Prophylactic and Ameliorative Effect of N-Acetylcysteine on Doxorubicin-Induced Neurotoxicity in Wister Rats

Walaa I Mohammed,Hoda M Elsayed,Rania A Radwan

doi:10.32527/2019/101396

Walaa I Mohammed, Hoda M Elsayed + Show 1 more

Open Access

https://doi.org/10.32527/2019/101396

Copy DOI

Abstract

Doxorubicin (DOX) is an anthracycline antibiotic and a quinone-containing chemotherapeutic drug used for various types of cancers. However, as with most anticancer drugs, it causes many toxic effects, one of them is cognitive impairment. The present study investigated the prophylactic and ameliorative effect of n-acetylcysteine (NAC) against DOX-induced neurotoxicity in rats. Rats were divided into four groups. Control group: rats received saline. NAC treated group: rats received NAC (100 mg/kg, p.o.) daily for 35 days. DOX-treated group: rats received DOX (4 mg/kg, i.p.) for four weeks on day 7, 14, 21 and 28. DOX+NAC treated group 1: rats received NAC (100 mg/kg, p.o.) daily for 35 days and DOX (4 mg/kg, i.p.) for four weeks on day 7, 14, 21 and 28). DOX+NAC treated group 2: rats received NAC (100 mg/kg, p.o.) daily started at the 7th day of the experiment till the end of the experiment and DOX (4 mg/kg, i.p.) for four weeks on day 7, 14, 21 and 28. The present results showed a significant reduction in the body weight, which was associated with a significant increase in brain to body weight ratio in DOX-treated rats. Tumor necrosis factor (TNF-α) level, malondialdehyde (MDA) and total protein levels were significantly elevated. Whilst, reduced glutathione (GSH) and glutathione peroxidase (GPx) levels were significantly decreased. Moreover, there were histopathological abnormalities in the brain tissue of DOX-treated rats, as most of the neurons degenerated and the blood vessels surrounded with wide perivascular spaces. In addition, the neuropil was vacuolated. The present study demonstrated that NAC has a neuroprotective effect on the brain damage induced by DOX, through inhibition of inflammation and oxidative stress. This neuroprotective effect was more pronounced in DOX+NAC treated group 1, as it produced a significant increase in brain GSH and GPx levels and more improvement in the histopathological abnormality compared to DOX+NAC treated group 2.

Highlights

Doxorubicin (DOX) is an anthracycline antibiotic and a quinone-containing chemotherapeutic drug, usually used for chemotherapy of breast cancer and other cancers [1]
Doxorubicin does not pass through the blood-brain barrier (BBB), so the decline in cognition occurs with its administration is attributed to the peripheral increase in the circulating tumor necrosis factor (TNF-α) [5,6,7]
N-Acetylcysteine was purchased from AK Scientific, Inc. (USA), while Doxorubicin was purchased as Adriblastina vials from Pharmacia Italia S.P.A., Italy

Summary

Introduction

Doxorubicin (DOX) is an anthracycline antibiotic and a quinone-containing chemotherapeutic drug, usually used for chemotherapy of breast cancer and other cancers [1]. DNA, inhibiting topoisomerase II and producing large amounts of free radicals to kill cancer cells [2]. This mechanism of action is implicated in the toxicity of several non-targeted organs the heart, kidney, and brain [3] and limits its dosage in cancer patients. Doxorubicin does not pass through the blood-brain barrier (BBB), so the decline in cognition occurs with its administration is attributed to the peripheral increase in the circulating tumor necrosis factor (TNF-α) [5,6,7]. TNF-α migrates across the BBB and activates glial cells to release large amounts of the local TNF-α in the cortex and hippocampus leading to inflammation and induced oxidative stress in the brain [8]. Antagonizing circulating TNF-α with TNF-α antibody led to a manifest decrease in TNF-α levels and the observed mitochondrial dysfunction in brain tissues [5]

Objectives

Results

Conclusion