Anti-mouse CX3CR1 Antibody Alleviates Cognitive Impairment, Neuronal Loss and Myelin Deficits in an Animal Model of Brain Ischemia. (1st July 2020)

• Record Type: Journal Article
• Authors: Du, Bingying; Liang, Meng; Zheng, Huiwen; Fan, Cunxiu; Zhang, Hailing; Lu, Xiaoyan; Du, Zengkan; Lian, Yongjie; Zhang, Yanbo; Bi, Xiaoying
• Is Part Of: Neuroscience. Volume 438(2020)
• Page Start: 169
• Page End: 181
• Publication Date: 2020-07-01
• Subjects: BCCAO bilateral common carotid artery occlusion -- CA cornu ammonis -- CC corpus callosum -- CNS central nervous system -- DG dentate gyrus -- FST forced swimming test -- GCI global cerebral ischemia -- i.c.v. intracerebroventricular -- Iba-1 ionized calcium-binding adapter-1 -- IL-1β interleukin-1β -- IL-6 interleukin-6 -- IOD integrated optical densities -- MBP myelin basic protein -- MWM Morris water maze -- NeuN neuronal nuclei -- NG2 nerve/glial antigen 2 -- NO nitric oxide -- OLs oligodendrocytes -- OPCs oligodendrocyte precursor cells -- POD post-operation day -- ROI region of interest -- RT room temperature -- SEM standard error of the mean -- TNF-α tumor necrosis factor-α -- TST tail suspension test -- VCI vascular cognitive impairment -- VD vascular depression -- WML white matter lesion; cerebral ischemia -- CX3CR1 -- oligodendrocyte -- myelin -- microglia -- global cerebral ischemia; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2020.05.011
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Microglia activation and subsequent inflammation contribute to demyelination in GCI mice. CX3CR1 block has an anti-depressant and cognition-improvement effect in GCI mice. CX3CR1 block inhibits microglial activation and ameliorated peripheral inflammation. CX3CR1 block reverses demyelination in striatum, cortex and hippocampus but not corpus callosum of GCI mice. CX3CR1 block protects hippocampal neurons of GCI mice. Abstract: White matter lesions are common when global cerebral ischemia (GCI) occurs in the elderly, and cause damage to neurological and psychological functions. Remyelination often fails because of the limited recruitment of oligodendrocyte progenitor cells (OPCs) to the demyelinated site or the inefficient differentiation of OPCs to mature oligodendrocytes (OLs). The activation of microglia, the most important immune cells in the central nervous system, and subsequent inflammation have been implicated in myelination repair disorder. Little is known about the role of the Fractalkine/CX3CR1 signaling pathway, the key regulator of microglia activation, on myelin in microglia. In this study, a GCI animal model was generated through bilateral common carotid artery occlusion to induce ischemic inflammation and white matter damage; then, we downregulated CX3CR1 by intracerebroventricular administration of neutralizing antibody anti-FKR. Downregulation of CX3CR1 significantly reversed the depression-like behavior and cognitive impairment in GCI mice. Activation of microglia was inhibited, and the peripheral inflammatory responses were also ameliorated as revealed by decreased serum levels of IL-1β, IL-6 and TNF-α. CX3CR1 block substantially reversed demyelination in striatum, cortex and hippocampus and promoted differentiation and maturation of OPCs into mature OLs in the hippocampus. No effect was found on myelin in the corpus callosum. Besides, hippocampal neurons were protected by anti-FKR treatment after GCI. Collectively, our data demonstrated that downregulating of the Fractalkine/CX3CR1 signaling pathway had an anti-depressant and cognition-improvement effect by inhibiting microglia activation, promoting OPCs maturation and remyelination.