N-Acetylcysteine Protects against the Anxiogenic Response to Cisplatin in Rats.

Rade Vukovic,Vladimir Mihailovic,Jelena S Katanic Stankovic,Jovana Joksimovic Jovic,Nemanja Jovicic,Gvozden Rosic,Dragica Selakovic,Igor Kumburovic,Aleksandra Arnaut,Stefan Velickovic,Milos Djuric

doi:10.3390/biom9120892

Rade Vukovic, Vladimir Mihailovic + Show 9 more

Open Access

https://doi.org/10.3390/biom9120892

Copy DOI

Abstract

Since cisplatin therapy is usually accompanied with numerous toxicities, including neurotoxicity, that involve tissue oxidative damage, the aim of this study was to evaluate the possible protective effect of N-acetylcysteine (NAC) on the anxiogenic response to cisplatin (CIS). Thirty-two male Wistar albino rats divided into four groups (control, cisplatin, NAC, and CIS + NAC). All treatments were delivered intraperitoneally. On day one, the control and cisplatin groups received saline while the NAC and CIS + NAC groups were administered with NAC (500 mg/kg). On the fifth day, the control group received saline while the CIS group was treated with cisplatin (7.5 mg/kg), the NAC group again received NAC (500 mg/kg), and the CIS + NAC group was simultaneously treated with cisplatin and NAC (7.5 and 500 mg/kg, respectively). Behavioral testing, performed on the tenth day in the open field (OF) and elevated plus maze (EPM) tests, revealed the anxiogenic effect of cisplatin that was significantly attenuated by NAC. The hippocampal sections evaluation showed increased oxidative stress (increased lipid peroxidation and decline in antioxidant enzymes activity) and proapoptotic action (predominantly by diminished antiapoptotic gene expression) following a single dose of cisplatin. NAC supplementation along with cisplatin administration reversed the prooxidative and proapoptotic effects of cisplatin. In conclusion, the results obtained in this study confirmed that antioxidant supplementation with NAC may attenuate the cisplatin-induced anxiety. The mechanism of anxiolytic effect achieved by NAC may include the decline in oxidative damage that down regulates increased apoptosis and reverses the anxiogenic action of cisplatin.

Highlights

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II) is a well-known chemotherapeutic drug used to treat a number of different types of cancers including sarcomas, cancers of the soft tissue, muscles, bones, and blood vessels [1]
The results of this study showed that NAC, when applied on its own, did not affect any of the estimated parameters obtained in behavioral testing and hippocampus analysis for oxidative stress and apoptotic markers when compared to the values obtained in the control group
According to the results obtained in this study, it seems that the antioxidant supplementation performed by NAC may attenuate the cisplatin-induced neurotoxicity manifestations

Summary

Introduction

Cisplatinum, or cis-diamminedichloroplatinum (II) is a well-known chemotherapeutic drug used to treat a number of different types of cancers including sarcomas, cancers of the soft tissue, muscles, bones, and blood vessels [1]. Synthesized in 1844, cisplatin has been increasingly interesting since it anticancer activity was shown. Cisplatin was the first FDA-approved platinum compound for cancer treatment in 1978 [3], which has significantly affected the further development of related platinum-based drugs as potential anticancer treatments [4]. Highly effective as a cytostatic, cisplatin treatment leads to dose-dependent adverse effects as a consequence of DNA damage, increased production of proinflammatory cytokines, mitochondrial dysfunction, apoptosis, and oxidative stress [5]. These adverse effects include neurotoxicity, hepatotoxicity, nephrotoxicity, ototoxicity, myelosuppression, gastrointestinal toxicity, and cardiotoxicity. Common neurological adverse effects are cognitive deficits, disorientation, visual perception, and hearing disorders [6]

Objectives

Methods

Results

Discussion

Conclusion