Melatonin/nicotinamide mononucleotide/ubiquinol: a cocktail providing superior cardioprotection against ischemia/reperfusion injury in a common co-morbidities modelled rat

Mol Biol Rep. 2023 Apr;50(4):3525-3537. doi: 10.1007/s11033-022-08189-0. Epub 2023 Feb 14.

Abstract

Background: The metabolic and intracellular abnormalities in aging and diabetes cause loss of cardioprotection by routine interventions against myocardial ischemia/reperfusion (I/R) injury. We aimed to evaluate the possible interaction of aging and type-2 diabetes mellitus with cardioprotection and the potential protective effect of a mitochondrial cocktail (melatonin/nicotinamide mononucleotide (NMN)/ubiquinol) on myocardial I/R injury in aged diabetic rats.

Methods: Male Wistar rats (n = 108, 22-24 months old, 400-450 g) received high-fat diet/low dose of streptozotocin to induce type-2 diabetes, then were randomized into 9 groups of 12 rats each with/without I/R and/or melatonin, NMN, and ubiquinol, alone or in dual or triple combinations. Myocardial I/R was induced by LAD occlusion for 30 min followed by 24 h reperfusion. NMN (100 mg/kg/48 h, intraperitoneally) was administered for 28 days before I/R operation. Melatonin (10 mg/kg, intraperitoneally) and/or ubiquinol (30 mg/kg, intravenously) were administered at early reperfusion. Finally, hemodynamic index changes, infarct size, CK-MB levels, mitochondrial functional endpoints, and expression of mitochondrial biogenesis genes (SIRT-1/PGC-1α/NRF-2/TFAM) were assessed.

Results: The solo and dual applications of melatonin, NMN, and ubiquinol did not exert remarkable cardioprotective impacts. However, the triple combination improved myocardial function and decreased infarct size and CK-MB levels following myocardial I/R (P < .05 to P < .01). It also improved mitochondrial function and restored mitochondrial biogenesis genes (P < .01).

Conclusions: Combination therapy with melatonin, NMN, and ubiquinol exerted significant cardioprotection and improved mitochondrial function and biogenesis via upregulation of SIRT-1/PGC-1α/NRF-2/TFAM profiles in aged diabetic rats and, thus, offers a promising strategy for providing noticeable cardioprotection against I/R injury also in aged diabetic patients.

Keywords: Aging; Cardioprotection; Diabetes; Melatonin; Nicotinamide mononucleotide; Ubiquinol.

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental* / drug therapy
  • Diabetes Mellitus, Type 2* / drug therapy
  • Infarction / drug therapy
  • Ischemia
  • Male
  • Melatonin* / pharmacology
  • Melatonin* / therapeutic use
  • Morbidity
  • Myocardial Ischemia*
  • Myocardial Reperfusion Injury* / drug therapy
  • Myocardial Reperfusion Injury* / metabolism
  • Myocardial Reperfusion Injury* / prevention & control
  • Nicotinamide Mononucleotide / pharmacology
  • Nicotinamide Mononucleotide / therapeutic use
  • Rats
  • Rats, Wistar
  • Ubiquinone / analogs & derivatives

Substances

  • Melatonin
  • Nicotinamide Mononucleotide
  • ubiquinol
  • Ubiquinone