Table 3.

Therapeutic effects of melatonin against ischemia-reperfusion injury.

Melatonin dose	Route of administration	I/R duration	Treatment duration	Target	Effect	Model	References
10 mg/kg	Intraperitoneal	30 min/3 h, or 30 min/6 h	5 days	cGMP, PKG, Nrf-2-HO-1, MAPK	Ameliorated diabetic I/R injury, reduced cardiac cell apoptosis, and oxidative stress	In vivo (rats)	(222)
10 μM or 10 nM	Administered into perfusion solution	20/40 min	5 min before ischemia, also simultaneous with reperfusion	–	Decreased arrythmia and VF caused by reperfusion	In vivo (rats)	(275)
50 mg	Intraoperative	–	3 days	Troponin I (TpI)	Reduced cardiac damage	Humans	(261)
10 mg	Oral
10 mg/kg	–	30/120 min	10 days	Fas, cytochrome b-245 beta chain (Cybb), irisin, nuclear factor-κB (Nf-κB)	Improved protective effect of remote ischemic preconditioning (RIPerC) against I/R injury	In vivo (rats)	(276)
50 mM	Added to reperfusion solution	30 min/60 min	20 min	ROS	Reduced mitochondrial oxidative stress, increased mitochondrial membrane potential	In vivo (rats)	(277)
10 mg/kg	Intravenous	30/120 min	10 min	GSH, MDA	Increased antioxidants in cardiac cells, inhibited lipid peroxidation	In vivo (rats)	(278)
2/5, 5, 10 mg/kg	Intraperitoneal	10/15 min	10 min	–	Inhibited myocardial apoptosis during IR, protected mitochondrial structure & function	In vivo (rats)	(279)
5 μM	–	12/12 h	12 h	ERK1, IP3R, SERCA2a	Inhibited cardiomyocyte apoptosis, improved actin filament organization	In vitro	(274)
20 mg/kg	Intraperitoneal	30 min/2 h	12 h	IP3R and SERCA2a	Induced cardioprotection against IR injury	In vivo (rats)	(274)
50 μM	Administered into perfusion medium	30/15 min	15 min	Cardiolipin	Improved cardiac cell viability by keeping MPTPs closed	In vivo (rats)	(280)
6 mg/kg	Intraperitoneal	30/30 min	3 weeks	TBARS, MDA	Prevented microvascular injury & ventricular arrhythmia	In vivo (hamsters)	(281)
50 mg/kg	Intraperitoneal	20/20 min	30 min	Troponin T (cTn-T), MDA, SOD, myeloperoxidase (MPO)	Protected against cardiac IR injury	In vivo (rats)	(282)
20 mg/kg	Intraperitoneal	30 min/2 h	12 h	Beclin 1, LC3-II, AMPK, mTOR	Protected CMECs against IRI by inhibiting autophagy	In vivo (rats)	(283)
5, 10, 20, 50 μM	Melatonin added to perfusion solution	10 min/–	10 min	–	Decreased arrhythmia, suppressed oxidative damage	In vivo (rats)	(284)
50 μM	Administered into perfusion medium	30/45 min	3 min	MDA	Significantly suppressed of apoptosis	In vivo (rats)	(285)
10 mg/d 20 mg/d	Oral	–	5 days	Troponin-I, IL-1β, iNOS, caspase-3	Suppressed IR damage	Humans	(262)
10 mg/kg	Intraperitoneal	30 min/3 h	5 days	Sirt3	Protected against IR injury, alleviated myocardial oxidative stress	In vivo (mice)	(286)
50 μM	–	35/30 or 120 min	40 min	p38MAPK, ERK, PKB/Akt, NOS, guanylyl cyclase	Cardioprotective effects, anti-adrenergic activity	In vivo (rats)	(36)
10 mg/kg 20 mg/kg	Intraperitoneal	45 min/4 h	24 h	OPA1, LDH, CK-MB, troponin T, TNFα, IL-6, and MCP1	Promoted mitochondrial fusion, restored energy generation, prevented myocardial IR injury	In vivo (rats)	(287)
10, 20 μM	–	45 min/ 4 h	24 h	OPA1	Reversed IR-mediated myocardial dysfunction	In vitro	(287)
0.025 μg/h	Infusion into hypothalamic paraventricular nucleus (PVN)	30 min/6 h	1 week	Cu/Zn-SOD, NOX2, NOX4, IL-1b, NF-kB, p65, IL-10	Modulated oxidative stress & inflammatory pathways in PVN, reduced myocardial IR injury	In vivo (rats)	(288)
10 mg/kg	Intraperitoneal	15/30 min	7 days	MMP-9, IL-6, TNF-α, MDA, SOD, GPx, Nrf2, NQO1, cytochrome-C, Bax, Bcl-2, caspase-3, p-JAK2, p-STAT3	Decreased edema, inflammation, oxidative damage, & apoptosis in cardiomyocytes	In vivo (rats)	(240)
20 mg/kg			30 min
0.3, 50 μM	–	20/30 min	10 + 10 min	Cytosolic beclin 1, LC3 II/I, p62, ULK1, Rab9, Drp1	Prevented mitochondrial fission, modulated non-conventional mitophagy, promoted autophagy	In vivo (rats)	(251)
50 μM	Melatonin added to perfusion solution	30/15 min	15 min	–	Preserved mitochondrial complexes I, III, cardiolipin from oxidative damage	In vivo (rats)	(246)
0.3 mM	Melatonin and HTK (histidine, tryptophan, ketoglutarate) added to Tyrode's solution	80/45 min	30 min	ROS	Attenuated postischemic ROS burst, but was unable to improve the functional recovery provided by HTK	In vivo (guinea pigs)	(289)
20 mg/kg	Intraperitoneal	45 min/4 h	24 h	OPA1	Protected cardiac function, increased survival	In vivo (mice)	(290)
5 μM	–	45 min/4 h	12 h	OPA1	Reversed loss of MMP, restored energy production in cardiac cells	In vitro	(290)
20 mg/kg	Intraperitoneal	30 min/3 h	10 min	Sirtuin-3 (SIRT3), lactate dehydrogenase	Improved post-ischemic cardiac structure & function, decreased apoptosis, & oxidative damage	In vivo (mice)	(291)
20 mg/kg	Intraperitoneal	45 min/6 h	12 h	Ripk3-PGAM5-CypD-MPTP cascade, LDH, troponin T, CK-MB	Decreased endothelial necroptosis	In vivo (mice)	(266)
20 mg/kg	Intraperitoneal	2/4 h	12 h	PPARγ	Suppressed HR damage, inhibited platelet activation, reduced FUNDC1 (FUN14 domain-containing protein 1) mediated mitophagy	In vivo (mice)	(292)
12 mg/kg/d	Intraperitoneal	30 min/4 h, 30 min/6 h, 30 min/72 h	3 days+15 min	PERK, eIF2α, ATF4, RISK, SAFE pathway, ERK1/2 pathway	Reduced myocardial apoptosis & oxidative stress, improved cardiac function	In vivo (mice)	(293)
20 mg/kg/d	Oral	30 min/4 h, 30 min/6 h, 30 min/72 h	1 week	MDA, SOD, PERK, eIF2a, ATF4, CHOP, SIRT1	Ameliorated reperfusion-induced oxidative & ER stress, reduced MI/R damage, improved cardiac function	In vivo (rats)	(294)
5 μM	Melatonin added to perfusion solution	45/60 min	5 min	JAK2/STAT3 signaling pathway, SOD, H2O2, MDA, LDH, GSH	Melatonin pretreatment attenuated IR injury, reduced mitochondrial oxidative damage	In vivo (rats)	(295)