A refined model of chronic cerebral hypoperfusion resulting in cognitive impairment and a low mortality rate in rats

Abstract

OBJECTIVE The cognitive deficits of vascular dementia and the vasoocclusive state of moyamoya disease have often been mimicked with bilateral stenosis/occlusion of the common carotid artery (CCA) or internal carotid artery. However, the cerebral blood flow (CBF) declines abruptly in these models after ligation of the CCA, which differs from "chronic" cerebral hypoperfusion. While some modified but time-consuming techniques have used staged occlusion of both CCAs, others used microcoils for CCA stenosis, producing an adverse effect on the arterial endothelium. Thus, the authors developed a new chronic cerebral hypoperfusion (CCH) model with cognitive impairment and a low mortality rate in rats. METHODS Male Sprague-Dawley rats were subjected to unilateral CCA occlusion and contralateral induction of CCA stenosis (modified CCA occlusion [mCCAO]) or a sham operation. Cortical regional CBF (rCBF) was measured using laser speckle flowmetry. Cognitive function was assessed using a Barnes circular maze (BCM). MRI studies were performed 4 weeks after the operation to evaluate cervical and intracranial arteries and parenchymal injury. Behavioral and histological studies were performed at 4 and 8 weeks after surgery. RESULTS The mCCAO group revealed a gradual CBF reduction with a low mortality rate (2.3%). White matter degeneration was evident in the corpus callosum and corpus striatum. Although the cellular density declined in the hippocampus, MRI revealed no cerebral infarctions after mCCAO. Immunohistochemistry revealed upregulated inflammatory cells and angiogenesis in the hippocampus and cerebral cortex. Results of the BCM assessment indicated significant impairment in spatial learning and memory in the mCCAO group. Although some resolution of white matter injury was observed at 8 weeks, the animals still had cognitive impairment. CONCLUSIONS The mCCAO is a straightforward method of producing a CCH model in rats. It is associated with a low mortality rate and could potentially be used to investigate vascular disease, moyamoya disease, and CCH. This model was verified for an extended time point of 8 weeks after surgery.

A New Rat Model of Chronic Cerebral Hypoperfusion Resulting in Early-Stage Vascular Cognitive Impairment

“…A chronic decline in sustained cerebral blood flow is the main mechanism underlying the development of vascular cognitive impairment (VCI) (Kazumata et al, 2019;Kim et al, 2019;Mansour et al, 2019;McKetton et al, 2019). Thus, animal models of chronic cerebral hypoperfusion are most commonly used to study VCI (Duncombe et al, 2017;Mansour et al, 2018;Washida et al, 2019).Therefore, our future studies aim to combine age factors with chronic cerebral hypoperfusion allowing the exploration of changes in the white matter and cognitive functions in elderly rats under different degrees of hypoperfusion and to establish a new VCI model of elderly rats with bilateral common carotid artery (CCA) stenosis (BCAS).…”

Dysfunction of Cerebrovascular Endothelial Cells: Prelude to Vascular Dementia

“…International Classification of Diseases-10 (ICD-10) defines dementia that occurs after cerebrovascular disease as VaD. Most of VaD is caused by cerebral hypoperfusion ( Mansour et al, 2018 ). Cerebrovascular endothelial cells (CECs) are usually the foremost in bearing the attack of hypoperfusion.…”

Regulatory microRNAs and vascular cognitive impairment and dementia

“…This model shares several common pathological consequences with small vessel disease, including microinfarcts and WM changes 28,29 . WM lesions and rarefaction mainly occur in the corpus callosum with remarkable myelin loss, axonal damage, microglia, and astrocyte activation, without causing neuronal damage 30‐33 . In the model of small vessel occlusion, microglia/macrophage polarization was also found strongly linked to VCID 34 .…”