Permanent, bilateral common carotid artery occlusion in the rat: A model for chronic cerebral hypoperfusion-related neurodegenerative diseases

Abstract

Chronic cerebral hypoperfusion has been associated with cognitive decline in aging and Alzheimer's disease. Moreover, the pattern of cerebral blood flow in mild cognitive impairment has emerged as a predictive marker for the progression into Alzheimer's disease. The reconstruction of a pathological condition in animal models is a suitable approach to the unraveling of causal relationships. For this reason, permanent, bilateral occlusion of the common carotid arteries (2VO) in rats has been established as a procedure to investigate the effects of chronic cerebral hypoperfusion on cognitive dysfunction and neurodegenerative processes. Over the years, the 2VO model has generated a large amount of data, revealing the 2VO-related pattern of cerebral hypoperfusion and metabolic changes, learning and memory disturbances, failure of neuronal signaling, and the neuropathological changes in the hippocampus. In addition, the model has been introduced in research into ischemic white matter injury and ischemic eye disease. The present survey sets out to provide a comprehensive summary of the achievements made with the 2VO model, and a critical evaluation and integration of the various results, and to relate the experimental data to human diseases. The data that have accumulated from use of the 2VO model in the rat permit an understanding of the causative role played by cerebral hypoperfusion in neurodegenerative diseases. Thorough characterization of the model suggests that 2VO in the rat is suitable for the development of potentially neuroprotective strategies in neurodegenerative diseases.

Consensus statement for diagnosis of subcortical small vessel disease

“…133 A number of anti-inflammatory agents and free radical scavenging agents have shown benefit. 114 Treatments with minocycline significantly attenuated the hypoxia-ischemia-induced brain injury and improved neurobehavioral performance; the protection of minocycline was associated with its ability to reduce microglial activation. 134 In the SHR/SP with the Japanese permissive diet and unilateral carotid artery occlusion, treatment with minocycline blocked the full development of white-matter injuries seen on MRI and improved behavior in the Morris water maze.…”

“…Treatments in rats with hypoxic hypoperfusion due to either BCAO or spontaneous hypertension have indicated a number of potential therapeutic agents. 114,131 Cyclosporin A suppressed both glial activation and white-matter changes after chronic cerebral hypoperfusion, suggesting that immunologic reaction may have a role in the pathogenesis of the whitematter changes. 132 Cyclosporine A inhibits BBB breakdown in APOE4 Tg mice by inihibiting cyclophilin A-MMP-9 pathway in pericytes leading to reversal of neuronal dysfunction and secondary neurodegenerative changes.…”

The neuron-astrocyte-microglia triad in CA3 after chronic cerebral hypoperfusion in the rat: Protective effect of dipyridamole

“…Bilateral common carotid artery occlusion (two-vessel occlusion, 2VO) was carried out in rats (Sarti et al 2002a(Sarti et al , 2002bFarkas et al 2007) according to the scheme represented in Fig. 1A, according to the method previously published (Lana et al 2014).…”

“…The permanent, bilateral occlusion of the common carotid arteries of rats (two-vessel occlusion, 2VO) is a procedure that mimics age-related cerebrovascular stenosis and is widely utilized to investigate the mechanisms of chronic cerebral hypoperfusion and consequent neurodegenerative processes (Farkas et al 2007;Sarti et al 2002aSarti et al , 2002bLana et al 2014). The 2VO model has revealed that, the CA1 region of the hippocampus is particularly vulnerable not only to acute ischemia but also to hypoperfusion given by the 2VO, with consequent failure of neuronal signaling, and to learning and memory disturbances (Farkas et al 2006;Melani et al 2010;Ohtaki et al 2006;Schmidt-Kastner et al 2001;Shibata et al 2004).…”

Micro-Heterogeneity of Flow in a Mouse Model of Chronic Cerebral Hypoperfusion Revealed by Longitudinal Doppler Optical Coherence Tomography and Angiography

“…4 Bilateral common carotid artery occlusion has been widely used in the rat to model chronic cerebral hypoperfusion. 5 Recently, mouse bilateral common carotid artery stenosis (BCAS) models have emerged. 6 In these models, although the degree of hypoperfusion is correlated with the extent of ischemic lesions and neurologic impairment, 7 the magnitude of flow reductions after BCAS were moderate at best (~30 to 40%), 8 at least relative to classic ischemic thresholds of 80 to 85%, [9][10][11] and lasted only a few days before collateral development and recovery of flow.…”