Construction, Evaluation and Significance of Animal Models of Chronic Cerebral Hypoperfusion

摘要

The aging of the social population has drawn much attention to the etiology, prevention and treatment of neurodegenerative diseases such as Alzheimer's Disease(AD) and Vascular Dementia(VD). Chronic Cerebral Hypoperfusion(CCH), which is long-term associated with chronic diseases that are highly prevalent among middle-aged and elderly people, such as hyperglycemia, hypertension, hyperlipidemia, atherosclerosis, heart failure, and metabolic syndrome, has become a potential risk factor for the occurrence and development of these diseases. Some studies have found that CCH can aggravate the pathological changes related to AD, including β-amyloid protein deposition and tau protein hyperphosphorylation, indicating that chronic hypoperfusion might not only be an important pathogenic factor for vascular cognitive impairment, but also play a promoting role in the course of AD. This makes stable and reliable animal models of CCH important research tools for the early study of neurodegenerative diseases, the study of potential risk factors, and early prevention and treatment strategies. CCH could lead to structural and functional disorders of neurovascular units and induce cognitive dysfunction. Currently, widely adopted models include Two-Vessel Occlusion in rats. The 2VO model and the Bilateral Common Carotid Artery Stenosis(BCAS) model in mice. Furthermore, the Asymmetric Carotid Artery Stenosis(ACAS) and non-human primate ThreeVessel Occlusion(3VO) models are closer to human pathology compared to the rodent models. The 2VO model is simple to operate but prone to optic nerve ischemia. The BCAS model is delicate and difficult to operate, but more stable and long-lasting of perfusion. The ACAS model has a low mortality rate, but the induction method is complex. The 3VO model can simulate human ischemic cerebral small vessel disease, but the cost is high. The success of model establishment and its impact on brain function can be evaluated through cerebral blood flow detection, behavioral assessment and histopathological analysis. The cerebral blood flow significantly decreased to 30%～50% of the initial level after the operation. Although it recovered slowly within several weeks, it remained persistently below the normal level, causing continuous hypoperperfusion of the brain tissue and resulting in a series of injuries. In behavioral tests such as the Morris water maze experiment, animals may show prolonged latency, prolonged distance, etc. The pathological morphology is mainly manifested as ischemic injury of the white matter of the brain, including demyelination and axonal damage, as well as apoptosis of oligodendrocytes and excessive activation of microglia and/or astrocytes. However, the gray matter regions of the cortex and hippocampus are different from the severe lesions of AD or VD, presenting only with mild neuronal loss. Furthermore, whether the integrity of the Blood-Brain Barrier(BBB) is damaged is also an important evaluation index. CCH can increase the permeability of the BBB, thereby leading to dysfunction of the neurovascular unit and aggravating brain tissue damage. CCH animal models play a significant role in the exploration of the mechanisms of neurodegenerative diseases, the mechanisms of complications of "three highs", and the development of drugs for the prevention and treatment of these diseases. Through the CCH model, not only can the pathological processes such as white matter degeneration, neuroinflammation and BBB destruction in brain tissue be clarified, but also the pathogenesis of vascular cognitive impairment can be deeply understood; Screening and evaluation of candidate drugs and cell therapy regimens can also be conducted to explore effective strategies for improving cognitive impairment caused by hypoperfusion.

关键词

chronic cerebral hypoperfusion / animal model / blood-brain barrier

基金资助

Open Project of Hebei Key Laboratory of Nerve Injury and Repair (NJKF202402); Natural Science Research Project of Hebei North University (XJ2024021); Graduate Student Innovation Funding Project of Hebei North University