A refined model of chronic cerebral hypoperfusion resulting in cognitive impairment and a low mortality rate in rats.

OBJECTIVEThe cognitive deficits of vascular dementia and the vasoocclusive state of moyamoya disease have often been mimicked with bilateral stenosis/occlusion of the common carotid artery (CCA) or internal carotid artery. However, the cerebral blood flow (CBF) declines abruptly in these models after ligation of the CCA, which differs from "chronic" cerebral hypoperfusion. While some modified but time-consuming techniques have used staged occlusion of both CCAs, others used microcoils for CCA stenosis, producing an adverse effect on the arterial endothelium. Thus, the authors developed a new chronic cerebral hypoperfusion (CCH) model with cognitive impairment and a low mortality rate in rats.METHODSMale Sprague-Dawley rats were subjected to unilateral CCA occlusion and contralateral induction of CCA stenosis (modified CCA occlusion [mCCAO]) or a sham operation. Cortical regional CBF (rCBF) was measured using laser speckle flowmetry. Cognitive function was assessed using a Barnes circular maze (BCM). MRI studies were performed 4 weeks after the operation to evaluate cervical and intracranial arteries and parenchymal injury. Behavioral and histological studies were performed at 4 and 8 weeks after surgery.RESULTSThe mCCAO group revealed a gradual CBF reduction with a low mortality rate (2.3%). White matter degeneration was evident in the corpus callosum and corpus striatum. Although the cellular density declined in the hippocampus, MRI revealed no cerebral infarctions after mCCAO. Immunohistochemistry revealed upregulated inflammatory cells and angiogenesis in the hippocampus and cerebral cortex. Results of the BCM assessment indicated significant impairment in spatial learning and memory in the mCCAO group. Although some resolution of white matter injury was observed at 8 weeks, the animals still had cognitive impairment.CONCLUSIONSThe mCCAO is a straightforward method of producing a CCH model in rats. It is associated with a low mortality rate and could potentially be used to investigate vascular disease, moyamoya disease, and CCH. This model was verified for an extended time point of 8 weeks after surgery.

[1]  Si-Qi Du,et al.  Molecular Mechanisms of Vascular Dementia: What Can Be Learned from Animal Models of Chronic Cerebral Hypoperfusion? , 2016, Molecular Neurobiology.

[2]  T. Hishikawa,et al.  Combined gene therapy with vascular endothelial growth factor plus apelin in a chronic cerebral hypoperfusion model in rats. , 2017, Journal of neurosurgery.

[3]  A. Daliry,et al.  The impact of early aerobic exercise on brain microvascular alterations induced by cerebral hypoperfusion , 2017, Brain Research.

[4]  Jianping Wang,et al.  Preconditioning with VEGF Enhances Angiogenic and Neuroprotective Effects of Bone Marrow Mononuclear Cell Transplantation in a Rat Model of Chronic Cerebral Hypoperfusion , 2016, Molecular Neurobiology.

[5]  H. Fukuyama,et al.  Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory , 2016, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[6]  A. Dorrance,et al.  Bilateral common carotid artery stenosis in normotensive rats impairs endothelium-dependent dilation of parenchymal arterioles. , 2016, American journal of physiology. Heart and circulatory physiology.

[7]  I. Kanno,et al.  Long-term effects of cerebral hypoperfusion on neural density and function using misery perfusion animal model , 2016, Scientific Reports.

[8]  Qingsong Wang,et al.  Chronic cerebral hypoperfusion induces long-lasting cognitive deficits accompanied by long-term hippocampal silent synapses increase in rats , 2016, Behavioural Brain Research.

[9]  Kyoung-Hee Lee,et al.  Effect of exercise-induced neurogenesis on cognitive function deficit in a rat model of vascular dementia , 2016, Molecular medicine reports.

[10]  W. Liu,et al.  BMSCs transplantation improves cognitive impairment via up-regulation of hippocampal GABAergic system in a rat model of chronic cerebral hypoperfusion , 2015, Neuroscience.

[11]  Jianping Wang,et al.  A modified bilateral carotid artery stenosis procedure to develop a chronic cerebral hypoperfusion rat model with an increased survival rate , 2015, Journal of Neuroscience Methods.

[12]  M. Chopp,et al.  Models and mechanisms of vascular dementia , 2015, Experimental Neurology.

