Elucidation of protective efficacy of Pentahydroxy flavone isolated from Madhuca indica against arsenite-induced cardiomyopathy: Role of Nrf-2, PPAR-γ, c-fos and c-jun

Environ Toxicol Pharmacol. 2017 Dec:56:172-185. doi: 10.1016/j.etap.2017.08.027. Epub 2017 Sep 1.

Abstract

Background: Madhuca indica J. F. Gmel. (Sapotaceae) is widely used ethnobotanically as anti-diabetic, antipyretic, hepatoprotective, anti-inflammatory and analgesic. It was shown to possess potent anti-apoptotic property.

The aim of the study: To evaluate the possible mechanism of action of isolated phytoconstituent from Madhuca indica Leaves methanolic extract (MI-ALC) on arsenic-induced cardiotoxicity in rats.

Materials and methods: The 3,5,7,3',4'-Pentahydroxy flavone (QTN) was isolated and characterized by using HPTLC, 1H NMR, and LC-MS from MI-ALC. QTN (5, 10 and 20mg/kg, p.o.) was administered in arsenic intoxicated rats (5mL/kg, p.o.) for 28days and evaluated for various behavioral, biochemical, molecular and ultra-histological changes.

Results: Treatment with QTN (10 and 20mg/kg, p.o.) significantly inhibited (p<0.05) arsenic-induced electrocardiographic, hemodynamic and left ventricular function alterations. Elevated levels of cardiac markers (LDH, CK-MB, AST, ALT, and ALP), altered lipid metabolism (total cholesterol, triglyceride, LDL, HDL, and VLDL) was significantly restored (p<0.05) by QTN. It also significantly inhibited (p<0.05) altered cardiac oxido-nitrosative stress, Na-K-ATPase level and mitochondrial enzymes (I-IV) activity after arsenite administration. QTN significantly increased (p<0.05) myocardial Nrf-2, PPAR-γ and significantly decreased (p<0.05) myocardial c-fos and c-jun mRNA expressions. Flow cytometric analysis showed that treatment with QTN (10 and 20mg/kg) significantly inhibited (p<0.05) arsenite-induce ROS and apoptosis. It also reduced ultra-histological aberrations induced by sodium arsenite.

Conclusion: Administration of 3,5,7,3',4'- Pentahydroxy flavone (i.e. Quercetin (QTN)) isolated from MI-ALC showed significant protection against arsenic-induced oxido-nitrosative stress and myocardial injury via modulation of Nrf2, PPAR-γ, and apoptosis.

Keywords: 3,5,7,3′,4′- Pentahydroxy flavone; Apoptosis; Cardiotoxicity; Nrf-2; PPAR-γ; Sodium arsenite; c-fos; c-jun.

MeSH terms

  • Animals
  • Arsenic / toxicity*
  • Cardiomyopathies / chemically induced
  • Cardiomyopathies / genetics
  • Cardiomyopathies / physiopathology
  • Cardiomyopathies / prevention & control*
  • Disease Models, Animal
  • Flavonoids / isolation & purification
  • Flavonoids / pharmacology*
  • Gene Expression Regulation / drug effects
  • Madhuca / chemistry*
  • NF-E2-Related Factor 2 / genetics
  • Nitrosative Stress / drug effects
  • PPAR gamma / genetics
  • Plant Extracts / isolation & purification
  • Plant Extracts / pharmacology
  • Plant Leaves / chemistry
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-jun / genetics
  • Rats
  • Sodium-Potassium-Chloride Symporters / drug effects

Substances

  • Flavonoids
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, rat
  • PPAR gamma
  • PPAR gamma, rat
  • Plant Extracts
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Sodium-Potassium-Chloride Symporters
  • peflavit
  • Arsenic