Kamthorn Thamprasert

Investigating the protective effects of aged garlic extract on cyclosporin-induced nephrotoxicity in rats.

Cyclosporin A (CsA) nephrotoxicity has been described in solid organ recipients and in the patients who were treated for autoimmune diseases. Reactive oxygen species‐induced oxidative stress and lipid peroxidations are implicated in the pathophysiology of CsA‐induced renal injury. Aged garlic extract (AGE) has been reported to exhibit potent antioxidative and free radical scavenging abilities in various disease conditions. The present study was designed to investigate whether AGE could possibly have a protective effect against nephrotoxicity induced by CsA. Male Wistar rats were treated orally with CsA (50 mg/kg/day), CsA + AGE (0.25, 0.5, 1, and 2 g/kg/day started 3 days before the first dose of CsA), or the vehicle of CsA for a period of 10 days. Blood urea nitrogen, serum creatinine, creatinine clearance, and renal histopathological changes were evaluated after 24 h of the last treatment. CsA caused an increase in blood urea nitrogen and serum creatinine by 117 and 100%, respectively, whereas it decreased creatinine clearance by 78% compared with the vehicle‐treated rats (all P < 0.001). AGE treatment (0.5, 1 and 2 g/kg) significantly protected animals against CsA‐induced biochemical changes, albeit blood urea nitrogen and creatinine clearance in the 0.5 g/kg AGE treated‐animals were only partially restored. Kidney sections taken from CsA‐treated rats showed severe vacuolations and tubular necrosis. These histopathological changes were markedly improved by pretreatment of rats with AGE at the dose of 0.5–2 g/kg. The results indicate that AGE ameliorates renal dysfunction and morphological changes induced by CsA, and imply that it could be a beneficial remedy for attenuating the CsA nephrotoxicity.

Renoprotective effect of trolox against ischaemia-reperfusion injury in rats

1 Although α‐tocopherol has been shown to improve renal function following ischaemia–reperfusion (I/R) injury, its clinical use is not common because α‐tocopherol requires several days of pretreatment to exhibit anti‐oxidative benefits. The advent of trolox, a water‐soluble analogue of α‐tocopherol, has raised the possibility that this compound may function more rapidly during acute oxidative stress than the conventional α‐tocopherol. 2 The present study was undertaken to determine the effects of the short‐term administration of trolox on renal excretory function following I/R in rats. 3 Male Wistar rats were subjected to 45 min unilateral renal artery occlusion followed by 120 min reperfusion. The control I/R group was subjected to I/R and received saline as an intravenous bolus (2 mL/kg) followed by a continuous infusion of 2 mL/kg per h starting 30 min before ischaemia, whereas the three trolox‐treated I/R groups were given an i.v. bolus of trolox (2.5 mg/kg) followed by a continuous infusion (12 mg/kg per h) starting at 30 min before ischaemia, 5 min before reperfusion and 5 min after reperfusion, respectively. Renal function, malondialdehyde, glutathione and histopathology were evaluated. 4 Ischaemia–reperfusion produced a significant deterioration of renal function, which was accompanied by an elevated malondialdehyde and depleted glutathione content. Kidneys from control I/R rats demonstrated tubular cell transformation, brush border loss, vacuolation, cast formation and tubular obstruction. These changes were attenuated by trolox treatment, with the best improvement achieved when trolox was delivered 5 min before reperfusion. 5 The results demonstrate the renoprotective effects of the short‐term administration of trolox on I/R injury. These findings indicate the ability of trolox to overcome a major drawback of using α‐tocopherol and suggest that trolox may offer a therapeutic advantage over α‐tocopherol in acute ischaemic renal failure settings.

Caffeic acid phenethyl ester protects against oxidative stress-related renal dysfunction in rats treated with cyclosporin A.

The therapeutic index of cyclosporin A (CsA), an immunosuppressive drug, is limited by its nephrotoxic effect. Oxidative stress is suggested to play a crucial role as pathogenic factors. The present study aimed at investigating the effects of caffeic acid phenethyl ester (CAPE), a phenolic antioxidant, on renal function, morphology, and oxidative stress following CsA treatment. Rats were treated with vehicle, CsA (50 mg/kg), and CsA plus CAPE (10 and 30 μmol/kg) for 10 days. Renal function, histopathology, and tissue malondialdehyde (MDA) and reduced glutathione (GSH) levels were evaluated 24 h after the last treatment. CsA produced nephrotoxicity as indicated by a significant increase in serum creatinine and blood urea nitrogen, but decrease creatinine and urea clearance compared to those treated with vehicle. Severe vacuolations and tubular necrosis were evident in the kidney of CsA‐treated rats. CsA also increased renal MDA and decreased GSH content significantly. Administration of CAPE along with CsA restored all the changes caused by CsA. These results clearly demonstrate the pivotal role of oxidative stress and its relation to renal dysfunction and also point to the protective potential of CAPE against CsA nephrotoxicity. The protection afforded by CAPE is mediated, at least in part, through inhibiting renal lipid peroxidation and enhancing or maintaining the antioxidant glutathione content.

Alpha-Lipoic Acid Attenuates Renal Injury in Rats with Obstructive Nephropathy

This study was established to determine the possible protective effects of alpha-lipoic acid (ALA), a powerful antioxidant, on renal injury in obstructive nephropathy. Male Sprague-Dawley rats were assigned into sham-operated unilateral ureteral obstruction (UUO) and UUO treated with ALA groups. ALA 60 mg/kg was injected intraperitoneally 2 days before UUO induction and continued afterward for 7 days. Renal function, oxidative stress markers, nitric oxide, transforming growth factor-1 (TGF-β1), and histological changes were evaluated at the end of the experiment. Obstruction of the ureter resulted in renal dysfunction as indicated by significant increases in blood urea nitrogen and serum creatinine. Nonobstructed contralateral kidneys in all groups examined did not show any morphological or biochemical alterations. In untreated UUO group, the obstructed kidney developed marked hydronephrosis, leukocyte infiltration, and severe interstitial fibrosis. These functional and structural changes were associated with significant increases in tissue levels of malondialdehyde, nitric oxide, and TGF-β1 but decreases in reduced glutathione and total antioxidant capacity. Pretreatment with ALA significantly minimized all the changes elicited by ureteral obstruction. These findings demonstrate that ALA supplementation attenuates renal injury in rats with obstructive nephropathy and further suggest that oxidative stress inhibition is likely to be involved in the beneficial effects of this compound.