Attenuation of gentamicin‐induced nephrotoxicity: trimetazidine versus N‐acetyl cysteine

Abstract

Gentamicin (G) is a highly nephrotoxic aminoglucoside. It was used to experimentally induce nephrotoxicity in male Wistar rats. To find a drug capable of protecting the nephron we assayed a cardioprotector (trimetazidine, TMZ) and a hepatoprotector (N-acetyl cysteine, NAC). The rats were divided into six groups (n = 8): (A) control without drugs; (B) treated with 50 mg kg(-1) per day (i.p.) of G for 7 days; (C) diet supplemented with 20 mg kg(-1) per day of TMZ for 7 days; (D) treated with 10 mg kg(-1) per day (i.p.) of NAC for 7 days; (E) pretreated for 7 days with 20 mg kg(-1) per day of TMZ and during the following 7 days with G + TMZ; (F) pretreated for 7 days with 10 mg kg(-1) per day (i.p.) of NAC and during the following 7 days with G + NAC. Urea and creatinine as well as the excretion of urinary gamma-glutamyl transpeptidase (GGT(u)) and urinary N-acetyl-glucosaminidase (NAG(u)) were determined and structural and ultrastructural studies were carried out. Group B was used as a G-induced nephrotoxicity control. Pretreatment with TMZ (E) showed a protector effect against induced nephrotoxicity, with no biochemical or functional changes nor alterations in histoarchitecture or ultrastructure. Pretreatment with NAC (F) showed no protector effect against G-induced nephrotoxicity since no statistically significant differences were found with respect to the control group with G. We conclude that G-induced nephrotoxicity is attenuated by the cytoprotective effect of TMZ. We may infer that TMZ inhibits the reabsorption and consequently the accumulation of G in the proximal tubule cell.

Trimetazidine Decreases Risk of Contrast-Induced Nephropathy in Patients With Chronic Kidney Disease

“…These effects have been experimentally assessed in various models including cell cultures, isolated tissues, and different perfused organs. It was found to decrease IRI in an animal model of acute renal failure, 29,30 gentamicininduced nephrotoxicity, 31 and CIN in the studies included in this analysis. With regard to IRI, TMZ was shown to prevent the mitochondrial membrane dissipation, restore nicotinamide adenine dinucleotide phosphate levels, decrease Ca 2þ -induced mitochondrial swelling, restore glutathione peroxidase levels, 32 and enhance the expression of hypoxia-inducible factor 1a.…”

Protective Role of Trimetazidine Against Neomycin-induced Hair Cell Damage in Zebrafish

“…Trimetazidine (TMZ), 1-2,3,4 tri-metoxibencil piperazine dihydrochloride, is a clinically available drug used for ischemic heart disease because it prevents cell death secondary to transient myocardial ischemia that occurs during reperfusion [8,9]. Numerous experimental studies have reported that TMZ prevents an excessive release of free radicals, which are particularly toxic to phospholipid membranes and are responsible for the decrease in intracellular adenosin triphosphate (ATP) concentration and the extracellular leakage of potassium and protects mitochondrial function [8,10,11].…”

“…Numerous experimental studies have reported that TMZ prevents an excessive release of free radicals, which are particularly toxic to phospholipid membranes and are responsible for the decrease in intracellular adenosin triphosphate (ATP) concentration and the extracellular leakage of potassium and protects mitochondrial function [8,10,11]. Zebrafish have hair cells on the surfaces of their bodies that function as part of the lateral line sensory system [12,13].…”

On the Performance of Trimetazidine and Vitamin E as Pharmacoprotection Agents in Cyclosporin A-Induced Toxicity

“…Some authors have reported that TMZ exerts a cytoprotective effect on the cardiomyocyte [16–20]. Our previous works have demonstrated the cytoprotection of TMZ in an in vivo model of gentamicin-induced nephrotoxicity [21]. …”

“…Our experiments using an in vivo model to study the effect of TMZ on the nephrotoxicity induced by gentamicin demonstrated that TMZ, when used in a 7-day pretreatment, was able to attenuate the nephrotoxic effect of this aminoglycoside [21]. …”