Acetaminophen attenuates lipopolysaccharide-induced cognitive impairment through antioxidant activity

Wei-Xing Zhao,Wei-Dong Mi,Wei Wang,Dong-Xin Wang,Yong-Yi Zhang,Jiang-Bei Cao,Jun-Han Zhang,You-Zhi Zhang,Xiao-Ying Zhang,Jun Yu

doi:10.1186/s12974-016-0781-6

Abstract

BackgroundConsiderable evidence has shown that neuroinflammation and oxidative stress play an important role in the pathophysiology of postoperative cognitive dysfunction (POCD) and other progressive neurodegenerative disorders. Increasing evidence suggests that acetaminophen (APAP) has unappreciated antioxidant and anti-inflammatory properties. However, the impact of APAP on the cognitive sequelae of inflammatory and oxidative stress is unknown. The objective of this study is to explore whether APAP could have neuroprotective effects on lipopolysaccharide (LPS)-induced cognitive impairment in mice.MethodsA mouse model of LPS-induced cognitive impairment was established to evaluate the neuroprotective effects of APAP against LPS-induced cognitive impairment. Adult C57BL/6 mice were treated with APAP half an hour prior to intracerebroventricular microinjection of LPS and every day thereafter, until the end of the study period. The Morris water maze was used to assess cognitive function from postinjection days 1 to 3. Animal behavioural tests as well as pathological and biochemical assays were performed to evaluate LPS-induced hippocampal damage and the neuroprotective effect of APAP.ResultsMice treated with LPS exhibited impaired performance in the Morris water maze without changing spontaneous locomotor activity, which was ameliorated by treatment with APAP. APAP suppressed the accumulation of pro-inflammatory cytokines and microglial activation induced by LPS in the hippocampus. In addition, APAP increased SOD activity, reduced MDA levels, modulated glycogen synthase kinase 3β (GSK3β) activity and elevated brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Moreover, APAP significantly decreased the Bax/Bcl-2 ratio and neuron apoptosis in the hippocampus of LPS-treated mice.ConclusionsOur results suggest that APAP may possess a neuroprotective effect against LPS-induced cognitive impairment and inflammatory and oxidative stress via mechanisms involving its antioxidant and anti-inflammatory properties, as well as its ability to inhibit the mitochondrial permeability transition (MPT) pore and the subsequent apoptotic pathway.

Highlights

Considerable evidence has shown that neuroinflammation and oxidative stress play an important role in the pathophysiology of postoperative cognitive dysfunction (POCD) and other progressive neurodegenerative disorders
Spontaneous locomotor activity was not changed 24 h after LPS administration To evaluate whether the changes in performance after LPS administration were attributable to changes in spontaneous locomotor activity, the open field test was conducted [37]
APAP suppressed the accumulation of pro-inflammatory cytokines induced by LPS in the mouse hippocampus We investigated the levels of several pro-inflammatory cytokines (IL-1β, IL-6 and tumour necrosis factor α (TNF-α)) in the hippocampus, a brain region where neuroinflammation mainly occurs in response to brain injury and inflammation [38, 39]

Summary

Introduction

Considerable evidence has shown that neuroinflammation and oxidative stress play an important role in the pathophysiology of postoperative cognitive dysfunction (POCD) and other progressive neurodegenerative disorders. The impact of APAP on the cognitive sequelae of inflammatory and oxidative stress is unknown. There is emerging evidence that neuroinflammation is implicated in the pathophysiology of POCD and other progressive neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) [5,6,7]. Evidence has shown that oxidative stress is harmful to cognitive function and is thought to contribute to the pathogenesis of the above neurodegenerative diseases [8,9,10]. The exact pathogenesis underlying the effect of neuroinflammation and oxidative stress on cognitive function is still unclear

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