Dexmedetomidine reduces lipopolysaccharide induced neuroinflammation, sickness behavior, and anhedonia.

Ching-Hua Yeh,Chia-Cheng Chang,Hui-Ching Lin,Ming-Chung Lin,Tsui-Shan Wei,Liang-Po Hsieh,Chung-Hsi Hsing,Zhongcong Xie

doi:10.1371/journal.pone.0191070

Abstract

BackgroundPeripheral innate immune response may induce sickness behavior through activating microglia, excessive cytokines production, and neuroinflammation. Dexmedetomidine (Dex) has anti-inflammatory effect. We investigated the effects of Dex on lipopolysaccharide (LPS)-induced neuroinflammation and sickness behavior in mice.Materials and methodsBALB/c mice were intraperitoneally (i.p.) injected with Dex (50 ug/kg) or vehicle. One hour later, the mice were injected (i.p.) with Escherichia coli LPS (0.33 mg/kg) or saline (n = 6 in each group). We analyzed the food and water intake, body weight loss, and sucrose preference of the mice for 24h. We also determined microglia activation and cytokines expression in the brains of the mice. In vitro, we determine cytokines expression in LPS-treated BV-2 microglial cells with or without Dex treatment.ResultsIn the Dex-pretreated mice, LPS-induced sickness behavior (anorexia, weight loss, and social withdrawal) were attenuated and microglial activation was lower than vehicle control. The mRNA expression of TNF-α, MCP-1, indoleamine 2, 3 dioxygenase (IDO), caspase-3, and iNOS were increased in the brain of LPS-challenged mice, which were reduced by Dex but not vehicle.ConclusionDexmedetomidine diminished LPS-induced neuroinflammation in the mouse brain and modulated the cytokine-associated changes in sickness behavior.

Highlights

The symptoms of sickness, such as the loss of appetite, decline in cognitive function, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue was defined as sickness behavior
In the Dex-pretreated mice, LPS-induced sickness behavior were attenuated and microglial activation was lower than vehicle control
The mRNA expression of tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, indoleamine 2, 3 dioxygenase (IDO), caspase-3, and inducible nitric oxide synthase (iNOS) were increased in the brain of LPS-challenged mice, which were reduced by Dex but not vehicle

Summary

Introduction

The symptoms of sickness, such as the loss of appetite, decline in cognitive function, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue was defined as sickness behavior. The sickness behavior occurs during infections by pathogenic microorganisms [1,2,3]. Sepsis is a systemic inflammatory response to infection and septic patients have high risk of developing multiple organ failure. Activation of the peripheral innate immune system stimulates cytokine secretion in the CNS [6]. Neuroinflammation is a multiple immune response against the harmful effects of different stimulation within the CNS. The overexpression of inflammatory cytokines in the brain is associated with cognitive dysfunction, sickness behavior, and depression [12,13,14]. Peripheral innate immune response may induce sickness behavior through activating microglia, excessive cytokines production, and neuroinflammation. We investigated the effects of Dex on lipopolysaccharide (LPS)induced neuroinflammation and sickness behavior in mice

Methods

Results

Conclusion