Nootkatone attenuates myocardial oxidative damage, inflammation, and apoptosis in isoproterenol-induced myocardial infarction in rats

M F Nagoor Meeran; Sheikh Azimullah; Ernest Adeghate; Shreesh Ojha

doi:10.1016/j.phymed.2020.153405

Nootkatone attenuates myocardial oxidative damage, inflammation, and apoptosis in isoproterenol-induced myocardial infarction in rats

Phytomedicine. 2021 Apr:84:153405. doi: 10.1016/j.phymed.2020.153405. Epub 2020 Nov 7.

Authors

M F Nagoor Meeran¹, Sheikh Azimullah¹, Ernest Adeghate², Shreesh Ojha³

Affiliations

¹ Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box - 17666, Al Ain, UAE.
² Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box - 17666, Al Ain, UAE.
³ Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box - 17666, Al Ain, UAE. Electronic address: shreeshojha@uaeu.ac.ae.

PMID: 33636578
DOI: 10.1016/j.phymed.2020.153405

Abstract

Background: Myocardial infarction (MI) is a lethal manifestation of cardiovascular diseases. Oxidative stress, inflammation, and subsequent cell death are known to play crucial roles in the pathogenesis of MI. Despite tremendous developments in interventional cardiology, there is need for novel drugs for the prevention and treatment of MI. For the development of novel drugs, usage of natural products has gained attention as a therapeutic approach for ischemic myocardial injury. Among many popular plant-derived compounds, Nootkatone (NKT), a natural bioactive sesquiterpene, abundantly found in grapefruit, has attracted attention for its plausible health benefits and pharmacological properties.

Purpose: The present study investigated the cardioprotective effects of NKT in rats against MI induced by isoproterenol (ISO), a synthetic catecholamine and β-adrenergic agonist that produces MI in a physiologically relevant manner.

Methods: MI was induced in male Wistar albino rats by subcutaneous injection of ISO (85 mg/kg body weight) on 9^th and 10^th day. Rats were pre- and co-treated with NKT (10 mg/kg) through daily oral administration for eleven days.

Results: ISO-induced MI was characterized by a significant decline in cardiac function, increased serum levels of cardiomyocyte injury markers, enhanced oxidative stress, and altered PI3K/Akt and NrF2/Keap1/HO-1 signaling pathways. ISO also elevated the levels of myocardial pro-inflammatory cytokines, promoted lysosomal dysfunction, altered TLR4-NFκB/MAPK signaling, and triggered intrinsic apoptotic pathway in heart tissues. However, NKT administration significantly restored or modulated majority of the altered biochemical and molecular parameters in ISO-treated rats. Furthermore, histopathological observations confirmed the myocardial restoring effect of NKT.

Conclusion: The present study concludes the cardioprotective effects and underlying mechanisms of NKT against ISO-induced MI in rats, and suggests that NKT or plants containing NKT could be an alternative to cardioprotective agents in ischemic heart diseases.

Keywords: Apoptosis; Inflammation; Isoproterenol; Lysosomal dysfunction; Myocardial infarction; Nootkatone.

MeSH terms

Animals
Apoptosis / drug effects*
Heart / drug effects*
Inflammation / drug therapy
Isoproterenol / toxicity*
Male
Myocardial Infarction / chemically induced*
Myocardial Infarction / prevention & control
Myocardium / metabolism
Oxidative Stress / drug effects*
Polycyclic Sesquiterpenes / pharmacology*
Rats
Rats, Wistar

Substances

Polycyclic Sesquiterpenes
nootkatone
Isoproterenol