The selective 5-LOX inhibitor 11-keto-β-boswellic acid protects against myocardial ischemia reperfusion injury in rats: involvement of redox and inflammatory cascades

Naunyn Schmiedebergs Arch Pharmacol. 2013 Sep;386(9):823-33. doi: 10.1007/s00210-013-0885-9. Epub 2013 Jun 15.

Abstract

Myocardial ischemia induces 5-lipoxygenase (LOX) translocation and leukotriene production in the heart. Leukotrienes increase inflammatory responses aggravating, thereby, ischemia-reperfusion (I/R) injury. This study aimed to investigate whether the selective 5-LOX inhibitor 11-keto-β-boswellic acid (11-keto BA), in three different dose levels, exert a protective effect on myocardial I/R injury in an in vivo rat heart model. Sixty male Wister rats were used in this study and divided into five equal groups (n=12): GP1, sham-operated receiving normal saline; Gp 2, rats were subjected to 45 min left anterior descending coronary artery ligation followed by 4 h reperfusion to serve as I/R group. Gps 3-5 received 11-keto BA in doses 250, 500, 1,000 mg/kg, respectively, via an oral gavage for 7 days then were exposed to I/R. I/R injury induced a significant elevation in myeloperoxidase activity and gene expression of intracellular adhesion molecules, cyclooxygenase-2, 5-lipooxygenasae, nuclear factor kappa-beta, tumor necrosis factor alpha, nuclear factor (erythroid-derived 2)-like 2, and hemeoxygenease-1 consequently with reduction in glutathione peroxidase in heart tissues. Furthermore, immunohistochemical examination of the heart tissues showed positive immuostaining for both 3-nitrotyrosine and caspase-3 with DNA-ladder formation in all diseased rats. 11-keto BA in three dose levels exerted dose dependent cardioprotective effect manifested by dose-dependent reduction in serum lactate dehydrogenase and infract size through mechanisms related to enhancement of antioxidant capacity and prevention of inflammatory cascades.

MeSH terms

  • Animals
  • Arachidonate 5-Lipoxygenase / genetics
  • Cardiotonic Agents / pharmacology
  • Cardiotonic Agents / therapeutic use*
  • Caspase 3 / metabolism
  • Cyclooxygenase 2 / genetics
  • DNA Fragmentation
  • Gene Expression Regulation / drug effects
  • Glutathione Peroxidase / metabolism
  • Heme Oxygenase (Decyclizing) / genetics
  • Intercellular Adhesion Molecule-1 / genetics
  • Lipoxygenase Inhibitors / pharmacology
  • Lipoxygenase Inhibitors / therapeutic use*
  • Male
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / metabolism
  • Myocardium / pathology
  • NF-E2-Related Factor 2 / genetics
  • NF-kappa B / genetics
  • Oxidation-Reduction
  • Peroxidase / metabolism
  • Rats
  • Rats, Wistar
  • Triterpenes / pharmacology
  • Triterpenes / therapeutic use*
  • Tumor Necrosis Factor-alpha / metabolism
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • 11-keto-boswellic acid
  • Cardiotonic Agents
  • Lipoxygenase Inhibitors
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Nfe2l2 protein, rat
  • Triterpenes
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • 3-nitrotyrosine
  • Tyrosine
  • Peroxidase
  • Glutathione Peroxidase
  • Arachidonate 5-Lipoxygenase
  • Heme Oxygenase (Decyclizing)
  • Hmox1 protein, rat
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • Caspase 3