Physical Exercise-Induced Astrocytic Neuroprotection and Cognitive Improvement Through Primary Cilia and Mitogen-Activated Protein Kinases Pathway in Rats With Chronic Cerebral Hypoperfusion

Abstract

Chronic cerebral hypoperfusion (CCH) is closely related to vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD). The neuroinflammation involving astrocytes is an important pathogenic mechanism. Along with the advancement of the concept and technology of astrocytic biology, the astrocytes have been increasingly regarded as the key contributors to neurological diseases. It is well known that physical exercise can improve cognitive function. As a safe and effective non-drug treatment, physical exercise has attracted continuous interests in neurological research. In this study, we explored the effects of physical exercise on the response of reactive astrocytes, and its role and mechanism in CCH-induced cognitive impairment. A rat CCH model was established by 2 vessel occlusion (2VO) and the wheel running exercise was used as the intervention. The cognitive function of rats was evaluated by morris water maze and novel object recognition test. The phenotypic polarization and the primary cilia expression of astrocytes were detected by immunofluorescence staining. The activation of MAPKs cascades, including ERK, JNK, and P38 signaling pathways, were detected by western blot. The results showed that physical exercise improved cognitive function of rats 2 months after 2VO, reduced the number of C3/GFAP-positive neurotoxic astrocytes, promoted the expression of S100A10/GFAP-positive neuroprotective astrocytes, and enhanced primary ciliogenesis. Additionally, physical exercise also alleviated the phosphorylation of ERK and JNK proteins induced by CCH. These results indicate that physical exercise can improve the cognitive function of rats with CCH possible by promoting primary ciliogenesis and neuroprotective function of astrocytes. The MAPKs signaling cascade, especially ERK and JNK signaling pathways may be involved in this process.

Uncovering cilia function in glial development

“…This finding proposes an unexplored signaling axis between mitochondria and primary cilia in astrocytes. Finally, a mouse model of chronic cerebral hypoperfusion displays neuro‐inflammation that causes reactive gray matter astrocytes and fewer, shorter cilia (Cao et al., 2022). The connections of cilia and neurological impairments provide tantalizing models and suggest that cilia may contribute to astrocyte function.…”

Acrobatic training prevents learning impairments and astrocyte remodeling in the hippocampus of rats undergoing chronic cerebral hypoperfusion: sex-specific benefits

“…Pathological conditions trigger morphological, molecular, and functional changes in astrocytes that become reactive ( 55 ). According to reports, after 2VO, the rats presented reactive astrocytes with neurotoxic characteristics, but early physical exercise prevents this effect ( 20 , 56 ). In the present study, the number of astrocytes increased in the CA1 and CA3 subfields caused by 2VO, as assessed 7 days after the event, supporting the hypothesis that 2VO leads to neurotoxic reactive gliosis due to the ischemic insult.…”

“…This set of evidence is suggestive of neurotoxic astrogliosis, possibly modulated by oxidative and inflammatory agents. Disruption of primary astrocyte cilia can lead to gliosis and neuroinflammation ( 60 ), increasing the number of C3 (a marker for neurotoxic astrocytes)/GFAP-positive astrocytes in rats 2 months after 2VO ( 56 ). In the present study, the 2VO-trained animals also showed branched astrocytes in response to ischemia.…”

A Study on the Pathogenesis of Vascular Cognitive Impairment and Dementia: The Chronic Cerebral Hypoperfusion Hypothesis

“…All of these functional and structural changes collectively lead to hypoperfusion at rest [ 23 ]. Therefore, chronic cerebral hypoperfusion (CCH) is acknowledged as the chief cerebral hemodynamic alteration of CBF dysregulation, which may lead to ischemic neuronal damage and varied degrees of cognitive deficits, such as VCID [ 24 ]. However, the precise pathophysiological mechanisms of CCH underlying VCID still remain a mystery.…”