1 Plant Archives Vol. 20, Supplement 2, 2020 pp. 2948-2958 e-ISSN:2581-6063 (online), ISSN:0972-5210 SODIUM THIOSULPHATE SHOWS PROMISING ANTI-INFLAMMATORY ROLE AGAINST DOXORUBICIN-INDUCED RENAL INJURY DEPENDING ON TLR4 PATHWAY INHIBITION Ali Khames 1 , Amany M. Gad 3 , Ola M. Abd El-raouf 4 , Mohamed Ahmed Kandeil 5 , and Marwa M. Khalaf 2 . 1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Deraya University, Minya, Egypt. 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt. 3,4 Department of Pharmacology, National Organization for Drug Control and Research (NODCAR), Cairo, Egypt. 5 Department of Biochemistry, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt Running Title: TLR4 impact on doxorubicin-induced nephrotoxicity . Correspondence: All correspondence should be addressed to: Dr.Ali Khames Abd El-twab Department of Pharmacology and Toxicology, Faculty of Pharmacy, Deraya University. Postal code: 62514, Salah Salem Street, Minya, Egypt E-mail: ali.khames@deraya .edu.eg; ali_khamies@yahoo.com Abstract Doxorubic in nephrotoxicity is always a major cause of death for cancer patients. objectives: our study aimed at proving the potential curative mechanisms of sodium thiosulphate, on experimentally-induced nephrotoxicity in rats by doxorubicin explaining the mechanisms of the serious inflammation pathway TLR4/MAPK P38/NF-B/TNF-. Methods: nephrotoxicity was induced by parenteral administration of doxorubicin (5.2mg/kg/ weekly for 4 weeks). And the treatment depends on giving sodium thiosulphate (400 mg/kg, p.o.) One hour before doxorubicin injection for4 weeks. Doxorubicin injection caused severerenal dysfunction evident from a significant increase in the kidney biomarkers; urea,creatinine, KIM.1, and serum cystatin C,together with decreasing serum albumin and total protein.Besides,increased MDA and MPOassociated with a significant decrease inGSH, Nrf-2,SOD and catalase activities, heightened inflammatory markers TLR4, MAPK P38,NF-B,IL-1, and TNF- alpha also, induced apoptotic markers expression in renal tissues of doxorubicin group.However, treatment with sodium thiosulphate normalized oxidative markers, inflammatory markers,MDA,MPO, GSH, SOD, Nrf-2and catalase. Also, prevented apoptotic changesthroughsuppressing BAX and increasing Bcl-2. Conclusion: Our study provides a promising protective use of sodium thiosulphate against doxorubicin nephrotoxicity. Keywords: Doxorubicin, Nephrotoxicity, oxidative stress, Inflammation, Apoptosis, TLR4 Introduction Doxorubicin (DOX) is a natural anthracycline anti- tumor agent used in several cancer treatment protocols for several types of cancer including, blood malignancy leukemia, lymphoma and solid cancers such as breast, cervical, uterine, ovarian, pulmonary and liver cancers Shi et al. (2018); Zidan et al., 2018). Unfortunately, despite being a very important anti-cancer drug, doxorubicin use can cause damage to vital organs including heart and kidney (Zhao et al., 2014; Ren et al., 2016; Nagai et al., 2018). Nephrotoxicity is an important dose-limiting adverse effect in the doxorubicin treatment protocol. Different pathways are included in doxorubicin-induced renal injury including oxidative stress, inflammation (Benzer et al., 2018), fibrotic kidney changes (Cardoso et al., 2018), and apoptosis that may trigger renal injury through tubular degeneration (Shaker et al., 2018). Furthermore, hyperuricemia can be another causative factor in doxorubicin-induced renal injury (Khames et al., 2017). Danmaigoro et al. (2018), reported that up till now there is no protective drug that could completely reverse doxorubicin-induced nephrotoxicity. Also, most of the previous work that considers doxorubicin nephrotoxicity was limited only to estimating oxidative stress and hyperuricemia markers (Khan et al., 2018). However, in this study, we will try to cast light on the effect of TLR4 activation in doxorubicin-induced nephrotoxicity. TLR4 has been reported to play a great role in renal diseases and tubular damage, however, its mechanism isn’t completely understood (Molteni et al., 2016). It is considered to be a leading receptor in the inflammatory cascade induced by doxorubicin, besides being a part of the innate immunity activated by several ligands such as bacterial lipopolysaccharides and drugs (XIAO et al., 2013, Molteni et al., 2016, Kuzmich et al., 2017). Binding of a ligand to TLR4 results in its activation and then activating mitogen-activated protein kinases (MAPK), Nuclear factor-kappa B (NF-B) signaling pathways and TNF- inducing inflammation (Zhu et al., 2015; Molteni et al., 2016; Kuzmich et al., 2017). Sodium thiosulphate is a sulfur salt that has been generally used for decades in human medicine in conjunction with sodium nitrite for the treatment of cyanide intoxications (McGeer and McGeer, 2016; Corona et al., 2018). Sodium thiosulphate has been previously reported to protect against oxidative stress and inflammation (Bijarnia et al., 2015; Ravindran et al., 2017). Furthermore, sodium thiosulphate has many clinical applications including inhibiting calciphylaxis (Cicone et al., 2004; Hayden and Goldsmith, 2010), ameliorating chondrocyte mineralization, reducing the severity of murine osteoarthritis (Nasi et al., 2016) and protecting cardiac cells against ischemia-reperfusion (Ravindran et al., 2017). Importantly, it has been previously reported to protect against nephrotoxicity (Ishikawa et al., 2015; Freyer et al., 2017)