Abstract
Myelin is closely associated with cognitive function and is extremely vulnerable to damage in ischemic cerebrovascular diseases. The failure of remyelination is mainly due to limitations in oligodendrocyte progenitor cells (OPCs) differentiation in the damaged area. Previous studies have shown that physical exercise can improve vascular cognitive impairment, but whether it can reverse the defect in remyelination during ischemic injury and the underlying mechanism remains unclear. In this study, we observed the effects of physical exercise on chronic cerebral hypoperfusion (CCH) established by bilateral carotid artery occlusion. The cognitive function, myelin integrity, OPCs proliferation and differentiation, as well as microglia polarization were analyzed at 28 days after CCH. Besides, the expression of CX3CL1/CX3CR1 axis and activation of mitogen-activated protein kinase (MAPK) signal cascades were also evaluated. We found that physical exercise improved the cognitive function of rats with CCH, alleviated myelin injury, triggered OPCs proliferation and differentiation, facilitated microglia polarization toward M2, augmented the expression of CX3CL1/CX3CR1 axis, and reduced ERK and JNK phosphorylation. The results indicated that physical exercise improved the cognitive function of rats with CCH, possibly through microglial phenotype modulation and enhancement of oligodendrocytegenesis and remyelination. Moreover, the CX3CL1/CX3CR1 axis played an important role in this process by mediating ERK- and JNK-dependent pathways.
Highlights
Myelin is an insulating sheath around the axons formed by oligodendrocytes in the central nervous system (CNS) and plays an important role in the development and maintenance of cognitive function
We explored whether physical exercise can rescue chronic cerebral hypoperfusion (CCH)-induced cognitive impairment by switching microglia to a neuroprotective phenotype and producing a more favorable microenvironment for oligodendrocytegenesis and remyelination
The sham group was further subdivided into sham group and sham + PE group, the successful model of 2VO rats were randomly divided into 2VO control group and 2VO + PE group, and there were no significant differences in mortality rates between the two groups of sham and sham + PE group, and between 2VO and 2VO + PE group (Supplementary Table S1)
Summary
Myelin is an insulating sheath around the axons formed by oligodendrocytes in the central nervous system (CNS) and plays an important role in the development and maintenance of cognitive function. Myelin is vulnerable to damage in various neurological diseases, such as ischemic cerebrovascular diseases (Pantoni et al, 1996; Sun et al, 2013). OPCs can respond immediately to myelin damage through proliferation and recruitment to the demyelinated area, and differentiate into myelinating oligodendrocytes to restore myelin (Gensert and Goldman, 1997; Franklin and Ffrench-Constant, 2008). OPCs are often not recruited to the injured area or do not differentiate into myelinating oligodendrocytes, leading to ineffective remyelination during disease progression (Fancy et al, 2009; Sun et al, 2013)
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