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Azadirachta indica attenuates cisplatin-induced nephrotoxicity and oxidative stress.

ABSTRACT: We investigated the effects of methanolic leaves extract of Azadirachta indica (MLEN, 500 mg/kg bwt) on cisplatin- (CP-) induced nephrotoxicity and oxidative stress in rats. CP (5 mg/kg bwt) was injected intraperitoneally and MLEN was given by gastric gavage for 5 days before or after CP injection. After 5 days of CP injection, CP-induced injury of the renal tissue was evidenced (i) as histopathological damage of the renal tissue, (ii) as increases in serum uric acid, urea, and creatinine, (iii) as increases in malondialdehyde (MDA) and nitric oxide (NO), (iv) as decreases in the level of glutathione and activities of superoxide dismutase, catalase, glutathione reductase, glutathione-S-transferase, and glutathione peroxidase, and (v) as increase in the expression of nuclear factor kappa B and apoptosis in kidney tissues. However, the oral administration of MLEN to CP-intoxicated rats for 5 days brought back MDA, NO production, and enzymatic and nonenzymatic antioxidants to near normalcy. Moreover, the histological observations evidenced that neem extract effectively rescues the kidney from CP-mediated oxidative damage. Furthermore, PCR results for caspase-3 and caspase-9 and Bax genes showed downregulation in MLEN treated groups. Therefore, Azadirachta indica can be considered a potential candidate for protection of nephrotoxicity induced by cisplatin.

SUBMITTER: Abdel Moneim AE

PROVIDER: S-EPMC4137610 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Azadirachta indica attenuates cisplatin-induced nephrotoxicity and oxidative stress.

Abdel Moneim Ahmed E AE Othman Mohamed S MS Aref Ahmed M AM

BioMed research international 20140803

We investigated the effects of methanolic leaves extract of Azadirachta indica (MLEN, 500 mg/kg bwt) on cisplatin- (CP-) induced nephrotoxicity and oxidative stress in rats. CP (5 mg/kg bwt) was injected intraperitoneally and MLEN was given by gastric gavage for 5 days before or after CP injection. After 5 days of CP injection, CP-induced injury of the renal tissue was evidenced (i) as histopathological damage of the renal tissue, (ii) as increases in serum uric acid, urea, and creatinine, (iii) ...[more]

PMID: 25162019

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Project description:Puerarin was a major isoflavonoid derived from the Chinese medical herb radix puerariae (Gegen). In present study effect of puerarin on cisplatin nephrotoxicity was evaluated. Rat model of nephrotoxicity was established by a single intraperitoneal injection of cisplatin (7mg/kg). Puerarin was administrated through caudal vein injection once per day at the dose of 10mg/kg, 30mg/kg and 50mg/kg. Biochemical assays showed that after cisplatin treatment the serum urea and creatinine increased significantly compared with control (P<0.05). Cisplatin treatment significantly increased xanthine oxidase (XO) activity and malondialdehyde (MDA) formation, and significantly decreased the levels and /or activities of enzymatic and non-enzymatic antioxidants (GSH, GPx, GST, GR, SOD, CAT), in the kidney tissues. Renal levels of TNF-α and IL-6, two important inflammatory cytokines, were also upregulated by cisplatin. Histopathological examination indicated that cisplatin treatment resulted in severe necrosis and degeneration, hyaline casts in the tubules, intertubular hemorrhage, congestion and swelling in glomerulus and leukocytes infiltration in the kidney tissues. Western blot results demonstrated that cisplatin increased TLR4 and NF-κB protein expression in the kidney tissues. However, all these changes induced by cisplatin were significantly attenuated by puerarin treatment in dose-dependent manner, which indicated the renal protective effect of puerarin. Cell culture experiments illustrated that puerarin alone treatment concentration-dependently inhibited COLO205 and HeLa tumor cell growth and dose-dependently promoted the antitumor activity of cisplatin in COLO205 and HeLa tumor cells. The promotion effects might be attributed to suppression of cisplatin-increased NF-κB p65 expression by puerarin. Taken together, findings in this study suggested that puerarin exhibited renal protection against cisplatin nephrotoxicity via inhibiting TLR4/NF-κB signaling, with no inhibition but promotion effect on the antitumor activity of cisplatin. Puerarin might be a promising adjuvant agent for cisplatin chemotherapy.

Project description:Cisplatin (Cis) is considered to be one of the most effective drugs for killing cancer cells and remains a first-line chemotherapeutic agent. However, Cis's multiple toxicities (especially nephrotoxicity) have limited its clinical use. Marsdenia tenacissima (Roxb.) Wight et Arn. (MT), a traditional Chinese medicine (TCM) employed extensively in China, not only enhances the antitumor effect in combination with Cis, but is also used for its detoxifying effect, as it reduces the toxic side effects of chemotherapy drugs. The aim of this study was to explore the therapeutic effect of MT on Cis-induced nephrotoxicity, along with its underlying mechanisms. In this study, liquid-mass spectrometry was performed to identify the complex composition of the extracts of MT. In addition, we measured the renal function, antioxidant enzymes, and inflammatory cytokines in mice with Cis-induced nephrotoxicity and conducted renal histology evaluations to assess renal injury. The expressions of the proteins related to antioxidant, anti-inflammatory, and apoptotic markers in renal tissues was detected by Western blotting (WB). MT treatment improved the renal function, decreased the mRNA expression of the inflammatory factors, and increased the antioxidant enzyme activity in mice. A better renal histology was observed after MT treatment. Further, MT inhibited the expression of the phospho-NFκB p65 protein/NFκB p65 protein (p-p65)/p65, phospho-inhibitor of nuclear factor kappa B kinase beta subunit/inhibitor of nuclear factor kappa B kinase beta subunit (p-IKKβ/IKKβ), Bcl-2-associated X (Bax), and Cleaved Caspase 3/Caspase 3 proteins, while the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Recombinant NADH Dehydrogenase, Quinone 1 (NQO1), and B-cell lymphoma-2 (Bcl-2) was increased. The present study showed that MT ameliorated renal injury, which mainly occurs through the regulation of the Nrf2 pathway, the NF-κB pathway, and the suppression of renal tissue apoptosis. It also suggests that MT can be used as an adjuvant to mitigate the nephrotoxicity of Cis chemotherapy.

Dataset Information

Azadirachta indica attenuates cisplatin-induced nephrotoxicity and oxidative stress.

Publications

Azadirachta indica attenuates cisplatin-induced nephrotoxicity and oxidative stress.

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