Effects of pentoxifylline and alpha lipoic acid on methotrexate-induced damage in liver and kidney of rats.

The aim of the current study was to investigate the probable protective effects of Pentoxifylline (PTX) and Alpha Lipoic Acid (ALA), which display anti-oxidative efficacy against hepatotoxicity and nephrotoxicity, those being the major side effects of Methotrexate (MTX). Rats were divided into four groups: a control group; MTX (20mg/kg/day) group; MTX+PTX (20mg/kg/day+50mg/kg/day) group; and an MTX+ALA (20mg/kg/day+100mg/kg/day) group. At the end of the experiment, biochemical, histochemical and immunohistochemical analyses were performed on liver and kidney tissues of rats. We determined Glutathione Peroxidase (GSH-Px), Superoxide Dismutase (SOD), Catalase (CAT), Malondialdehyde (MDA), Nitric Oxide (NO) and Xanthine Oxidase (XO) levels in the liver and kidney. Moreover, Gamma Glutamyl Transferase (GGT), Direct Bilirubin (DBil), Blood Urea Nitrogen (BUN), and urea levels were measured in the serum. The histochemical evaluation revealed a significant decrease in MTX caused damage in the PTX- and ALA-treated groups (especially in ALA group). On the other hand, the immune staining of iNOS and TNF-α were observed most densely in the MTX group, while the density decreased in the PTX- and ALA-administered groups. We determined increased GGT, BUN, urea and levels of CAT, MDA, NO, and XO values in both groups, while GSH-Px (an increase in liver tissue) and DBil levels were decreased in the group that received MTX. However, we determined decreased SOD levels in liver tissue. In the PTX and ALA groups, the levels of GGT, BUN and urea as well as the levels of CAT, MDA, NO and XO decreased (SOD increased in the liver tissue), and the levels of GSH-Px and DBil increased. In conclusion, it can be stated that, although ALA is more effective in preventing the toxic effects of MTX on the liver and kidney, PTX also has a preventive effect. As a result, we can readily suggest that ALA and PTX can have protective effects by decreasing MDA, NO, BUN and urea values as antioxidants against MTX-induced damage in liver and kidney of rats.

Armagan I ，Bayram D ，Candan IA ，Yigit A ，Celik E ，Armagan HH ，Uğuz AC ... -  《-》

Protective effect of pentoxyfilline in renal toxicity after methotrexate administration.

Asvadi I ，Hajipour B ，Asvadi A ，Asl NA ，Roshangar L ，Khodadadi A ... -  《European Review for Medical and Pharmacological Sciences》

The protective effects of alpha lipoic acid on methotrexate induced testis injury in rats.

Methotrexate (MTX) is frequently used in the treatment of several diseases including cancers, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, and dermatomyositis. Previously, chemotherapeutic agents have been reported to cause permanent azoospermia and infertility in men. Methotrexate has been also shown to damage the seminiferous tubules of the testicles, lower the sperm count, and cause genetic mutations (in DNA) in sperm. In this study, we aimed to investigate the protective effects of alpha lipoic acid (ALA) on MTX-induced testicle damage in a rat model. A total of 40 male Wistar Albino rats were used in this study. The rats were divided into four groups including 10 rats in each. The first group (control group) received only saline intraperitoneal (i.p.); the second group (ALA group) was given ALA 100 mg/kg i.p.; the third group (MTX group) received single dose MTX 20 mg/kg i.p.; and the fourth group (MTX + ALA group) received single dose MTX 20 mg/kg i.p. and ALA 100 mg/kg i.p. Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), myeloperoxidase (MPO) levels in the testicular tissue and serum testosterone, serum total antioxidant status (TAS) and total oxidant status (TOS) levels were biochemically evaluated. Testicular tissues histopathologically evaluated. In the MTX group, the MDA, TAS and TOS levels were higher, while the SOD, CAT, GPx, MPO and serum testosterone levels decreased. Compared to the MTX group, the MDA, TAS and TOS levels were lower and the SOD, CAT, GPx, MPO and serum testosterone levels increased in the MTX + ALA group. In the histopathological examination, the mean seminiferous tubule length (MSTD), germinal epithelial cell thickness (GECT), and mean testicular biopsy score (MTBS) were found to significantly decrease in the MTX group, compared to the control group. These values were significantly higher in the MTX + ALA group, compared to the MTX group (p < 0.05). In our experimental study, MTX caused severe tissue destruction in testicles by increasing the formation of free oxygen radicals. Based on our study results, we suggest that, as a potent free radical scavenger, ALA can reduce MTX-induced testicular tissue damage thanks to its antioxidant and anti-inflammatory properties.

Pınar N ，Çakırca G ，Özgür T ，Kaplan M ... -  《-》

Protective effect of alpha-lipoic acid in methotrexate-induced ovarian oxidative injury and decreased ovarian reserve in rats.

Soylu Karapinar O ，Pinar N ，Özcan O ，Özgür T ，Dolapçıoğlu K ... -  《-》

Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats.

Hepatic injury is a major side effect associated with methotrexate (MTX) therapy resulting from inflammatory reactions and oxidative stress induction. Therefore, liver fibrosis incidence is augmented with long-term MTX therapy. Alpha lipoic acid (ALA) is a naturally occurring compound with potent antioxidant activity. This study explored the hepatoprotective mechanisms of ALA against MTX-induced hepatic injury in rats. Hepatic injury was induced in MTX group by 20 mg/kg body weight ip. injection of MTX. ALA group was pretreated with ALA 60 mmol/kg body weight ip. for five days followed by a single dose of MTX in the sixth day. Blood samples and liver tissues were then obtained to assess several biochemical parameters as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), reduced glutathione (GSH), total antioxidant capacity (TAC) and lipid peroxidation. Nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway was studied by determining the extent of mRNA Nrf2 expression and the level of HO-1. Hepatic stellate cells (HSCs) activation was evaluated by estimating the expression of α-smooth muscle actin (α-SMA) and hydroxyproline content. Also, tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and caspase-3 were assessed by ELISA in addition to histopathological examination of liver samples. Results showed that ALA pretreatment improved liver function since serum ALT, AST and ALP levels were reduced. Additionally, ALA restored GSH and TAC levels when compared to MTX group and decreased lipid peroxidation. ALA exerted its antioxidant effect via Nrf2/HO-1 pathway as well as it showed anti-inflammatory and antiapoptotic effects by reducing TNF-α, iNOS, COX-2 and caspase-3 levels in liver tissue homogenate. Finally, ALA suppressed HSCs activation by decreasing α-SMA expression and hydroxyproline content in liver. It was concluded that ALA has hepatoprotective effects against MTX-induced hepatic injury mediated by Nrf2/HO-1 pathway as well as anti-inflammatory and antiapoptotic properties.

Fayez AM ，Zakaria S ，Moustafa D 《-》