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. 1. Introduction Subcortical ischemic vascular dementia (SIVD) is characterized by white matter (WM) changes and lacunar infarctions, which occur as a result of a reduction in cerebral blood flow (CBF) over an extended period of time, causing small vessel changes [1–3]. Cerebrovascular WM lesions, neurodegenerative manifestations characterized by hyperintense signals on magnetic resonance images, are frequently associated with aging and are responsible for the cognitive decline in the elderly population [1–7]. Chronic cerebral hypoperfusion is likely to cause such WM lesions as CBF is decreased in these patients [2, 8]; indeed, similar WM lesions can be induced in rats, gerbils, and mice after chronic cerebral hypoperfusion, with experimental conditions mimicking chronic cerebral ischemia in humans [9–11]. These model animals can be generated by bilateral common carotid artery (CCA) occlusion in rats (2-vessel occlusion (2VO)) [9, 12, 13] or in mice [14], bilateral CCA stenosis in mice (BCAS) [10] or in gerbils [11], and unilateral CCA occlusion in mice [15]. Nonhuman primates appear to represent the best model for the study of WM lesions, because they have well-developed WM and vascular architectures which closely resemble those in human brains [16]. Nevertheless, most experiments studying chronic cerebral hypoperfusion have been performed in rodents because of the ease of handling and higher acceptability
References
[1]
G. C. Román, T. Erkinjuntti, A. Wallin, L. Pantoni, and H. C. Chui, “Subcortical ischaemic vascular dementia,” Lancet Neurology, vol. 1, no. 7, pp. 426–436, 2002.
[2]
M. Ihara, H. Tomimoto, K. Ishizu et al., “Decrease in cortical benzodiazepine receptors in symptomatic patients with leukoaraiosis: a positron emission tomography study,” Stroke, vol. 35, no. 4, pp. 942–947, 2004.
[3]
K. A. Jellinger, “The enigma of vascular cognitive disorder and vascular dementia,” Acta Neuropathologica, vol. 113, no. 4, pp. 349–388, 2007.
[4]
L. Pantoni and J. H. Garcia, “The significance of cerebral white matter abnormalities 100 years after Binswanger's report: a review,” Stroke, vol. 26, no. 7, pp. 1293–1301, 1995.
[5]
K. Meguro, J. Hatazawa, T. Yamaguchi et al., “Cerebral circulation and oxygen metabolism associated with subclinical periventricular hyperintensity as shown by magnetic resonance imaging,” Annals of Neurology, vol. 28, no. 3, pp. 378–383, 1990.
[6]
L. Pantoni and J. H. Garcia, “Pathogenesis of leukoaraiosis: a review,” Stroke, vol. 28, no. 3, pp. 652–659, 1997.
[7]
P. Scheltens, F. Barkhof, and F. Fazekas, “White-matter changes on MRI as surrogate marker,” International Psychogeriatrics, vol. 15, supplement 1, pp. 261–265, 2003.
[8]
H. Yao, S. Sadoshima, Y. Kuwabara, Y. Ichiya, and M. Fujishima, “Cerebral blood flow and oxygen metabolism in patients with vascular dementia of the Binswanger type,” Stroke, vol. 21, no. 12, pp. 1694–1699, 1990.
[9]
H. Wakita, H. Tominoto, I. Akiguchi, and J. Kimura, “Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study,” Acta Neuropathologica, vol. 87, no. 5, pp. 484–492, 1994.
[10]
M. Shibata, R. Ohtani, M. Ihara, and H. Tomimoto, “White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion,” Stroke, vol. 35, no. 11, pp. 2598–2603, 2004.
[11]
T. Kudo, K. Tada, M. Takeda, and T. Nishimura, “Learning impairment and microtubule-associated protein 2 decrease in gerbils under chronic cerebral hypoperfusion,” Stroke, vol. 21, no. 8, pp. 1205–1209, 1990.
[12]
E. Farkas, P. G. M. Luiten, and F. Bari, “Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases,” Brain Research Reviews, vol. 54, no. 1, pp. 162–180, 2007.
[13]
C. Sarti, L. Pantoni, L. Bartolini, and D. Inzitari, “Persistent impairment of gait performances and working memory after bilateral common carotid artery occlusion in the adult Wistar rat,” Behavioural Brain Research, vol. 136, no. 1, pp. 13–20, 2002.
