Minocycline attenuation of rat corpus callosum abnormality mediated by low-dose lipopolysaccharide-induced microglia activation

Jingdong Zhang,Ya Zheng,Huangui Xiong,Howard S Fox,Michael Boska,Jianuo Liu

doi:10.1186/s12974-021-02142-x

Abstract

BackgroundMicroglia are resident innate immune cells in the brain, and activation of these myeloid cells results in secretion of a variety of pro-inflammatory molecules, leading to the development of neurodegenerative disorders. Lipopolysaccharide (LPS) is a widely used experimental stimulant in microglia activation. We have previously shown that LPS produced microglia activation and evoked detectable functional abnormalities in rat corpus callosum (CC) in vitro. Here, we further validated the effects of low-dose LPS-induced microglia activation and resultant white matter abnormality in the CC in an animal model and examined its attenuation by an anti-inflammatory agent minocycline.MethodsTwenty-four SD rats were divided randomly into three groups and intra-peritoneally injected daily with saline, LPS, and LPS + minocycline, respectively. All animals were subject to MRI tests 6 days post-injection. The animals were then sacrificed to harvest the CC tissues for electrophysiology, western blotting, and immunocytochemistry. One-way ANOVA with Tukey’s post-test of all pair of columns was employed statistical analyses.ResultsSystemic administration of LPS produced microglial activation in the CC as illustrated by Iba-1 immunofluorescent staining. We observed that a large number of Iba-1-positive microglial cells were hyper-ramified with hypertrophic somata or even amoeba like in the LPS-treated animals, and such changes were significantly reduced by co-administration of minocycline. Electrophysiological recordings of axonal compound action potential (CAP) in the brain slices contained the CC revealed an impairment on the CC functionality as detected by a reduction in CAP magnitude. Such an impairment was supported by a reduction of fast axonal transportation evidenced by β-amyloid precursor protein accumulation. These alterations were attenuated by minocycline, demonstrating minocycline reduction of microglia-mediated interruption of white matter integrity and function in the CC.ConclusionsSystemic administration of LPS produced microglia activation in the CC and resultant functional abnormalities that were attenuated by an anti-inflammatory agent minocycline.

Highlights

Microglia are resident innate immune cells in the brain, and activation of these myeloid cells results in secretion of a variety of pro-inflammatory molecules, leading to the development of neurodegenerative disorders
We have previously shown that LPS, at low doses, produced microglia activation in rat corpus callosum (CC) in vitro and evoked detectable functional abnormalities on white matter tracts in the absence of overt axonal injury, hypoxia, and trauma that could be detrimental to the white matter [17]
Our results showed that systemic administration of LPS produced microglial activation in the CC and impaired CC functionality as revealed by reduction of axonal compound action potential (CAP) magnitude and fast axonal transportation evidenced by β-amyloid precursor protein (β-APP) accumulation

Summary

Introduction

Microglia are resident innate immune cells in the brain, and activation of these myeloid cells results in secretion of a variety of pro-inflammatory molecules, leading to the development of neurodegenerative disorders. Microglia are resident innate immune cells in the central nervous system (CNS) [1, 2] and have diverse functions in the brain under normal and disease conditions. The activated microglia release a variety of pro-inflammatory molecules including, but not limited to, chemokines, cytokines, cyclooxygenase-2, inducible nitric oxide synthase, and nitric oxide. These substances provoke inflammatory responses and brain tissue damage that contribute to the pathogenesis of neurodegenerative disorders including Alzheimer’s disease [4,5,6,7,8], Parkinson’s disease [9, 10], and human immunodeficiency virus type 1(HIV-1)-associated neurocognitive disorders [11, 12]

Methods

Results

Discussion

Conclusion