scholarly journals Animal Models of Chronic Cerebral Hypoperfusion: From Mouse to Primate

2019 ◽  
Vol 20 (24) ◽  
pp. 6176 ◽  
Author(s):  
Kazuo Washida ◽  
Yorito Hattori ◽  
Masafumi Ihara
Keyword(s):  
White Matter ◽  
Animal Models ◽  
Mouse Model ◽  
Carotid Arteries ◽  
Amyloid Β ◽  
Chronic Cerebral Hypoperfusion ◽  
Motor Dysfunction ◽  
Cerebral Hypoperfusion ◽  
Left Vertebral Artery ◽  
Vessel Occlusion

Vascular cognitive impairment (VCI) or vascular dementia occurs as a result of brain ischemia and represents the second most common type of dementia after Alzheimer’s disease. To explore the underlying mechanisms of VCI, several animal models of chronic cerebral hypoperfusion have been developed in rats, mice, and primates. We established a mouse model of chronic cerebral hypoperfusion by narrowing the bilateral common carotid arteries with microcoils, eventually resulting in hippocampal atrophy. In addition, a mouse model of white matter infarct-related damage with cognitive and motor dysfunction has also been established by asymmetric common carotid artery surgery. Although most experiments studying chronic cerebral hypoperfusion have been performed in rodents because of the ease of handling and greater ethical acceptability, non-human primates appear to represent the best model for the study of VCI, due to their similarities in much larger white matter volume and amyloid β depositions like humans. Therefore, we also recently developed a baboon model of VCI through three-vessel occlusion (both the internal carotid arteries and the left vertebral artery). In this review, several animal models of chronic cerebral hypoperfusion, from mouse to primate, are extensively discussed to aid in better understanding of pathophysiology of VCI.

scholarly journals Chronic Cerebral Hypoperfusion Induces MMP-2 but Not MMP-9 Expression in the Microglia and Vascular Endothelium of White Matter

2001 ◽  
Vol 21 (7) ◽  
pp. 828-834 ◽  
Author(s):  
Masafumi Ihara ◽  
Hidekazu Tomimoto ◽  
Makoto Kinoshita ◽  
Junseo Oh ◽  
Makoto Noda ◽  
...  
Keyword(s):  
White Matter ◽  
Corpus Callosum ◽  
Optic Tract ◽  
White Matter Lesions ◽  
Chronic Cerebral Hypoperfusion ◽  
Motor Dysfunction ◽  
Cerebral Hypoperfusion ◽  
Matrix Metalloproteinase 2 ◽  
Capillary Endothelial Cells ◽  
Common Carotid Arteries

White matter lesions are closely associated with cognitive impairment and motor dysfunction in the aged. To explore the pathophysiology of these lesions, the authors examined the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 in the white matter in a rat model of chronic cerebral hypoperfusion. After bilateral clipping of the common carotid arteries, myelin staining revealed demyelinating changes in the optic tract and the corpus callosum on day 7. Zymographic analyses indicated an increase in the level of MMP-2, but not MMP-9, after the hypoperfusion. Immunohistochemical analyses revealed the presence (most abundantly on day 3) of MMP-2–expressing activated microglia in the optic tract and corpus callosum. In contrast, the capillary endothelial cells expressed MMP-2 later. IgM-immunoreactive glial cells were absent in the sham-operated animals, but were present in the hypoperfused animals by day 3, reflecting the disrupted blood–brain barrier. These findings suggest that the main sources of the elevated MMP-2 were the microglia and the endothelium, and that these cells may contribute to the remodeling of the white matter myelin and microvascular beds in chronic cerebral hypoperfusion.

scholarly journals White Matter Lesions and Glial Activation in a Novel Mouse Model of Chronic Cerebral Hypoperfusion

Stroke ◽  
2004 ◽  
Vol 35 (11) ◽  
pp. 2598-2603 ◽  
Author(s):  
Masunari Shibata ◽  
Ryo Ohtani ◽  
Masafumi Ihara ◽  
Hidekazu Tomimoto
Keyword(s):  
White Matter ◽  
Mouse Model ◽  
White Matter Lesions ◽  
Glial Activation ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion

scholarly journals Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia

2017 ◽  
Vol 131 (19) ◽  
pp. 2451-2468 ◽  
Author(s):  
Jessica Duncombe ◽  
Akihiro Kitamura ◽  
Yoshiki Hase ◽  
Masafumi Ihara ◽  
Raj N. Kalaria ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Small Vessel Disease ◽  
Amyloid Β ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Pathophysiological Mechanism ◽  
Rodent Models ◽  
Recent Refinement

Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.