[14]
Y. Murakami, Q. Zhao, K. Harada, et al., “Choto-san, a Kampo formula, improves chronic cerebral hypoperfusion-induced spatial learning deficit via stimulation of muscarinic M1 receptor,” Pharmacology Biochemistry and Behavior, vol. 81, no. 3, pp. 616–625, 2005.
[15]
K. Yoshizaki, K. Adachi, S. Kataoka et al., “Chronic cerebral hypoperfusion induced by right unilateral common carotid artery occlusion causes delayed white matter lesions and cognitive impairment in adult mice,” Experimental Neurology, vol. 210, no. 2, pp. 585–591, 2008.
[16]
Stroke Therapy Academic Industry Roundtable (STAIR), “Recommendations for standards regarding preclinical neuroprotective and restorative drug development,” Stroke, vol. 30, no. 12, pp. 2752–2758, 1999.
[17]
J. W. Ni, K. Matsumoto, H. B. Li, Y. Murakami, and H. Watanabe, “Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat,” Brain Research, vol. 673, no. 2, pp. 290–296, 1995.
[18]
N. S. Jiwa, P. Garrard, and A. H. Hainsworth, “Experimental models of vascular dementia and vascular cognitive impairment: a systematic review,” Journal of Neurochemistry, vol. 115, no. 4, pp. 814–828, 2010.
[19]
H. Hattori, M. Takeda, T. Kudo, T. Nishimura, and S. Hashimoto, “Cumulative white matter changes in the gerbil brain under chronic cerebral hypoperfusion,” Acta Neuropathologica, vol. 84, no. 4, pp. 437–442, 1992.
[20]
M. Shibata, N. Yamasaki, T. Miyakawa et al., “Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion,” Stroke, vol. 38, no. 10, pp. 2826–2832, 2007.
[21]
K. Nakaji, M. Ihara, C. Takahashi et al., “Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents,” Stroke, vol. 37, no. 11, pp. 2816–2823, 2006.
[22]
K. Miki, S. Ishibashi, L. Sun et al., “Intensity of chronic cerebral hypoperfusion determines white/gray matter injury and cognitive/motor dysfunction in mice,” Journal of Neuroscience Research, vol. 87, no. 5, pp. 1270–1281, 2009.
[23]
W. Duan, L. Gui, Z. Zhou et al., “Adenosine A2A receptor deficiency exacerbates white matter lesions and cognitive deficits induced by chronic cerebral hypoperfusion in mice,” Journal of the Neurological Sciences, vol. 285, no. 1-2, pp. 39–45, 2009.
[24]
D. Schifilliti, G. Grasso, A. Conti, and V. Fodale, “Anaesthetic-related neuroprotection: intravenous or inhalational agents?” CNS Drugs, vol. 24, no. 11, pp. 893–907, 2010.
[25]
S. Kelly, J. McCulloch, and K. Horsburgh, “Minimal ischaemic neuronal damage and HSP70 expression in MF1 strain mice following bilateral common carotid artery occlusion,” Brain Research, vol. 914, no. 1-2, pp. 185–195, 2001.
[26]
K. Nishio, M. Ihara, N. Yamasaki et al., “A mouse model characterizing features of vascular dementia with hippocampal atrophy,” Stroke, vol. 41, no. 6, pp. 1278–1284, 2010.
[27]
A. Dorr, J. G. Sled, and N. Kabani, “Three-dimensional cerebral vasculature of the CBA mouse brain: a magnetic resonance imaging and micro computed tomography study,” NeuroImage, vol. 35, no. 4, pp. 1409–1423, 2007.
[28]
I. Akiguchi, H. Tomimoto, T. Suenaga, H. Wakita, and H. Budka, “Blood-brain barrier dysfunction in Binswanger's disease; an immunohistochemical study,” Acta Neuropathologica, vol. 95, no. 1, pp. 78–84, 1998.
[29]
I. Akiguchi, H. Tomimoto, T. Suenaga, H. Wakita, and H. Budka, “Alterations in glia and axons in the brains of Binswanger's disease patients,” Stroke, vol. 28, no. 7, pp. 1423–1429, 1997.
[30]
H. Wakita, H. Tomimoto, I. Akiguchi, and J. Kimura, “Dose-dependent, protective effect of FK506 against white matter changes in the rat brain after chronic cerebral ischemia,” Brain Research, vol. 792, no. 1, pp. 105–113, 1998.
