Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2017 Sep;390(9):919-928. doi: 10.1007/s00210-017-1393-0. Epub 2017 Jun 23.
Sodium valproate (VP) is an important antiepileptic drug, although it can produce deleterious hepatotoxic reactions. Diallyl trisulfide (DATS) is the principle component of garlic oil that possesses antioxidant properties. This study explored the potential hepatoprotective activity of DATS against VP-induced hepatic damage and its underlying mechanisms. In addition, the study assessed the effect of DATS on VP antiepileptic activity. Rats were given DATS once daily at two different doses along with VP for 2 weeks. Results have shown the ability of DATS to counteract VP-induced hepatic damage as it decreased elevated serum transaminases (aspartate aminotransferase and alanine aminotransferase) and alkaline phosphatase. Liver histopathology indicated that DATS preserved the hepatic structural integrity and protected against VP-induced hepatic steatosis and necro-inflammation injury. DATS ameliorated VP-induced oxidative stress and increased the antioxidant capacity of the liver. Immunohistochemical analysis showed activation of nuclear factor kappa-B along with high expression of cyclo-oxygenase-2 (COX-2) upon VP administration. This was accompanied by overproduction of proinflammatory mediators (TNF-α, IL-1β, IL-6). Tracing the apoptotic pathway, VP administration induced marked apoptosis using TUNEL staining. Furthermore, VP-treated animals exhibited high immunoexpression of Bax protein and increased levels of Bax and caspase-3 while level of Bcl2 was significantly decreased in hepatic tissue. However, DATS simultaneous treatment counteracted all of these molecular pathological changes. Using pentylenetetrazole (PTZ)-induced seizures model in mice, the effect of DATS on the anticonvulsant activity of VP was found to be positive, meaning that combination of DATS with VP can confer protection against VP-induced hepatic injurious effects through its antioxidant, antiinflammatory, and antiapoptotic properties without affecting VP antiepileptic activity.
丙戊酸钠（VP）是一种重要的抗癫痫药物，尽管它会产生有害的肝毒性反应。二烯丙基三硫（DATS）是大蒜油的主要成分，具有抗氧化特性。本研究探讨了 DATS 对 VP 诱导的肝损伤的潜在保护作用及其潜在机制。此外，本研究评估了 DATS 对 VP 抗癫痫活性的影响。大鼠在 2 周内每天接受一次 DATS 两种不同剂量，同时接受 VP。结果表明，DATS 能够抵抗 VP 引起的肝损伤，因为它降低了升高的血清转氨酶（天冬氨酸转氨酶和丙氨酸转氨酶）和碱性磷酸酶。肝组织病理学表明，DATS 保持了肝结构的完整性，并防止了 VP 引起的肝脂肪变性和坏死性炎症损伤。DATS 改善了 VP 引起的氧化应激并增加了肝脏的抗氧化能力。免疫组织化学分析显示，VP 给药后核因子 kappa-B 被激活，环加氧酶-2（COX-2）表达升高。这伴随着促炎介质（TNF-α、IL-1β、IL-6）的过度产生。通过 TUNEL 染色追踪凋亡途径，VP 给药导致明显的凋亡。此外，VP 处理的动物在肝组织中表现出 Bax 蛋白的高免疫表达增加，Bax 和 caspase-3 水平增加，而 Bcl2 水平显著降低。然而，DATS 同时治疗拮抗了所有这些分子病理学变化。使用戊四氮（PTZ）诱导的惊厥模型，发现 DATS 对 VP 抗惊厥活性的影响是阳性的，这意味着 DATS 与 VP 的联合使用可以通过其抗氧化、抗炎和抗凋亡特性来保护免受 VP 引起的肝损伤，而不影响 VP 的抗癫痫活性。
