Safety assessment and attenuation of cisplatin induced nephrotoxicity by tuberous roots of Boerhaavia diffusa Ritu Karwasra a , Prerna Kalra a , T.C. Nag b , Y.K. Gupta a , Surender Singh a, * , Anuj Panwar c a Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi,110029, India b Department of Anatomy, All India Institute of Medical Sciences, New Delhi, 110029, India c Division of Environmental Toxicology, AES Laboratories (P) Ltd., Noida, Uttar Pradesh, 201304, India article info Article history: Received 8 June 2016 Received in revised form 19 September 2016 Accepted 20 September 2016 Available online 22 September 2016 Keywords: Acute toxicity study Boerhaavia diffusa Cisplatin Inflammation Nephrotoxicity Oxidative stress abstract Cisplatin (Cis-diaminedichloroplatinum II) is a chemotherapeutic agent having well documented adverse effect as nephrotoxicity. This study was designed to evaluate the nephroprotective role of Boerhaavia diffusa in cisplatin-induced acute kidney injury. Wistar rats (n ¼ 6) were allocated into six groups constituting normal control, cisplatin-induced, Boerhaavia diffusa root extract in doses 50, 100 and 200 mg/kg and Boerhaavia diffusa per se group, administered orally for a period of ten days. Intraperi- toneal injection of cisplatin was administered on day 7, to all groups except normal control and Boer- haavia diffusa per se group. On day 10, cisplatin resulted in substantial nephrotoxicity in Wistar rats with significant (p < 0.001) elevation in serum creatinine and blood urea nitrogen, decline in the concen- trations of reduced glutathione and superoxide dismutase, elevation in TNF-a level in renal tissues. Boerhaavia diffusa at a dose of 200 mg/kg body weight significantly (p < 0.001) ameliorates increased in serum creatinine, blood urea nitrogen, oxidative stress and inflammatory markers. In parallel to this, it also exhibits antiapoptotic activity through the reduction of active caspase-3 expression in kidneys. Findings indicate that Boerhaavia diffusa is effective in mitigating cisplatin-induced nephrotoxicity and thus, for this the acute and sub-acute toxicity studies conducted to evaluate the safety profile of Boer- haavia diffusa. The no-observed adverse effect level (NOAEL) of tuberous roots of Boerhaavia diffusa root extract was 1000 mg/kg. © 2016 Elsevier Inc. All rights reserved. 1. Introduction Nephrotoxicity is one of the primary complications allied with the therapeutic use of numerous drugs. Cisplatin comes under the category of highly nephrotoxic drugs. It is a potent chemothera- peutic agent used to treat multiple tumor forms, but the thera- peutic utility of this drug is restricted due to its dose dependent nephrotoxicity (Langerak and Dreisbach, 2001). The mechanism of cisplatin-induced renal injury is not yet completely understood, while few studies elucidate inflammation, oxidative stress injury, and apoptosis as drivers of nephrotoxicity (Malik et al., 2015). The accumulation of oxidative stress and endogenous reactive oxygen species (ROS) induces inflammation, mitochondrial dysfunction, inhibition of protein synthesis, DNA damage, and ultimately causes cell death in the proximal tubule epithelium (Mukhopadhyay et al., 2012). It is also evident from various studies that cisplatin mediates its uptake into renal tubular cells by organic cation transporter-2 (Ciarimboli et al., 2010) and involved in development of discerning toxicity in proximal tubules and distal nephron, result- ing in acute kidney injury (AKI) and kidney failure (Dupre et al., 2016). To curtail the nephrotoxic effect of cisplatin various reno- protective interventions (such as slowing cisplatin infusion, frac- tionating cisplatin, induce diuresis, hydrate the patients with saline, amifostine) have been used, but the protective effects pro- duced by these interventions are mostly partial and persistent kidney damage still found, so till now there is no efficient phar- macotherapies to attenuate this devastating complication of cisplatin (Uppuluri et al., 2013). Recently a study showed that cisplatin toxicity can be reduced either by using competitive OCT-2 transporter or by using OCT-2 transporter knockout gene (Ciarimboli et al., 2010). All these therapeutic interventions aimed at minimizing cisplatin-induced nephrotoxicity while augmenting or retaining its antineoplatic efficacy. A number of studies con- ducted on cisplatin-induced nephrotoxicity specified that the * Corresponding author. E-mail address: surenderaiims@gmail.com (S. Singh). Contents lists available at ScienceDirect Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph http://dx.doi.org/10.1016/j.yrtph.2016.09.020 0273-2300/© 2016 Elsevier Inc. All rights reserved. Regulatory Toxicology and Pharmacology 81 (2016) 341e352