Characterization of White Matter Injury in a Rat Model of Chronic Cerebral Hypoperfusion

Abstract

Background and Purpose-Chronic cerebral hypoperfusion can lead to ischemic white matter injury resulting in vascular dementia. To characterize white matter injury in vascular dementia, we investigated disintegration of diverse white matter components using a rat model of chronic cerebral hypoperfusion. Methods-Chronic cerebral hypoperfusion was modeled in Wistar rats by permanent occlusion of the bilateral common carotid arteries. We performed cognitive behavioral tests, including the water maze task, odor discrimination task, and novel object test; histological investigation of neuroinflammation, oligodendrocytes, myelin basic protein, and nodal or paranodal proteins at the nodes of Ranvier; and serial diffusion tensor imaging. Cilostazol was administered to protect against white matter injury. Results-Diverse cognitive impairments were induced by chronic cerebral hypoperfusion. Disintegration of white matter was characterized by neuroinflammation, loss of oligodendrocytes, attenuation of myelin density, structural derangement at the nodes of Ranvier, and disintegration of white matter tracts. Cilostazol protected against cognitive impairments and white matter disintegration. Conclusions-White matter injury induced by chronic cerebral hypoperfusion can be characterized by disintegration of diverse white matter components. Cilostazol might be a therapeutic strategy against white matter disintegration in patients with vascular dementia.

Fingolimod Protects Against Ischemic White Matter Damage by Modulating Microglia Toward M2 Polarization via STAT3 Pathway

“…Major components of the WM include neuronal axons, the surrounding myelin sheath and myelin-producing oligodendrocytes 3 . To further determine which components of WM suffered from the heaviest damage and the impact of FTY720, we assessed WM related markers in CCm using immunofluorescence and Western blot analysis.…”

“…The structural organization of nodes of Ranvier is vulnerable to ischemia and is a sensitive indicator of WM ischemic injury 3, 16 . To test the integrity of the paranodal septate-like junctions and the nodal regions, we analyzed three key proteins (Caspr, Nav1.6 and panNfasc) of nodes of Ranvier at 1 month after BCAS.…”

“…Characterized by loss of axon-glial integrity and demyelination, WM injury is an important cause of cognitive deficits after cerebral ischemia and is often associated with microglial activation 3 . A persistent pro-inflammatory microenvironment after cerebral hypoperfusion is considered an underlying mechanism that hinders remyelination and white matter repair 4 .…”

Long-term cilostazol treatment reduces gliovascular damage and memory impairment in a mouse model of chronic cerebral hypoperfusion

“…The effects of cilostazol have been predominantly studied in more severe models of cerebral hypoperfusion such as a rat 2-vessel occlusion (2VO) model and within 1 to 5 weeks hypoperfusion 13–15 . The rat 2VO model shows marked BBB disruption, as early as 3 days post-operation 22 , leading to prominent white matter lesions, glial activation and profound impairment of various aspects of cognition 15, 23, 24 . In contrast, our mouse model of cerebral hypoperfusion shows gradual and progressive temporal changes of white matter dysfunction, gliovascular unit disruption and glial activation leading to working memory impairment 3, 5 .…”

“…In support of this, despite the lack of protection against white matter changes, cilostazol was able to improve white matter function as assessed using electrophysiological approaches and improve spatial working memory which is dependent on frontal cortical circuitry. Increased microglial density accompany hypoperfusion-induced damage to white matter 3–5, 15, 16 and may contribute to the damage via pro-inflammatory mechanisms. Notably increased microglia were determined in the corpus callosum of hypoperfused mice and reduced by cilostazol-treatment.…”