Cannabinoid 2 receptor agonist and L-arginine combination attenuates diabetic cardiomyopathy in rats via NF-ĸβ inhibition

Can J Physiol Pharmacol. 2022 Mar;100(3):259-271. doi: 10.1139/cjpp-2021-0046. Epub 2021 Dec 3.


Beta-caryophyllene (BCP), a cannabinoid 2 (CB2) receptor agonist has recently been found to have cardioprotective activity as an anti-inflammatory and antioxidant molecule. L-arginine (LA), a nitric oxide (NO) donor, is a potential regulator of cardiovascular function. Considering the role of CB2 receptor activation and NO regulation in cardiovascular diseases, the combination of BCP with LA may be a possible treatment of diabetic cardiomyopathy (DCM). Hence, we investigated the efficacy of the novel combination of BCP with LA on cardiovascular inflammation and oxidative stress in diabetic rats. DCM was induced by streptozotocin (55 mg/kg) in Sprague-Dawley rats intraperitoneally. BCP, LA, and BCP with LA were administered to diabetic rats for 4 weeks. After completion of the study, hemodynamic parameters, biochemical parameters, and inflammatory cytokine levels were analyzed. Also, oxidative stress parameters, nuclear factor kappa beta (NF-ĸβ) expression, and histopathology in cardiac tissues were estimated. The combination of BCP (200 mg/kg) with LA (200 mg/kg) significantly normalized the hemodynamic parameters and decreased the glucose, cardiac markers, interleukin-6, and tumor necrosis factor-alpha levels. Treatment of BCP and LA showed a significant decrease in oxidative stress and downregulated the cardiac expression of NF-ĸβ. Thus, the combination of BCP with LA improves cardiac functions by attenuating inflammation through NF-ĸβ inhibition in DCM.

Keywords: L-arginine; NF-ĸβ inhibition; beta-caryophyllene; bêta caryophyllène; cardiomyopathie diabétique; diabetic cardiomyopathy; inhibition du NF-ĸβ; streptozotocin; streptozotocine.

MeSH terms

  • Animals
  • Arginine / pharmacology
  • Arginine / therapeutic use*
  • Diabetes Mellitus, Experimental
  • Diabetic Cardiomyopathies / drug therapy*
  • Diabetic Cardiomyopathies / genetics*
  • Down-Regulation / drug effects*
  • Drug Therapy, Combination
  • Male
  • NF-kappa B / metabolism*
  • Oxidative Stress / drug effects
  • Polycyclic Sesquiterpenes / pharmacology
  • Polycyclic Sesquiterpenes / therapeutic use*
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB2 / agonists*
  • Streptozocin


  • Cnr2 protein, rat
  • NF-kappa B
  • Polycyclic Sesquiterpenes
  • Receptor, Cannabinoid, CB2
  • Streptozocin
  • Arginine
  • caryophyllene