Renoprotective Effects of Gamma‐Aminobutyric Acid on Cisplatin‐induced Acute Renal Injury in Rats

Abstract

To investigate the effect of gamma-aminobutyric acid (GABA) on acute renal injury (ARI), we used here a rat model of acute tubular necrosis induced by the anticancer drug cisplatin (CP). GABA was given orally (100 or 500 mg/kg/day for ten consecutive days), and on the 6th day, some of the treated rats were also injected intraperitoneally with either saline or CP (6 mg/kg). Four days after CP treatment, urine was collected from all rats, which were then anaesthetized for blood pressure and renal blood flow monitoring. This was followed by intravenous injection of norepinephrine for the assessment of renal vasoconstrictor responses. Thereafter, blood and kidneys were collected for measurement of several functional, biochemical and structural parameters. GABA treatment (at 500 but not 100 mg/kg) significantly mitigated all the measured physiological and biochemical indices. Sections from saline-and GABA-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with GABA (500 mg/kg). The concentration of platinum in the cortical tissues was not significantly altered by GABA treatment. The results suggested that GABA can ameliorate CP nephrotoxicity in rats. Pending further pharmacological and toxicological studies, GABA may be considered a potentially useful nephroprotective agent in CP-induced ARI.Cisplatin (cis-diamminedichloroplatinum II, CP), first discovered in 1965, is still one of the most effective and commonly used chemotherapeutic agents in the treatment of a variety of solid tumours including those of the head, neck, testis, ovary breast and penis [1][2][3], mainly because of its high efficacy and low cost. The drug's efficacy increases with dose, but high doses are associated with many severe adverse effects, particularly nephrotoxicity [4], which is often the main doselimiting factor in therapy with CP [5,6]. Despite many studies, the mechanism underlying the side effects induced by CP is not fully understood but has been suggested to be multi-factorial in nature [5,[7][8][9][10][11]. These possible mechanisms include the generation of reactive oxygen species (ROS) and inflammation. The former could interfere with the antioxidant defence system and result in oxidative damage in different tissues, and reaction with thiols in protein and glutathione, which could cause cell dysfunction [12,13], and the latter (inflammation) could be provoked by damage to the epithelial cells of the kidneys and may amplify renal injury and dysfunction in vivo [14]. Mediated by glutathione S-transferase, CP is known to be transformed in vivo into a more toxic compound in the kidneys [15].Various strategies and drugs have been attempted to ameliorate or prevent CP nephrotoxicity via supplementation of preventive agents simultaneously. These include antioxidants, modulators of nitric oxide, diuretics, cytoprotective and antiapoptotic agents [13,[16][17][18][19]. However, none of these were ...

The Role of Gamma Amino Butyric Acid in Cisplatin-induced Nephrotoxicity in Streptozotocin-induced Diabetic Rats

“…[ 46 ] In the present study, CP alone increases the MDA level of kidney tissue in two genders. When compared with GABA alone, GABA reduces oxidative stress through increased activity of antioxidant enzymes and decreased lipid peroxidation;[ 14 18 ] also, we observed that GABA decreased serum MDA level in male diabetic rats. We are wise that GABA is upper in the male than female.…”

“…[ 11 ] GABA has vasorelaxant effects[ 17 ] and it can ameliorate CP nephrotoxicity in rats. [ 18 ] GABA exerts antidiabetic effects by acting β-cell restoration and immune suppression[ 19 ] and it could adjust insulin and glucagon secretion and could be used for type 1 diabetes therapy. [ 20 ] In the current study, we investigated the role of GABA in CP-induced nephrotoxicity in STZ-induced diabetic rat model.…”

Platycodin D protects acetaminophen-induced hepatotoxicity by inhibiting hepatocyte MAPK pathway and apoptosis in C57BL/6J mice

“…Oxidative stress has been known as an important factor to promote cisplatin-induced nephrotoxicity through increasing the accumulation of intracellular ROS [24][25][26]. Under normal physiological conditions, cells control ROS level through balancing the generation of ROS and their elimination by scavenging system [27].…”

Effects of High‐Dose Cisplatin Chemotherapy and Conventional Radiotherapy on Urinary Oxidative and Nitrosative Stress Biomarkers in Patients with Head and Neck Cancer

“…As suggested by this present study and previous ones cited, cisplatin causes high oxidative and nitrosative stress, which explains its toxicity. Therefore, numerous studies have been conducted using antioxidant compounds to attenuate cisplatin‐induced oxidative stress and adverse events . However, it appears that there is still no consensus on whether antioxidants should be administered during cancer treatment as a preventive strategy against the related toxicities of the chemotherapeutic agents.…”