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Cytoprotective effects of diallyl trisulfide against valproate-induced hepatotoxicity: new anticonvulsant strategy.

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. drabdelaziz8250@gmail.com.Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28646254

Citation

Shaaban, Ahmed A., and Dina S. El-Agamy. "Cytoprotective Effects of Diallyl Trisulfide Against Valproate-induced Hepatotoxicity: New Anticonvulsant Strategy." Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 390, no. 9, 2017, pp. 919-928.
Shaaban AA, El-Agamy DS. Cytoprotective effects of diallyl trisulfide against valproate-induced hepatotoxicity: new anticonvulsant strategy. Naunyn Schmiedebergs Arch Pharmacol. 2017;390(9):919-928.
Shaaban, A. A., & El-Agamy, D. S. (2017). Cytoprotective effects of diallyl trisulfide against valproate-induced hepatotoxicity: new anticonvulsant strategy. Naunyn-Schmiedeberg's Archives of Pharmacology, 390(9), pp. 919-928. doi:10.1007/s00210-017-1393-0.
Shaaban AA, El-Agamy DS. Cytoprotective Effects of Diallyl Trisulfide Against Valproate-induced Hepatotoxicity: New Anticonvulsant Strategy. Naunyn Schmiedebergs Arch Pharmacol. 2017;390(9):919-928. PubMed PMID: 28646254.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cytoprotective effects of diallyl trisulfide against valproate-induced hepatotoxicity: new anticonvulsant strategy. AU - Shaaban,Ahmed A, AU - El-Agamy,Dina S, Y1 - 2017/06/23/ PY - 2017/03/27/received PY - 2017/06/07/accepted PY - 2017/6/25/pubmed PY - 2018/7/13/medline PY - 2017/6/25/entrez KW - Apoptosis KW - Diallyl trisulfide KW - Hepatotoxicity KW - Nuclear factor kappa B KW - Sodium valproate SP - 919 EP - 928 JF - Naunyn-Schmiedeberg's archives of pharmacology JO - Naunyn Schmiedebergs Arch. Pharmacol. VL - 390 IS - 9 N2 - 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. SN - 1432-1912 UR - https://www.unboundmedicine.com/medline/citation/28646254/Cytoprotective_effects_of_diallyl_trisulfide_against_valproate_induced_hepatotoxicity:_new_anticonvulsant_strategy_ L2 - https://dx.doi.org/10.1007/s00210-017-1393-0 DB - PRIME DP - Unbound Medicine ER -