[31]
H. Wakita, H. Tomimoto, I. Akiguchi, J. Kimura, and J. A. Clemens, “Protective effect of cyclosporin A on white matter changes in the rat brain after chronic cerebral hypoperfusion,” Stroke, vol. 26, no. 8, pp. 1415–1422, 1995.
[32]
G. A. Rosenberg, M. Kornfeld, E. Estrada, R. O. Kelley, L. A. Liotta, and W. G. Stetler-Stevenson, “TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase,” Brain Research, vol. 576, no. 2, pp. 203–207, 1992.
[33]
G. F. Hamann, Y. Okada, R. Fitridge, G. J. Del Zoppo, and J. T. Povlishock, “Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion,” Stroke, vol. 26, no. 11, pp. 2120–2126, 1995.
[34]
A. M. Romanic and J. A. Madri, “The induction of 72-kD gelatinase in T cells upon adhesion to endothelial cells is VCAM-1 dependent,” Journal of Cell Biology, vol. 125, no. 5, pp. 1165–1178, 1994.
[35]
S. Chandler, R. Coates, A. Gearing, J. Lury, G. Wells, and E. Bone, “Matrix metalloproteinases degrade myelin basic protein,” Neuroscience Letters, vol. 201, no. 3, pp. 223–226, 1995.
[36]
E. J. Walker and G. A. Rosenberg, “Divergent role for MMP-2 in myelin breakdown and oligodendrocyte death following transient global ischemia,” Journal of Neuroscience Research, vol. 88, no. 4, pp. 764–773, 2010.
[37]
M. Ihara, H. Tomimoto, M. Kinoshita et al., “Chronic cerebral hypoperfusion induces MMP-2 but not MMP-9 expression in the microglia and vascular endothelium of white matter,” Journal of Cerebral Blood Flow and Metabolism, vol. 21, no. 7, pp. 828–834, 2001.
[38]
M. Ueno, H. Tomimoto, I. Akiguchi, H. Wakita, and H. Sakamoto, “Blood-brain barrier disruption in white matter lesions in a rat model of chronic cerebral hypoperfusion,” Journal of Cerebral Blood Flow and Metabolism, vol. 22, no. 1, pp. 97–104, 2002.
[39]
G. A. Rosenberg, N. Sullivan, and M. M. Esiri, “White matter damage is associated with matrix metalloproteinases in vascular dementia,” Stroke, vol. 32, no. 5, pp. 1162–1167, 2001.
[40]
L. R. Caplan, “Dilatative arteriopathy (dolichoectasia): what is known and not known,” Annals of Neurology, vol. 57, no. 4, pp. 469–471, 2005.
[41]
K. Washida, M. Ihara, K. Nishio et al., “Nonhypotensive dose of telmisartan attenuates cognitive impairment partially due to peroxisome proliferator-activated receptor-γ activation in mice with chronic cerebral hypoperfusion,” Stroke, vol. 41, no. 8, pp. 1798–1806, 2010.
[42]
R. Coltman, A. Spain, Y. Tsenkina et al., “Selective white matter pathology induces a specific impairment in spatial working memory,” Neurobiology of Aging, vol. 32, no. 12, pp. 2324 e7–2324 e12, 2011.
[43]
T. Maki, M. Ihara, Y. Fujita, et al., “Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice,” Stroke, vol. 42, no. 4, pp. 1122–1128, 2011.
[44]
P. R. Holland, M. E. Bastin, M. A. Jansen et al., “MRI is a sensitive marker of subtle white matter pathology in hypoperfused mice,” Neurobiology of Aging, vol. 32, no. 12, pp. 2325 e1–2325 e6, 2011.
[45]
R. Sood, Y. Yang, S. Taheri et al., “Increased apparent diffusion coefficients on MRI linked with matrix metalloproteinases and edema in white matter after bilateral carotid artery occlusion in rats,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 2, pp. 308–316, 2009.
[46]
H. Ohta, H. Nishikawa, H. Kimura, H. Anayama, and M. Miyamoto, “Chronic cerebral hypoperfusion by permanent internal carotid ligation produces learning impairment without brain damage in rats,” Neuroscience, vol. 79, no. 4, pp. 1039–1050, 1997.
[47]
S. Funahashi, C. J. Bruce, and P. S. Goldman-Rakic, “Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex,” Journal of Neurophysiology, vol. 61, no. 2, pp. 331–349, 1989.
