Ursodeoxycholic acid abrogates gentamicin-induced hepatotoxicity in rats: Role of NF-κB-p65/TNF-α, Bax/Bcl-xl/Caspase-3, and eNOS/iNOS pathways.
AIM
The present study focused on the possible underlying protective mechanisms of UDCA against GNT-induced hepatic injury.


METHODS
For achieving this goal, adult male rats were allocated into 4 groups: normal control (received vehicle), GNT (100 mg/kg, i.p. for 8 days), UDCA (60 mg/kg, P.O. for 15 days), and GNT + UDCA (received UDCA for 15 days and GNT started from the 7th day and lasted for 8 days).


RESULTS
The results revealed that UDCA significantly improved GNT-induced hepatic injury, oxidative stress, apoptosis, and inflammatory response. Interestingly, UDCA inhibited apoptosis by marked down-regulation of the Bax gene, Caspase-3, and cleaved Caspase-3 protein expressions while the level of Bcl-xL gene significantly increased. Moreover, UDCA strongly inhibited the inflammatory response through the down-regulation of both NF-κB-p65 and TNF-α accompanied by IL-10 elevation. Furthermore, the obtained results ended with the restored of mitochondria function that confirmed by electron microscopy. Histological analysis showed that UDCA remarkably ameliorated the histopathological changes induced by GNT.


SIGNIFICANCE
UDCA may be a promising agent that can be used to prevent hepatotoxicity observed in GNT treatment. This effect could be attributed to, at least in part, the ability of UDCA to modulate NF-κB-p65/TNF-α, Bax/Bcl-xl/Caspase-3, and eNOS/iNOS signaling pathways.
['Ali|Fares E M|FEM|', 'Hassanein|Emad H M|EHM|', 'Bakr|Adel G|AG|', 'El-Shoura|Ehab A M|EAM|', 'El-Gamal|Dalia A|DA|', 'Mahmoud|Amany R|AR|', 'Abd-Elhamid|Tarek Hamdy|TH|']
D000818:Animals D017209:Apoptosis D053148:Caspase 3 D056486:Chemical and Drug Induced Liver Injury D004347:Drug Interactions D005839:Gentamicins D022781:Hepatocytes D008297:Male D008930:Mitochondria, Liver D052247:Nitric Oxide Synthase Type II D052250:Nitric Oxide Synthase Type III D018384:Oxidative Stress D011897:Random Allocation D051381:Rats D017208:Rats, Wistar D015398:Signal Transduction D051996:Transcription Factor RelA D014409:Tumor Necrosis Factor-alpha D014580:Ursodeoxycholic Acid D051028:bcl-2-Associated X Protein D051020:bcl-X Protein
Ursodeoxycholic acid NF-κB-p65/TNF-α Bax/Bcl-xl/Caspase-3 Gentamicin Mitochondrial dysfunction