Metformin and silymarin afford protection in cyclosporine A induced hepatorenal toxicity in rat by modulating redox status and inflammation

Abstract

The use of cyclosporine A (CsA) as an immunosuppressive agent is often limited owing to its hepatotoxic and nephrotoxic properties. The present study was designed to evaluate the protective effect of metformin and silymarin in a rat model of CsA induced hepatorenal toxicity. The study included seven groups of Wistar albino rats (n = 6 per group): normal control, experimental control (CsA alone, 25 mg/kg), CsA + metformin (50 and 500 mg/kg), CsA + silymarin (50 and 200 mg/kg) and CsA + vitamin E (100 mg/kg). All the drugs were given daily for a period of 21 days by oral gavage and their effect was evaluated on serum levels of organ function markers (serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, bilirubin, urea/blood urea nitrogen, creatinine), markers of oxidative stress (thiobarbituric acid reactive substances, glutathione, superoxide dismutase), inflammation (nitrite, myeloperoxidase, tumour necrosis factor‐alpha, prostaglandin E2), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelling positivity) in addition to tissue histology, cyclooxygenase (COX)‐2 and inducible nitric oxide synthase (iNOS) immunoreactivity. Administration of metformin and silymarin along with CsA ameliorated functional damage to liver and kidneys in a dose‐dependent manner. Significant and comparable improvement in the tissue levels of oxidative stress, inflammation, apoptotic markers was also observed following treatment with both the test drugs. Normalization of histology scores, as well as COX‐2 and iNOS immunoreactivity scores, further strengthened these findings. The hepatoprotective and nephroprotective effects of metformin and silymarin were comparable and matched with that of reference drug, vitamin E. The findings of the present study suggest that both metformin and silymarin have a potential for clinical use in patients receiving long‐term CsA treatment to maintain their liver and kidney functions.

Inhibition of oxidative stress and apoptosis by camel milk mitigates cyclosporine‐induced nephrotoxicity: Targeting Nrf2/HO‐1 and AKT/eNOS/NO pathways

“…Likewise, the in vitro evidence has also reported that CsA increases the production of ROS in human renal mesangial cells (El‐Sheikh et al., 2019; Wu et al., 2018). The exaggerated overshooting of free radicals and ROS has been characterized to trigger lipid peroxidation of the renal cell membranes resulting in membrane derangements/dysfunction, as proved herein, and in previous reports (Ateyya, 2015; El‐Sheikh et al., 2019; Vangaveti et al., 2021). In the same regard, CsA has been reported to deplete the renal enzymatic/non‐enzymatic antioxidant armory, as seen herein, where CsA diminished the GSH, GPx, and SOD; observations that are in line with several reports (Ateyya, 2015; El‐Sheikh et al., 2019; Wu et al., 2018).…”

“…In fact, the depletion of GSH has been reported to disrupt the activity of GPx and sensitize the renal cells to diverse stresses, which contributes to the aggravation of renal oxidative stress (Arab et al., 2018b). Of note, the observed upregulation of NOX‐1 has been reported to mediate the renal injury in several toxicant‐induced renal pathologies (Arab et al., 2018a,b; El‐Naga, 2014; Vangaveti et al., 2021). In the current set of experiments, CsA triggered an upregulated expression of Nrf2 and its downstream HO‐1 target.…”

“…Virtually, the overshooting of the reactive oxygen species (ROS) and associated lipid peroxidation/oxidative aberrations are major hallmarks of CsA renal injury (Wu et al., 2018). In this regard, the overshooting of ROS has been characterized in CsA‐treated human renal mesangial cells (Vangaveti et al., 2021; Wu et al., 2018). Moreover, activated NADPH oxidase (NOX‐1) has been reported as a chief player in CsA‐evoked oxidative stress and aberrations.…”

Metformin: A Novel Weapon Against Inflammation

“…Significant protection of oxidative stress (increased SOD activity and GSH levels), inflammation (decreased MPO and TNF-α) is observed in kidney tissues of rat following metformin treatment. Normalization of histological changes, as well as COX-2 and iNOS immunoreactivity scores, further strengthens these findings (Vangaveti et al, 2020).…”

Metformin alleviates chronic obstructive pulmonary disease and cigarette smoke extract-induced glucocorticoid resistance by activating the nuclear factor E2-related factor 2/heme oxygenase-1 signaling pathway

“…Another study showed that MET could reduce the release of mitochondrial ROS and IL-6 in alveolar macrophages exposed to particulate matter of diameter ≤ 2.5 µm (PM2.5) [ 49 ]. The latest research suggests that MET and silymarin have a protective effect upon cyclosporine A-induced hepatorenal toxicity because they restore oxidative homeostasis and regulate the release of proinflammatory mediators [ 50 ]. Those findings provide a theoretical basis for MET in COPD treatment.…”