Elsevier

Neurobiology of Aging

Volume 33, Issue 5, May 2012, Pages 1012.e25-1012.e35
Neurobiology of Aging

Abstracts of online article
Selective white matter abnormalities in a novel rat model of vascular dementia

https://doi.org/10.1016/j.neurobiolaging.2011.10.033Get rights and content

Abstract

Rats subjected to bilateral common carotid artery (CCA) occlusion or 2-vessel occlusion (2VO) have been used as animal models of subcortical ischemic vascular dementia. However, this model possesses an inherent limitation in that cerebral blood flow (CBF) drops too sharply and substantially after ligation of CCAs. To circumvent such hypoxic-ischemic conditions, we tested implantation of the ameroid constrictor device on bilateral CCAs of male Wistar-Kyoto rats and more precisely replicated chronic cerebral hypoperfusion by gradual narrowing of the CCAs (2-vessel gradual occlusion; 2VGO). The acute cerebral blood flow reduction and resultant inflammatory responses observed in the 2VO rats were eliminated in the 2VGO rats. Thus, chronic cerebral hypoperfusion was segregated, and induced selective white matter changes with relatively preserved neurovascular coupling and substantially less metabolic and histological derangements in the gray matter including the hippocampus. This led to significant spatial working memory impairment of a magnitude similar to the 2VO rats at 28 days postoperation. The 2VGO model may more closely mimic cognitive impairment subsequent to selective white matter damage.

Introduction

Vascular dementia (VaD) is the second most common cause of dementing illnesses after Alzheimer's disease (AD). Approximately half of all cases of vascular dementia are explained by subcortical ischemic vascular dementia (SIVD) (Yoshitake et al., 1995), which is characterized by lacunar infarctions in the basal ganglia and ischemic white matter changes. Loss of vasomotor reactivity in the small vessels and resultant chronic cerebral hypoperfusion with blood-brain barrier (BBB) disruption and glial activation may underlie the white matter changes (Marshall and Lazar, 2011, Pantoni, 2010).

To mimic such a pathological condition and explore the underlying mechanisms, several animal models of chronic cerebral hypoperfusion have been developed, including bilateral common carotid artery (CCA) or 2-vessel occlusion (2VO) in rats, bilateral CCA stenosis in gerbils or mice (BCAS) (Shibata et al., 2004), and unilateral CCA occlusion in mice (Yoshizaki et al., 2008). Among these, the rat 2VO model has been frequently used (Jiwa et al., 2010) and may become more important when genetically-modified rats are widely available. The 2VO model exhibits characteristic features of SIVD, such as white matter damage (Wakita et al., 1994, Wakita et al., 2002), and cognitive impairment (Farkas et al., 2007, Hainsworth and Markus, 2008, Jiwa et al., 2010). Nevertheless, this model possesses an inherent limitation in that cerebral blood flow (CBF) drops too sharply and substantially after the ligation of the CCAs and remains too low (30%–45% of the baseline level) for 2–3 days; this therefore creates hypoxic-ischemic conditions too severe to replicate “chronic” cerebral hypoperfusion (Marosi et al., 2006). After this acute phase, CBF gradually recovers but still remains relatively low (50%–90%) for 8 weeks to 3 months postoperation (chronic phase) (Otori et al., 2003, Tomimoto et al., 2003). Although the sustained oligemia in the chronic phase is believed to better replicate chronic cerebral hypoperfusion associated with SIVD, the contribution of the preceding acute phase to the neuropathological and behavioral consequences is an ongoing concern (Farkas et al., 2007). We therefore sought to establish a novel rat model that eliminates the acute phase, meaning that CBF would gradually decrease to the level in the chronic phase, using the ameroid constrictor device. This device could predictably achieve gradual narrowing of the CCAs and establish a rat model of SIVD that replicates “chronic” cerebral hypoperfusion more precisely. We therefore henceforth refer to this novel rat model as the “2-vessel gradual occlusion (2VGO)” model.

Section snippets

Animals

We used 12- to 14-week-old male Wistar-Kyoto rats (WKY) (See Supplemental Method I for details).

Ameroid constrictor

The ameroid constrictor (Research Instruments NW, Lebanon, OR, USA) consists of a stainless steel casing surrounding a hygroscopic casein material that has an internal lumen. The casein component gradually absorbs water and consequently swells, leading to predictable narrowing and occlusion of the arterial lumen that it encases (Fig. 1). The inner diameter was 0.5 mm, the outer diameter 3.25 mm, and

Mortality rates and body weight changes of rats

The mortality rate in the 2VGO group was 2.0% (1/49). This was much lower than that of the 2VO group, which was 13.8% (8/58), in accordance with previous reports (Fujishima et al., 1976). In the sham group, all 48 rats survived until euthanized. Body weight decreased in both the 2VGO and 2VO groups, which was significantly less severe in the 2VGO group at 1 day postoperation (2VGO group, −14.1 ± 2.0% vs. 2VO group, −27.4 ± 1.7%; p < 0.01). Both groups of rats started to regain body weight at 3

Discussion

The findings in this study suggest circumvention of the acute phase of CBF reduction and resultant acute inflammatory response observed in the 2VO model by gradual narrowing of the bilateral CCAs using the ameroid constrictor device instead of ligation. As a result, segregation of the chronic phase from the acute phase was achieved, suggesting a more precise reconstruction of chronic cerebral hypoperfusion evident in clinical cases of SIVD. This method induced demyelinating changes with

Disclosure statement

The authors disclose no conflicts of interest.

All procedures were performed in accordance with the guidelines for animal experimentation from the ethical committee of Kyoto University.

Acknowledgements

We thank Dr. Matsuo and Dr. Wakita for generously giving us the anti-dMBP antibody, and Dr. Khundakar for insightful comments and editing. We are indebted to Ms. Tanigaki, Ms. Hikawa, Ms. Nakabayashi, Ms. Kawada, Ms. Katsukawa, and Mr. Kubota for their excellent technical assistance. This work was supported by grants from the Suzuken Memorial Foundation (to MI and JT) and the Japanese Vascular Disease Research Foundation (MI). The research work of R.N.K. is supported by the Medical Research

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