Exploration on Mechanism of a New Type of Melatonin Receptor Agonist Neu-p11 in Hypoxia–Reoxygenation Injury of Myocardial Cells

Abstract

To explore the mechanism of a new type of melatonin receptor agonist Neu-p11 in hypoxia-reoxygenation injury of myocardial cells. Hypoxia/reoxygenation (H/R) model of H9c2 myocardial cells was established, and the cells were divided into control group, H/R group, and Neu-p11 group. Apoptosis rates of myocardial cells in different groups, the contents of creatinine kinase (CK), lactic dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA) in cell culture media were compared. Myocardial cells in control group showed diverse shape, and the refractivity of cells were high and the pulse was strong with synchronous rhythm of 60-80/min; The refractivity of myocardial cells in H/R group decreased, the pseudopodium was thinner, and the rhythm was reduced to 30-40/min; The morphology and refractivity of myocardial cells in Neu-p11 group were significantly improved with rhythm of 50-60/min. The apoptosis rates in the control group, the H/R group, and the Neu-p11 group were 2.48, 39.66, and 17.94 %, respectively. Levels of CK, LDH, and MDA were significantly decreased in Neu-p11 compared with H/R group, yet, both of which were significantly higher than that in control group. The SOD level was significantly lower in H/R group compared to that in control group, and Neu-p11 group with no statistical difference between the Neu-p11 group and the control group. Neu-p11 has protective effects on hypoxia-reoxygenation injury of myocardial cells. It inhibits cell apoptosis and improves the morphology and rhythm of myocardial cells; It alleviates injury of cell membrane by reducing its permeability, which can stabilize myocardial cell membrane; It also alleviates lipid peroxidation and protects mitochondria from myocardial ischemia/reperfusion injury.

Membrane receptor‐dependent Notch1/Hes1 activation by melatonin protects against myocardial ischemia–reperfusion injury: in vivo and in vitro studies

“…We and others have previously demonstrated that melatonin's cardioprotective effect was partially mediated by its membrane receptors. Luzindole, a specific melatonin membrane receptor antagonist, inhibited its protective actions . In this study, both in vivo and in vitro data demonstrated that activation of Notch1/Hes1 signaling by melatonin treatment was abolished by luzindole administration.…”

Neuroprotective mechanism of the novel melatonin derivative Neu-P11 in brain ischemia related models

“…Neu-P11 has proved antidepressant and anxiolytic effects based on its interaction with 5HT1A/1D receptors; this effect correlates with the fact, that compared to melatonin, Neu-P11 presents better affinities for these receptors (16). In addition, Neu-P11 has demonstrated to be protective against myocardial ischemia/reperfusion injury in vitro (20).…”

“…Besides its neurological actions, Neu-P11 has demonstrated usefulness in reducing intraocular pressure (17). More recently, it has proven to be protective against myocardial ischemia/reperfusion injury in vitro (20).…”

Neu-p11 induces NLRP3 inflammasome-induced pyroptosis via provoking NOX4-mediated mitochondrial oxidative injury in chordoma cells

“…Neu-p11, as a novel melatonin receptor agonist, has the advantages of longer halflife, higher selectivity, less adverse reactions and easy synthesis compared with melatonin [25,26], which has great potential for clinical application. In this study, we found that Neu-p11 triggers mitochondrial translocation of NOX4 in U-CH1 and M-Chor chordoma cells, leading to mitochondrial oxidative damage and mediating NLRP3 inflammasome-dependent cell pyroptosis in chordoma cells.…”