Thymoquinone Triggers Anti-Apoptotic Signaling and Targets Apoptotic Regulators in a Model of Hepatic Ischemia Reperfusion Injury
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- Category: Vol. 77, September 2009
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Thymoquinone Triggers Anti-Apoptotic Signaling and Targets Apoptotic Regulators in a Model of Hepatic Ischemia Reperfusion Injury,OLA A. HEIKAL, LOBNA A. KASSEM, NADIA M. SHARAF, RADWA M. MANSOUR and LAILA G. MAHRAN
Abstract
Background and Aim: Thymoquinone (TQ) has been reported as potent inducer of apoptosis in cancer cells. How-ever, the role of TQ as apoptotic or antiapoptotic has not been yet established in other types of cell injuries. Our objective is to explore whether TQ exerts hepatoprotective effect against hepatic ischemia reperfusion injury (I/R) and to identify its potential effect on apoptotic pathways.
Methods: Rats were divided into eight groups: gp I: Sham operated; gp II: I/R (45 min. ischemia-60 min. reperfusion). The other six groups were given PO administration of TQ aqueous solution at 5, 20 & 50 mg/Kg/day dose levels for 10 days. At the end of treatment three groups were not subjected to any intervention (groups III, IV, V: TQ control groups) or subjected to 45 min ischemia followed by one-hour reperfusion as in group II (Group VI, VII, VIII: TQ pretreated I/R groups). Serum levels of liver enzymes, tissue levels of malondialdehyde (MDA), reduced glutathione (GSH) and TNF-a were measured. Activities of caspases 8, 9 & 3 were determined. Cytochrome C in cytosol was determined by solid phase ELISA. Expression of anti-apoptotic BcL-2 & pro-apoptotic Bax proteins as well as nuclear factor Kappa B (NF-kB) were assessed by poly-merase chain reaction. Apoptosis end point was detected by electrophoresis for analysis of DNA fragmentation.
Results: TQ administration before I/R resulted in signif-icant decrease in liver enzymes, MDA and TNF-a tissue levels with increased GSH content. It also inhibited cytochrome C release into the cytosol, down regulated the expression of NF-kB & Bax and up regulated the Bcl2 proteins. Hepatic apoptosis was significantly attenuated as evidenced by signif-icant decrease in all caspases activities and by DNA fragmen-tation.
Conclusions: TQ exerts antiapoptotic effect through attenuating oxidative stress and inhibiting TNF-a induced NF-kB activation. Furthermore, it regulates Bcl-2/Bax ratio inhibiting downstream caspases in I/R model.