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PO2-3-26

Xanthine Oxidase Inhibition protects against myocardial ischemia reperfusion injury through modulation of the MAPK/NF ·κB/TNF·α pathway

[Speaker] Jagriti Bhatia:1
[Co-author] Sana I. Khan:1, Dharamvir S. Arya:1
1:Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi, India

Background
It is well known that oxidative free radical generation, through various enzyme systems such as xanthine oxidase (XO), NADPH oxidase and myeloperoxidase, is the key pathophysiological process involved in myocardial ischemia reperfusion (IR) injury. In this study, Allopurinol (ALL) and Febuxostat (FEB) were used to inhibit XO in rats that were subjected to myocardial IR injury. The underlying molecular mechanism(s) responsible for the cardioprotection following XO inhibition were determined.

Methods
The study protocol was approved by the Institutional Animal Ethics Committee (IAEC no. 893/IAEC/15). Male wistar rats were divided into Sham, IR control, FEB 10 + IR and ALL 100 + IR groups with six rats per group. The rats in the drug treatment groups were administered FEB 10mg/kg/day and ALL 100mg/kg/day per orally respectively for 14 days. On the 15th day, the IR control and treatment groups were subjected to left anterior descending (LAD) coronary artery ligation for 45 minutes followed by 60 minute reperfusion. The rats were sacrificed and the rat hearts and blood samples were collected for further analysis.

Results
Febuxostat and allopurinol pretreatment improved hemodynamic parameters and reversed morphological alterations induced by IR. In addition, treatment with both the drugs also suppressed oxidative stress and apoptosis. The levels of pro·apoptotic proteins (Bax and caspase·3) were found to be reduced and that of antiapoptotic protein (Bcl·2) was increased along with reduction in the number of TUNEL positive cells. The levels of inflammatory markers (TNF·α, IL·6 and NF·κB) were also observed to be reduced with both FEB and ALL treatment. However, on comparing the degree of cardioprotection achieved, it was observed that FEB is superior to ALL. Further, FEB suppressed the expression of active JNK and p38 proteins and there was a concomitant rise in the levels of ERK1/ERK2, a prosurvival kinase, following XO inhibition.

Conclusion
Febuxostat exerts better cardioprotection following myocardial IR injury by suppressing inflammation and apoptosis which is mediated in part through the MAPK/NF·κBp65/TNF·α pathway.

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