Chronic cerebral hypoperfusion induced by right unilateral common carotid artery occlusion causes delayed white matter lesions and cognitive impairment in adult mice

https://doi.org/10.1016/j.expneurol.2007.12.005Get rights and content

Abstract

Some lines of evidence have suggested that subcortical ischemic vascular dementia (SIVD) is a common form of vascular dementia (VaD), and that its pathological changes are the development of ischemic white matter (WM) lesions under chronic hypoperfusion and lacunes. Here, we have developed a novel mouse model of VaD with WM lesions, which was induced by right unilateral common carotid artery occlusion (rUCCAO). The mice subjected to rUCCAO exhibited chronic cerebral hypoperfusion in the cerebral hemisphere ipsilateral to rUCCAO monitored using a laser-Doppler flow meter (p < 0.01), and significant WM damage in the corpus callosum (p < 0.05) and deficits in object recognition test correlated with the damage of frontal-subcortical circuits (p < 0.01). However, no differences in spontaneous alternation or spontaneous motor activity were observed. Furthermore, the levels of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and interleukin-6 (IL-6), significantly increased (p < 0.01), and those of anti-inflammatory cytokines, such as interleukin-4 (IL-4) and interleukin-10 (IL-10), significantly decreased in the ischemic brain (p < 0.05). These results suggest that this model is a useful tool for investigating the associations among inflammatory reactions, cognitive impairment, and WM damage, which may help elucidating the pathomechanism of VaD, particularly SIVD.

Introduction

Vascular dementia is the second most prevalent type of dementia in the world, which is characterized by heterogeneous pathological conditions (Roman et al., 2002). Ischemic WM lesions are the characteristic pathological changes in SIVD, a common form of vascular dementia, and the degree of cognitive impairment is related to lesion severity (Hachinski et al., 1987, Pantoni et al., 1999, de Groot et al., 2001). These WM lesions and cognitive impairment are caused by chronic cerebral hypoperfusion, which results from a severe stenosis of arteries or arterioles mainly deep in the white matter (Pantoni and Garcia, 1997, Roman, 2004). To elucidate the mechanisms underlying ischemic WM damage and cognitive impairment under chronic cerebral hypoperfusion, a rat model subjected to the ligation of bilateral common carotid arteries (CCAs) and a gerbil model subjected to the stenosis of bilateral CCAs have been investigated. These models show a chronic mild reduction in cerebral blood flow (CBF), WM rarefaction (Hattori et al., 1992, Wakita et al., 1994), and delayed memory impairment (Ohta et al., 1997, Sarti et al., 2002, Wakita et al., in press). Recently, a mouse model exhibiting ischemic WM damage (Shibata et al., 2004) induced by the stenosis of the bilateral CCAs using special instruments such as microcoils has been developed. This mouse model is a useful tool for investigating the molecular mechanisms underlying the development of WM lesions and cognitive impairment because a mouse model is applicable to transgenic or knockout animals (Shibata et al., 2004, Nakaji et al., 2006).

Inflammatory and immune mechanisms play important roles in the progression of ischemic brain injury (Chamorro and Hallenbeck, 2006). Cytokine dysregulation has been reported in cognitive disorders and dementia (Wilson et al., 2002). In VaD patients, the plasma levels of inflammatory biomarkers, such as α1-antichymotrypsin and C-reactive protein, increase before the clinical onset of symptoms (Engelhart et al., 2004). Cerebrospinal fluid (CSF) IL-6 level increases in VaD patients (Wada-Isoe et al., 2004). These findings suggest that inflammatory and immune reactions are involved in cognitive impairment of VaD.

In this study, we developed a novel mouse model of VaD with WM lesions, which was induced by the permanent occlusion of the unilateral CCA (rUCCAO). This model demonstrated a chronic mild reduction in CBF, WM lesions, and delayed memory impairment. Furthermore, the levels of pro-inflammatory cytokines increased and those of anti-inflammatory cytokines decreased in the brain. This mouse model is a powerful tool for investigating the associations among inflammatory reactions, WM damage and memory impairment, which may help elucidating the pathomechanism of VaD, particularly SIVD.

Section snippets

Animal preparation

All experiments were performed in accordance with the Guidelines for Animal Experiments of the NCGG/NILS animal experimentation committee. The procedures involving animals and the care of animals conformed with the international guidelines set out in the “Principles of Laboratory Animal Care” (NIH publication no. 85-23, revised 1985). Twelve-week-old male C57BL/6J mice (n = 84) weighing 24 to 26 g (Japan SLC. Inc. Hamamatsu, Japan) were used. After a habituation period of 1 week, the mice were

Mortality rates and temporal changes in CBF

No animals in the sham-or rUCCAO-operated group died. The mean CBF after rUCCAO operation decreased significantly in the cerebral hemisphere ipsilateral to the arterial occlusion, as compared with that after sham operation (p < 0.01) or that in the cerebral hemisphere contralateral to the arterial occlusion (p < 0.01). At 2 h, CBF decreased to 65.5 ± 10.3% of that before the operation. On day 3, CBF began to increase but remained significantly lower than the preoperative baseline CBF until 28 days

Discussion

In this study, we established a novel mouse model exhibiting a delayed development of WM lesions and cognitive impairment under chronic cerebral hypoperfusion induced by rUCCAO. In contrast to other strains of mice, C57BL6/J mice showed a significant decrease in CBF following rUCCAO, because of a poorly developed posterior communicating artery (Yang et al., 1997, Wellons et al., 2000, Kitagawa et al., 2005) without acute lesions, which is unlikely in immature mice (Comi et al., 2004). In

Acknowledgments

This study was supported by the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO). This work was supported by the Research Grant for Longevity Sciences (18C-4) from the Ministry of Health, Labour and Welfare.

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