Neuroprotective effect of N-acetylcysteine against cisplatin-induced toxicity in rat brain by modulation of oxidative stress and inflammation

Abstract

Background: Neurotoxicity is a major obstacle to the effectiveness of cisplatin (CDDP) in cancer chemotherapy. Oxidative stress and inflammation are considered to be the major mechanisms involved in CDDP-induced neurotoxicity. The rationale of our study was to investigate the efficacy of N-acetylcysteine (NAC) at two different doses in the management of CDDP-induced toxicity in rat brain by monitoring its antioxidant and anti-inflammatory effects.

Methods: Thirty-five male rats were divided into five groups (n=7) as follows: control group (0.5 mL saline), NAC₁₀₀ group (100 mg/kg), CDDP group (8 mg/kg), NAC₅₀-CDDP group (50 mg/kg NAC and 8 mg/kg CDDP), and NAC₁₀₀-CDDP group (100 mg/kg NAC and 8 mg/kg CDDP). NAC was administered for 20 consecutive days, while CDDP was injected once on day 15 of the treatment protocol.

Results: The neurotoxicity of CDDP was evidenced by a marked increase in acetylcholinesterase and monoamine oxidase activities. It also induced oxidative stress as indicated by increased levels of lipid peroxidation, nitric oxide, and protein carbonyl with a concomitant decline in reduced glutathione, glutathione peroxidase, glutathione S-transferase, superoxide dismutase, and catalase in the brain. Moreover, CDDP enhanced the synthesis of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6. Treatment with NAC at the two selected doses significantly attenuated CDDP-induced changes in the brain cholinergic function, improved the brain oxidant/antioxidant status, and also reversed the overproduction of pro-inflammatory cytokines in brain and serum.

Conclusion: NAC could serve as an appropriate and safe complementary therapeutic agent to attenuate the toxicity of CDDP in the brain and therefore improve its outcomes in chemotherapy.

Keywords: N-acetylcysteine; brain; cisplatin; neurotoxicity; rats.

Figure 1

Effect of NAC (50 and 100 mg/kg) on CDDP-induced changes in the activities of (A) AChE (µg/mg protein) and (B) MAO (nmol/mg protein) in the brain of rats. Notes: Data are shown as the mean ± standard error of mean (n=7). Bars with different superscripts (a–d) are significantly different (P=0.023 and P=0.016 for AChE and MAO, respectively). Abbreviations: AChE, acetylcholinesterase; CDDP, cisplatin; MAO, monoamine oxidase; NAC, N-acetylcysteine.

Figure 2

Effect of NAC (50 and 100 mg/kg) on CDDP-induced changes in the levels of (A) TAC (mmol Trolox equivalent/mg protein) and (B) GSH (mmol/mg protein) in the brain of rats. Notes: Data are shown as the mean ± standard error of mean (n=7). Bars with different superscripts (a–c) are significantly different (P=0.003 and P=0.007 for TAC and GSH, respectively). Abbreviations: CDDP, cisplatin; GSH, reduced glutathione; NAC, N-acetylcysteine; TAC, total antioxidant capacity.