Department of Physiology, Vidyasagar College, 39, Sankar Ghosh Lane, Kolkata, 700006, India; Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, 92, APC Road, Kolkata, 700009, India.
Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, 92, APC Road, Kolkata, 700009, India.
Chem Biol Interact. 2023 Sep 1;382:110611. doi: 10.1016/j.cbi.2023.110611. Epub 2023 Jun 20.
Ketorolac tromethamine (KT), is a widely used non-steroidal anti-inflammatory drug (NSAID) for treating moderate to severe pain. However, the use of KT has been restricted due to its highly toxic attributes that lead to severe gastric ulceration and bleeding. The protective effects of exogenous melatonin (MT) has been reported in conditions associated with gastro-intestinal disorders. This study aims at exploring the role of gastric endogenous MT level and it's metabolizing enzyme AANAT, at the onset of ketorolac mediated toxicities in the gastric mucosa. Gastric mucosal damage was induced in experimental rats by oral administration of graded doses of KT, where 50 mg/kg b.w. of KT was observed to incur maximum gastric lesions. However, gastric damages were found to be protected in rats, pre-treated with 60 mg/kg b.w. of MT. Post-sacrifice, mean ulcer index, oxidative status, total melatonin levels and enzyme activities associated with MT biosynthesis and catabolism were estimated. The results reveal that KT decreases AANAT activity with a concomitant decline in endogenous MT level which cumulatively aggravates gastric toxicity. Moreover, exogenous MT administration has been found to be protective in ameliorating this ulcerogenic process in rats, challenged with KT. Biochemical and histo-pathological observations revealed the reduction in oxidative stress level and replenishment of depleted gastric MT levels in MT pre-treated animals, which might be the causative factors in conferring protection to the gastric tissues and residing mitochondria. The results revealed a correlation between depleted gastric MT level and ulcer formation, which unveiled a novel ulcerogenic mechanism. This may bring forth future therapeutic relevance for treating patients suffering from KT mediated acute gastric toxicities.
酮咯酸氨丁三醇（KT）是一种广泛使用的非甾体抗炎药（NSAID），用于治疗中度至重度疼痛。然而，由于其具有高度毒性，会导致严重的胃溃疡和出血，因此 KT 的使用受到限制。外源性褪黑素（MT）已被报道在与胃肠疾病相关的情况下具有保护作用。本研究旨在探讨胃内源性 MT 水平及其代谢酶 AANAT 在 KT 介导的胃黏膜毒性发生中的作用。通过口服给予不同剂量的 KT 诱导实验大鼠胃黏膜损伤，其中 50mg/kg b.w.的 KT 观察到最大胃损伤。然而，预先用 60mg/kg b.w.的 MT 预处理的大鼠胃损伤得到了保护。安乐死后，估计平均溃疡指数、氧化状态、总褪黑素水平以及与 MT 生物合成和分解代谢相关的酶活性。结果表明，KT 降低了 AANAT 活性，同时内源性 MT 水平下降，这累积加重了胃毒性。此外，在 KT 挑战的大鼠中，外源性 MT 给药被发现具有保护作用，可以改善这种溃疡形成过程。生化和组织病理学观察显示，氧化应激水平降低，耗尽的胃 MT 水平得到补充，这可能是赋予胃组织和驻留线粒体保护作用的原因。结果显示胃内 MT 水平降低与溃疡形成之间存在相关性，揭示了一种新的溃疡形成机制。这可能为治疗因 KT 引起的急性胃毒性而受苦的患者带来未来的治疗相关性。
