Fig. 1.

The binding of MTR agonist to G-protein coupled receptors (Melatonin 1, 2) leads to the activation of Akt/Erk pathway (RISK pathway). This leads to reduction in the levels of proteins including beclin-1, LC3-II, PERK-eIF2α-ATF4 which are markers of autophagy. Also, the activation of RISK pathway increases the generation of NO via endothelial nitric oxide synthase. The increase in NO activates guanylyl cyclase enzyme which increases the production of cGMP (cyclic guanosine monophosphate) which in turn activates PKG-1α which inhibits p-38 MAPK (p-38 mitogen-activated protein kinases) and subsequent apoptosis. The activation of PKG-1α (Protein Kinase G-1α) also facilitates nuclear translocation of Nrf-2 (Nuclear factor erythroid 2-related factor 2) and triggers the transcription of genes with ARE sequence including haem oxygenase (HO) to curb MPTP (mitochondrial permeability transition pore) formation. Meanwhile, the activation of RISK pathway augments GSK-β (glycogen synthase kinase-3) phosphorylation which halts mPTP formation. Moreover, melatonin administration increased the expression of calcium handling proteins sarcoendoplasmic reticulum SERCA2a and sodium-calcium exchanger to reduce Ca²⁺ overloading and aid storage of calcium in the SR. Apart from this, melatonin modulates the expression of apoptotic proteins such it reduces the level of Bax, p53, p21, caspase-3 but increases Bcl-2 level to promote cardiomyocyte survival. Furthermore, melatonin can activate the SAFE pathway either via activation of TNFR or TLR4 which subsequently increases STAT transcription to provide myocardial protection.