[48]
C. W. Nordahl, C. Ranganath, A. P. Yonelinas, C. DeCarli, E. Fletcher, and W. J. Jagust, “White matter changes compromise prefrontal cortex function in healthy elderly individuals,” Journal of Cognitive Neuroscience, vol. 18, no. 3, pp. 418–429, 2006.
[49]
E. J. Burton, R. A. Kenny, J. O'Brien et al., “White matter hyperintensities are associated with impairment of memory, attention, and global cognitive performance in older stroke patients,” Stroke, vol. 35, no. 6, pp. 1270–1275, 2004.
[50]
F. E. De Leeuw, F. Barkhof, and P. Scheltens, “White matter lesions and hippocampal atrophy in Alzheimer's disease,” Neurology, vol. 62, no. 2, pp. 310–312, 2004.
[51]
M. M. Esiri, R. C. A. Pearson, J. E. Steele, D. M. Bowen, and T. P. S. Powell, “A quantitative study of the neurofibrillary tangles and the choline acetyltransferase activity in the cerebral cortex and the amygdala in Alzheimer's disease,” Journal of Neurology Neurosurgery and Psychiatry, vol. 53, no. 2, pp. 161–165, 1990.
[52]
R. Kalaria, “Similarities between Alzheimer's disease and vascular dementia,” Journal of the Neurological Sciences, vol. 203-204, pp. 29–34, 2002.
[53]
M. Sjobeck and E. Englund, “Glial levels determine severity of white matter disease in Alzheimer's disease: a neuropathological study of glial changes,” Neuropathology and Applied Neurobiology, vol. 29, no. 2, pp. 159–169, 2003.
[54]
M. J. Firbank, T. Minett, and J. T. O'Brien, “Changes in DWI and MRS associated with white matter hyperintensities in elderly subjects,” Neurology, vol. 61, no. 7, pp. 950–954, 2003.
[55]
E. Richard, A. A. Gouw, P. Scheltens, and W. A. Van Gool, “Vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of white matter lesions on MRI: the evaluation of vascular care in Alzheimer's disease (EVA) study,” Stroke, vol. 41, no. 3, pp. 554–556, 2010.
[56]
M. Ihara, T. M. Polvikoski, R. Hall et al., “Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with Lewy bodies,” Acta Neuropathologica, vol. 119, no. 5, pp. 579–589, 2010.
[57]
M. Ihara and R. N. Kalaria, “Amyloid-β and synaptic activity in mice and men,” NeuroReport, vol. 18, no. 12, pp. 1205–1206, 2007.
[58]
R. N. Kalaria, “The role of cerebral ischemia in Alzheimer's disease,” Neurobiology of Aging, vol. 21, no. 2, pp. 321–330, 2000.
[59]
R. N. Kalaria and C. Ballard, “Overlap between pathology of Alzheimer disease and vascular dementia,” Alzheimer Disease and Associated Disorders, vol. 13, no. 3, pp. S115–S123, 1999.
[60]
H. Kitaguchi, H. Tomimoto, M. Ihara et al., “Chronic cerebral hypoperfusion accelerates amyloid β deposition in APPSwInd transgenic mice,” Brain Research, vol. 1294, pp. 202–210, 2009.
[61]
M. Yamada, M. Ihara, Y. Okamoto, et al., “The influence of chronic cerebral hypoperfusion on cognitive function and amyloid beta metabolism in APP overexpressing mice,” PLoS ONE, vol. 6, no. 1, article e16567, 2011.
[62]
G. Bartzokis, “Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease,” Neurobiology of Aging, vol. 25, no. 1, pp. 5–18, 2004.
[63]
B. B. Fredholm, R. A. Cunha, and P. Svenningsson, “Pharmacology of adenosine A2A receptors and therapeutic applications,” Current Topics in Medicinal Chemistry, vol. 3, no. 4, pp. 413–426, 2003.
[64]
J. F. Chen, Z. Huang, J. Ma et al., “A(2A) adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice,” Journal of Neuroscience, vol. 19, no. 21, pp. 9192–9200, 1999.
[65]
J. W. Phillis, “The effects of selective A1 and A(2a) adenosine receptor antagonists on cerebral ischemic injury in the gerbil,” Brain Research, vol. 705, no. 1-2, pp. 79–84, 1995.
