Screening impacts of Tilmicosin induced-hepatic and renal toxicity in rats: Protection by Rhodiola Rosea extract through the involvement of oxidative stress, antioxidants, and inflammatory cytokines biomarkers

Abstract

Tilmicosin (TIL) is a semisynthetic macrolide antibiotic with a broad spectrum of activity derived from tylosin. TIL is effective in the treatment of bovine and ovine respiratory diseases caused by different microbes. In parallel, Rhodiola rosea (RHO) is a popular herbal remedy because of its anti-inflammatory and antioxidant qualities. Rats received saline or RHO for sequential 12 days. TIL was injected as a single dose subcutaneously (75 mg/kg BW) on day 6 of experiment. The protective group received RHO daily for sequential 12 days, TIL was injected as a single dose 1 hour after RHO administration on day 6 of experiment and continued for extra 6 successive days with RHO only. Samples and blood were collected for serum analysis, gene expression and immunohistochemistry screening at liver and kidney levels. TIL injection increased serum levels of hepatic and renal markers (ALP, ALT, AST, TC, TG, creatinine and urea) with a decrease in total proteins. In parallel, TIL induced hepatic and renal oxidative stress as there was an increase in malondialdehyde levels, with a decrease in catalase and reduced glutathione activities. Of interest, pre-administration of RHO inhibited TIL-induced increase in hepato-renal markers and decrease the oxidative stress and increased antioxidant activities of both liver and kidney. Quantitative RT-PCR showed that TIL increased HSP70 (heat shock protein), NFkB and TNF-α mRNA expression in liver. Moreover, TIL upregulated the expression of desmin, nestin, and vimentin expression in kidney. The upregulated genes were decreased significantly in the protective group received RHO. Serum inflammatory cytokines, together with genes of inflammatory markers in liver tissues (HSP70, NF_kB and TNF-α) and in kidney tissues (desmin, nestin, and vimentin) were all affected. TIL induced hepatic vacuolation and congestion together with glomerular atrophy. The immunoreactivity of PCNA and HMGB1 were examined immunohistochemically. At cellular levels, PCNA was decreased while HMGB1 immunoreactivity was increased in TIL injected rats and was improved by pre administration of RHO. RHO administration protected the altered changes in liver and renal histology. Current findings support the possible use of RHO to shield the liver and kidney from the negative effects of tilmicosin.