Disruption of White Matter Integrity by Chronic Cerebral Hypoperfusion in Alzheimer’s Disease Mouse Model

2016 ◽  
Vol 52 (4) ◽  
pp. 1311-1319 ◽  
Author(s):  
Yun Zhai ◽  
Toru Yamashita ◽  
Yumiko Nakano ◽  
Zhuoran Sun ◽  
Ryuta Morihara ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Mouse Model ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
White Matter Integrity

scholarly journals The effects of environmental enrichment on white matter pathology in a mouse model of chronic cerebral hypoperfusion

2017 ◽  
Vol 38 (1) ◽  
pp. 151-165 ◽  
Author(s):  
Yoshiki Hase ◽  
Lucinda Craggs ◽  
Mai Hase ◽  
William Stevenson ◽  
Janet Slade ◽  
...  
Keyword(s):  
White Matter ◽  
Mouse Model ◽  
Environmental Enrichment ◽  
Three Dimensional ◽  
Vascular Cognitive Impairment ◽  
Cognitive Testing ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Full Time ◽  
Time Exposure

White matter (WM) disintegration is common in the older population and is associated with vascular cognitive impairment (VCI). This study explored the effects of environmental enrichment (EE) on pathological sequelae in a mouse model of chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS). Male C57BL/6 J mice underwent BCAS or sham surgery. One-week after surgery, mice were exposed to three different degrees of EE; either standard housing conditions (std), limited 3 h exposure to EE per day (3 h) or full-time exposure to EE (full) for 12 weeks. At 13 weeks after surgery, cognitive testing was performed using a three-dimensional 9-arm radial maze. At 16 weeks after surgery, nesting ability was assessed in each mouse immediately before euthanasia. Brains retrieved after perfusion fixation were examined for WM pathology. BCAS caused WM changes, as demonstrated by corpus callosum atrophy and greater WM disintegrity. BCAS also caused impaired nesting ability and cognitive function. These pathological changes and working memory deficits were attenuated, more so by limited rather than full-time exposure to EE regime. Our results suggest that limited exposure to EE delays the onset of WM degeneration. Therefore, the implementation of even limited EE may be beneficial for patients diagnosed with VCI.

scholarly journals Lessons from a Mouse Model Characterizing Features of Vascular Cognitive Impairment with White Matter Changes

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Masafumi Ihara ◽  
Hidekazu Tomimoto
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Mouse Model ◽  
The Elderly ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Demographic Shift ◽  
White Matter Changes ◽  
Blood Brain Barrier Disruption

With the demographic shift in age in advanced countries inexorably set to progress in the 21st century, dementia will become one of the most important health problems worldwide. Vascular cognitive impairment is the second most common type of dementia after Alzheimer's disease and is frequently responsible for the cognitive decline of the elderly. It is characterized by cerebrovascular white matter changes; thus, in order to investigate the underlying mechanisms involved in white matter changes, a mouse model of chronic cerebral hypoperfusion has been developed, which involves the narrowing of the bilateral common carotid arteries with newly designed microcoils. The purpose of this paper is to provide a comprehensive summary of the achievements made with the model that shows good reproducibility of the white matter changes characterized by blood-brain barrier disruption, glial activation, oxidative stress, and oligodendrocyte loss following chronic cerebral hypoperfusion. Detailed characterization of this model may help to decipher the substrates associated with impaired memory and move toward a more integrated therapy of vascular cognitive impairment.

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