A brief overview of a mouse model of cerebral hypoperfusion by bilateral carotid artery stenosis

Abstract

Vascular cognitive impairment (VCI) refers to all forms of cognitive disorder related to cerebrovascular diseases, including vascular mild cognitive impairment, post-stroke dementia, multi-infarct dementia, subcortical ischemic vascular dementia (SIVD), and mixed dementia. Among the causes of VCI, more attention has been paid to SIVD because the causative cerebral small vessel pathologies are frequently observed in elderly people and because the gradual progression of cognitive decline often mimics Alzheimer's disease. In most cases, small vessel diseases are accompanied by cerebral hypoperfusion. In mice, prolonged cerebral hypoperfusion is induced by bilateral carotid artery stenosis (BCAS) with surgically implanted metal micro-coils. This cerebral hypoperfusion BCAS model was proposed as a SIVD mouse model in 2004, and the spreading use of this mouse SIVD model has provided novel data regarding cognitive dysfunction and histological/genetic changes by cerebral hypoperfusion. Oxidative stress, microvascular injury, excitotoxicity, blood-brain barrier dysfunction, and secondary inflammation may be the main mechanisms of brain damage due to prolonged cerebral hypoperfusion, and some potential therapeutic targets for SIVD have been proposed by using transgenic mice or clinically used drugs in BCAS studies. This review article overviews findings from the studies that used this hypoperfused-SIVD mouse model, which were published between 2004 and 2021.

Keywords: Bilateral carotid artery stenosis; cerebral hypoperfusion; cerebral small vessel disease; subcortical ischemic vascular dementia; vascular cognitive impairment.

Figure 1.

Flowchart of literature selection. We used terms for the initial search as follows; ‘bilateral carotid artery stenosis’ or ‘BCAS’, ‘cerebral hypoperfusion’ and ‘mouse’ or ‘mice’ on Pubmed. One hundred nineteen papers were selected by the initial search. Twenty-three papers were excluded because BCAS mice were not used in them. After assessing each paper, 19 papers with data using BCAS mice were added to the reference list. The final 115 papers were used in this study.

Figure 2.

Publications using bilateral carotid artery stenosis mouse model. The number of publications using the bilateral carotid artery stenosis mouse model has been increasing (a). From 2004 to 2016, this model was used mainly in Japan and the US (b). Recently, this mouse model was used in various countries (c).

Figure 3.

Operation of bilateral carotid artery stenosis. After the skin is cut, blunt dissection with a small clamp or forceps is conducted until the trachea can be seen. Expose both common carotid arteries from their sheaths under an operating microscope. Separating the carotid from the vagus nerve (green arrows) is very important and attention should be paid not to damage the nerve. Sutures should be located around the CCA for lifting the vessels (a). Then twine the microcoil (yellow) by rotating it around the left CCA (b) and right CCA (c).