[13]  Qing Lu,et al.  Long-lasting spatial learning and memory impairments caused by chronic cerebral hypoperfusion associate with a dynamic change of HCN1/HCN2 expression in hippocampal CA1 region , 2015, Neurobiology of Learning and Memory.

[14]  Qing Lu,et al.  Clonidine ameliorates cognitive impairment induced by chronic cerebral hypoperfusion via up-regulation of the GABABR1 and GAD67 in hippocampal CA1 in rats , 2015, Pharmacology Biochemistry and Behavior.

[15]  Yiwen Ruan,et al.  Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[16]  H. Iida,et al.  A Novel Mouse Model of Subcortical Infarcts with Dementia , 2015, The Journal of Neuroscience.

[17]  N. Hattori,et al.  L-Carnitine Enhances Axonal Plasticity and Improves White-Matter Lesions after Chronic Hypoperfusion in Rat Brain , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[18]  H. Tomimoto,et al.  Chronic cerebral hypoperfusion and dementia , 2014 .

[19]  Yan-Ling Wang,et al.  Bilateral Common Carotid Artery Occlusion in the Rat as a Model of Retinal Ischaemia , 2014, Neuro-ophthalmology.

[20]  Chao Jiang,et al.  Bone marrow mononuclear cell transplantation promotes therapeutic angiogenesis via upregulation of the VEGF–VEGFR2 signaling pathway in a rat model of vascular dementia , 2014, Behavioural Brain Research.

[21]  A. Planas,et al.  The Ins and Outs of the BCCAo Model for Chronic Hypoperfusion: A Multimodal and Longitudinal MRI Approach , 2013, PloS one.

[22]  Z. Zhou,et al.  Cognitive functions of carotid artery stenosis in the aged rat , 2012, Neuroscience.

[23]  Juliana Ben,et al.  Chronic brain hypoperfusion causes early glial activation and neuronal death, and subsequent long-term memory impairment , 2012, Brain Research Bulletin.

[24]  J. Hai,et al.  Cognitive dysfunction induced by chronic cerebral hypoperfusion in a rat model associated with arteriovenous malformations , 2009, Brain Research.

[25]  T. Kuroiwa,et al.  Intensity of chronic cerebral hypoperfusion determines white/gray matter injury and cognitive/motor dysfunction in mice , 2009, Journal of neuroscience research.

[26]  Hyung-Jin Lee,et al.  The neovascularization effect of bone marrow stromal cells in temporal muscle after encephalomyosynangiosis in chronic cerebral ischemic rats. , 2008, Journal of Korean Neurosurgical Society.

[27]  T. Tabira,et al.  Chronic cerebral hypoperfusion induced by right unilateral common carotid artery occlusion causes delayed white matter lesions and cognitive impairment in adult mice , 2008, Experimental Neurology.

[28]  F. Bari,et al.  Permanent, bilateral common carotid artery occlusion in the rat: A model for chronic cerebral hypoperfusion-related neurodegenerative diseases , 2007, Brain Research Reviews.

[29]  S. Itohara,et al.  Matrix Metalloproteinase-2 Plays a Critical Role in the Pathogenesis of White Matter Lesions After Chronic Cerebral Hypoperfusion in Rodents , 2006, Stroke.

[30]  I. Date,et al.  Enhanced brain angiogenesis in chronic cerebral hypoperfusion after administration of plasmid human vascular endothelial growth factor in combination with indirect vasoreconstructive surgery. , 2005, Journal of neurosurgery.

[31]  H. Milani,et al.  Permanent, 3-stage, 4-vessel occlusion as a model of chronic and progressive brain hypoperfusion in rats: a neurohistological and behavioral analysis , 2005, Behavioural Brain Research.

[32]  M. Ihara,et al.  White Matter Lesions and Glial Activation in a Novel Mouse Model of Chronic Cerebral Hypoperfusion , 2004, Stroke.

[33]  L. Pantoni,et al.  Cognitive impairment and chronic cerebral hypoperfusion: What can be learned from experimental models , 2002, Journal of Neurological Sciences.

[34]  P. Mcgeer,et al.  Axonal damage and demyelination in the white matter after chronic cerebral hypoperfusion in the rat , 2002, Brain Research.

[35]  H. Milani,et al.  Sildenafil provides sustained neuroprotection in the absence of learning recovery following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats , 2013, Brain Research Bulletin.