Neuroprotective Effects of dl-3-n-Butylphthalide against Doxorubicin-Induced Neuroinflammation, Oxidative Stress, Endoplasmic Reticulum Stress, and Behavioral Changes.

Dehua Liao,Pei Jiang,Daxiong Xiang,Pengfei Xu,Jiemin Wang,Ruili Dang,Yingzhou Fu,Dunwu Yao,Lizhi Cao,Wenxiu Han

doi:10.1155/2018/9125601

Abstract

Doxorubicin (DOX) is a broad-spectrum antitumor drug while its use is limited due to its neurobiological side effects associated with depression. We investigated the neuroprotective efficacy of dl-3-n-butylphthalide (dl-NBP) against DOX-induced anxiety- and depression-like behaviors in rats. dl-NBP was given (30 mg/kg) daily by gavage over three weeks starting seven days before DOX administration. Elevated plus maze (EPM) test, forced swimming test (FST), and sucrose preference test (SPT) were performed to assess anxiety- and depression-like behaviors. Our study showed that the supplementation of dl-NBP significantly mitigated the behavioral changes induced by DOX. To further explore the mechanism of neuroprotection induced by dl-NBP, several biomarkers including oxidative stress markers, endoplasmic reticulum (ER) stress markers, and neuroinflammatory cytokines in the hippocampus were quantified. The results showed that dl-NBP treatment alleviated DOX-induced neural apoptosis. Meanwhile, DOX-induced oxidative stress and ER stress in the hippocampus were significantly ameliorated in dl-NBP pretreatment group. Our study found that dl-NBP alleviated the upregulation of malondialdehyde (MDA), nitric oxide (NO), CHOP, glucose-regulated protein 78 kD (GRP-78), and caspase-12 and increased the levels of reduced glutathione (GSH) and activities of catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) in the hippocampus of rats exposed to DOX. Additionally, the gene expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) and protein levels of inducible nitric oxide synthase (iNOS) were significantly increased in DOX-treated group, whereas DOX-induced neuroinflammation was significantly attenuated in dl-NBP supplementation group. In conclusion, dl-NBP could alleviate DOX-induced anxiety- and depression-like behaviors via attenuating oxidative stress, ER stress, inflammatory reaction, and neural apoptosis, providing a basis as a therapeutic potential against DOX-induced neurotoxicity.

Highlights

Doxorubicin (DOX) is an anthracycline antibiotic used commonly in multidrug chemotherapy regimens to treat solid tumors [1, 2]
Number of entries (p < 0 01) and time spent in the open arms (p < 0 01) were significantly increased in the dl-NBP-pretreated group when compared with DOX
We clearly demonstrated the capability of dl-NBP to downregulate the levels of nitric oxide (NO) and MDA and upregulate the levels of GSH and activities of CAT, glutathione reductase (GR), and glutathione peroxidase (GPx), which acts as an antioxidant thereby reducing oxidative stress-induced apoptosis

Summary

Introduction

Doxorubicin (DOX) is an anthracycline antibiotic used commonly in multidrug chemotherapy regimens to treat solid tumors [1, 2]. Notwithstanding the fact that DOX poorly crosses the blood-brain barrier, it still penetrates the brain at doses sufficient to cause cytotoxicity [5]. More and more evidence showed that neurotoxicity is accompanied with long-term use of DOX and may cause many neuropsychiatric diseases including depression, anxiety, and impaired cognitive function [6, 7]. Clinical study showed that DOX treatment has a negative impact on cognitive function in women with breast cancer [8]. Several studies suggested that the pathogenesis of anxiety and depression is associated with oxidative stress and neuroinflammatory response in the hippocampal region [9,10,11].

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