock gene expression induced by isoflurane and improve aged mice’s circadian rhythm disorder and spatial memory impairment.
	Ohe et al., 2011; Mori et al., 2014	Sevoflurane		Sevoflurane anesthesia reversibly suppressed the expression of the clock gene, Period2 (Per2), in the mouse suprachiasmatic nucleus (SCN).
	Jia et al., 2021	Sevoflurane	Intraperitoneal injection of 10 mg/kg melatonin daily for 7 consecutive days before anesthesia	Melatonin could ameliorate the circadian rhythm disorder caused by operation under sevoflurane anesthesia in elderly mice.
	Imai et al., 2020	Desflurane		Desflurane anesthesia altered the relative mRNA expression of four major clock genes (Per2, Bmal, Clock, and Cry1) in the SCN and caused a phase shift in the circadian rhythm, which were dependent on the time of day of anesthesia.
	Kadota et al., 2012	Sevoflurane		Sevoflurane anesthesia inhibited the expression of mPer2 in SCN in a time-dependent manner, but no time-dependent effect on circadian rhythm was found.
	Xia et al., 2016	Isoflurane	Gavage at 10 mg/kg daily for 7 consecutive days before anesthesia	Sleep-awakening rhythm is involved in isoflurane-induced cognitive impairment, and melatonin can positively affect circadian rhythm normalization and cognitive reversal through the NR2B-CREB signal pathway.
	Liu et al., 2013	Isoflurane	Intraperitoneal melatonin 10 or 1 daily for 14 consecutive days before anesthesia	Prophylactic melatonin attenuated isoflurane-induced decreases in plasma/hippocampal melatonin levels and cognitive impairment in aged rats.
	Liu et al., 2017	Isoflurane	Intraperitoneal injection of melatonin 10 mg/kg 30 min before anesthesia	Preventive melatonin attenuated isoflurane-induced cognitive impairment and its effects were depended on the hippocampal MT2-CREB signaling pathway.
	Fan et al., 2017	Spinal anesthesia	1 mg oral melatonin daily 1 h before bedtime 1 day before surgery and for another 5 consecutive days postoperatively.	Exogenous melatonin increased perioperative sleep quality and improved early POCD.
Restoring cholinergic system function	Ni et al., 2013	Isoflurane	Intraperitoneal injection of 10 mg/kg melatonin daily for 7 consecutive days before anesthesia	Melatonin could inhibit the production of A β, increase the expression of ChAT and protect the function of the cholinergic system.
	Corrales et al., 2013		Oral melatonin 0.5 mg daily for 5 months	Melatonin alleviated cholinergic degeneration by increasing ChAT and improved the spatial learning and memory ability of mice.
	Chen et al., 2018		Intraperitoneal injection of melatonin 10 mg/kg daily for 2 and 4 weeks.	Melatonin treatment increased ChAT, CHT, VAChT and M1R immunoreactivity and their protein levels in the septum and hippocampus, restored cholinergic system function, and improved spatial learning and memory.
	Labban et al., 2021		Intraperitoneal injection of melatonin 80 mg/kg daily for 8 weeks	Melatonin increased AChE levels as well as BDNF/CREB1 protein expression levels in the prefrontal cortex of mice and improved recognition memory and passive avoidance performance
Protecting the nervous system	Zhong et al., 2018	Propofol		Propofol could induce extensive neuronal apoptosis by down-regulating the PKA-CREB-BDNF signaling pathway, thus leading to long-term spatial learning and memory disorders.
	Hosseini et al., 2019	Propofol	Intraperitoneal injection of melatonin 10 mg/kg every other day for 28 days	Melatonin could improve mitochondrial dysfunction and reduce apoptosis in the aged rat brain, thereby reversing aging-induced learning and memory deficits.
	Li et al., 2021	Propofol	Intraperitoneal injection of melatonin 10 mg/kg 20 min before anesthesia	Melatonin could alleviate mitochondrial dysfunction, apoptosis, inactivation of PKA/CREB/BDNF signaling, and synaptic dysfunction, thereby improving propofol-induced cognitive dysfunction.
	Yuan et al., 2019	Isoflurane	Intraperitoneal melatonin 10 mg/kg daily for 14 consecutive days before anesthesia	Melatonin could inhibit neuroinflammation by suppressing mTOR signaling in the hippocampus of aged mice, thereby reducing isoflurane-induced cognitive impairment.
	Yang et al., 2020		Intraperitoneal injection of melatonin 75 or 150 mg/kg	Melatonin could ameliorate intestinal I/R-induced neuroinflammation and cognitive dysfunction by inhibiting TLR4/MyD88 signaling pathway in microglia.
	Palmer et al., 2020		Oral melatonin 20 mg daily about 1 h before bedtime for 10 days	Melatonin could improve the adverse effects of ACBC on cognitive function, sleep quality, and depressive symptoms through its neuroprotective effect.