[66]
U. Aden, L. Halldner, H. Lagercrantz, I. Dalmau, C. Ledent, and B. B. Fredholm, “Aggravated brain damage after hypoxic ischemia in immature adenosine A2A knockout mice,” Stroke, vol. 34, no. 3, pp. 739–744, 2003.
[67]
C. Tzourio, C. Anderson, N. Chapman et al., “Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease,” Archives of Internal Medicine, vol. 163, no. 9, pp. 1069–1075, 2003.
[68]
B. K. Saxby, F. Harrington, K. A. Wesnes, I. G. McKeith, and G. A. Ford, “Candesartan and cognitive decline in older patients with hypertension: a substudy of the SCOPE trial,” Neurology, vol. 70, no. 19, pp. 1858–1866, 2008.
[69]
N. C. Li, A. Lee, R. A. Whitmer et al., “Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis,” British Medical Journal, vol. 340, p. b5465, 2010.
[70]
K. Ohno, Y. Amano, H. Kakuta, et al., “Unique “delta lock” structure of telmisartan is involved in its strongest binding affinity to angiotensin II type 1 receptor,” Biochemical and Biophysical Research Communications, vol. 404, no. 1, pp. 434–437, 2010.
[71]
S. C. Benson, H. A. Pershadsingh, C. I. Ho et al., “Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARγ-modulating activity,” Hypertension, vol. 43, no. 5, pp. 993–1002, 2004.
[72]
K. Kitamura, K. Kangawa, M. Kawamoto et al., “Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma,” Biochemical and Biophysical Research Communications, vol. 192, no. 2, pp. 553–560, 1993.
[73]
J. Kato, T. Tsuruda, T. Kita, K. Kitamura, and T. Eto, “Adrenomedullin: a protective factor for blood vessels,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 12, pp. 2480–2487, 2005.
[74]
N. Miyamoto, R. Tanaka, T. Shimosawa et al., “Protein kinase A-dependent suppression of reactive oxygen species in transient focal ischemia in adrenomedullin-deficient mice,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 11, pp. 1769–1779, 2009.
[75]
T. Kondoh, Y. Ueta, and K. Torii, “Pre-treatment of adrenomedullin suppresses cerebral edema caused by transient focal cerebral ischemia in rats detected by magnetic resonance imaging,” Brain Research Bulletin, vol. 84, no. 1, pp. 69–74, 2011.
[76]
M. Chopp, Y. Li, and Z. G. Zhang, “Mechanisms underlying improved recovery of neurological function after stroke in the rodent after treatment with neurorestorative cell-based therapies,” Stroke, vol. 40, no. 3, pp. S143–S145, 2009.
[77]
D. You, L. Waeckel, T. G. Ebrahimian et al., “Increase in vascular permeability and vasodilation are critical for proangiogenic effects of stem cell therapy,” Circulation, vol. 114, no. 4, pp. 328–338, 2006.
[78]
Y. Fujita, M. Ihara, T. Ushiki et al., “Early protective effect of bone marrow mononuclear cells against ischemic white matter damage through augmentation of cerebral blood flow,” Stroke, vol. 41, no. 12, pp. 2938–2943, 2010.
[79]
M. Fisher, “Pericyte signaling in the neurovascular unit,” Stroke, vol. 40, no. 3, pp. S13–S15, 2009.
[80]
J. Zhang, Y. Li, X. Zheng et al., “Bone marrow stromal cells protect oligodendrocytes from oxygen-glucose deprivation injury,” Journal of Neuroscience Research, vol. 86, no. 7, pp. 1501–1510, 2008.
[81]
K. Arai and E. H. Lo, “An oligovascular niche: cerebral endothelial cells promote the survival and proliferation of oligodendrocyte precursor cells,” Journal of Neuroscience, vol. 29, no. 14, pp. 4351–4355, 2009.
[82]
K. Arai and E. H. Lo, “Oligovascular signaling in white matter stroke,” Biological and Pharmaceutical Bulletin, vol. 32, no. 10, pp. 1639–1644, 2009.
[83]
C. Iadecola and M. Nedergaard, “Glial regulation of the cerebral microvasculature,” Nature Neuroscience, vol. 10, no. 11, pp. 1369–1376, 2007.
[84]
A. H. Hainsworth and H. S. Markus, “Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 12, pp. 1877–1891, 2008.
