Skip to main content

Advertisement

Log in

Rodent Models of Vascular Cognitive Impairment

  • SI: Challenges and Controversies in Translational Stroke Research
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Vascular cognitive impairment dementia (VCID), which is an increasingly important cause of dementia in the elderly, lacks effective treatments. Many different types of vascular disease are included under the diagnosis of VCID, including large vessel disease with multiple strokes and small vessel disease with lacunar infarcts and white matter disease. Animal models have been developed to study the multiple forms of VCID. Because of its progressive course, small vessel disease (SVD) is thought to be the optimal form of VCID for treatment. One theory is that the pathophysiology involves hypoxic hypoperfusion resulting in injury to the white matter and neuronal death. Bilateral occlusion of the common carotid arteries (BCAO) in a normotensive rat, which reduces cerebral blood flow, induces hypoxia with white matter damage; this model has been used to test drugs to block the injury. Another model is the spontaneously hypertensive/stroke prone rat (SHR/SP). Hypertension leads to small vessel disease resulting in progressive damage to the white matter, cortex, and hippocampus. Bilateral carotid artery stenosis (BCAS) with coils or ameroid constrictors produces a slower development of changes than BCAO, avoiding the acute ischemia. A few studies have been done with the two-clip, two-vessel occlusion renal model for induction of hypertension. There are benefits and drawbacks to each of these models with the model selected depending on the type of vascular damage that is to be studied. This review describes the most commonly used models, and the drugs that have been used to reduce the damage.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Gorelick PB et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:2672–713.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Snyder HM et al. Vascular contributions to cognitive impairment and dementia including Alzheimer’s disease. Alzheimers Dement. 2015;11:710–7.

    Article  PubMed  Google Scholar 

  3. Corriveau RA et al. The science of vascular contributions to cognitive impairment and dementia (VCID): a framework for advancing research priorities in the cerebrovascular biology of cognitive decline. Cell Mol Neurobiol. 2016;36:281–8.

    Article  CAS  PubMed  Google Scholar 

  4. Guerrini U et al. New insights into brain damage in stroke-prone rats: a nuclear magnetic imaging study. Stroke. 2002;33:825–30.

    Article  PubMed  Google Scholar 

  5. Nishio K et al. A mouse model characterizing features of vascular dementia with hippocampal atrophy. Stroke. 2010;41:1278–84.

    Article  PubMed  Google Scholar 

  6. Wakita H et al. Protective effect of cyclosporin a on white matter changes in the rat brain after chronic cerebral hypoperfusion. Stroke. 1995;26:1415–22.

    Article  CAS  PubMed  Google Scholar 

  7. Walker EJ, Rosenberg GA. Divergent role for MMP-2 in myelin breakdown and oligodendrocyte death following transient global ischemia. J Neurosci Res. 2010;88:764–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. De Reuck J et al. Pathogenesis of Binswanger chronic progressive subcortical encephalopathy. Neurology. 1980;30:920–8.

    Article  PubMed  Google Scholar 

  9. Rigsby CS, Pollock DM, Dorrance AM. Spironolactone improves structure and increases tone in the cerebral vasculature of male spontaneously hypertensive stroke-prone rats. Microvasc Res. 2007;73:198–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Weaver J et al. Tissue oxygen is reduced in white matter of spontaneously hypertensive-stroke prone rats: a longitudinal study with electron paramagnetic resonance. J Cereb Blood Flow Metab. 2014;34:890–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Derdeyn CP et al. Variability of cerebral blood volume and oxygen extraction: stages of cerebral haemodynamic impairment revisited. Brain. 2002;125:595–607.

    Article  PubMed  Google Scholar 

  12. Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol. 2014;9:47–71.

    Article  CAS  PubMed  Google Scholar 

  13. Cunningham LA, Wetzel M, Rosenberg GA. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia. 2005;50:329–39.

    Article  PubMed  Google Scholar 

  14. Yang Y et al. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab. 2007;27:697–709.

    Article  CAS  PubMed  Google Scholar 

  15. Rosenberg GA. Matrix metalloproteinase-mediated neuroinflammation in vascular cognitive impairment of the Binswanger type. Cell Mol Neurobiol. 2016;36:195–202.

    Article  CAS  PubMed  Google Scholar 

  16. Candelario-Jalil E, Yang Y, Rosenberg GA. Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience. 2009;158:983–94.

    Article  CAS  PubMed  Google Scholar 

  17. Chandler S et al. Matrix metalloproteinases degrade myelin basic protein. Neurosci Lett. 1995;201:223–6.

    Article  CAS  PubMed  Google Scholar 

  18. Cammer W et al. Degradation of basic protein in myelin by neutral proteases secreted by stimulated macrophages: a possible mechanism of inflammatory demyelination. Proc Natl Acad Sci U S A. 1978;75:1554–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cova L et al. Vascular and parenchymal lesions along with enhanced neurogenesis characterize the brain of asymptomatic stroke-prone spontaneous hypertensive rats. J Hypertens. 2013;31:1618–28.

    Article  CAS  PubMed  Google Scholar 

  20. Pillai JJ, Mikulis DJ. Cerebrovascular reactivity mapping: an evolving standard for clinical functional imaging. AJNR Am J Neuroradiol. 2015;36:7–13.

    Article  CAS  PubMed  Google Scholar 

  21. Cai ZY et al. Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion. Neurosci Bull. 2008;24:305–13.

    Article  CAS  PubMed  Google Scholar 

  22. Newcombe VF et al. Microstructural basis of contusion expansion in traumatic brain injury: insights from diffusion tensor imaging. J Cereb Blood Flow Metab. 2013;33:855–62.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Budde MD et al. The contribution of gliosis to diffusion tensor anisotropy and tractography following traumatic brain injury: validation in the rat using Fourier analysis of stained tissue sections. Brain. 2011;134:2248–60.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sonnen JA et al. Ecology of the aging human brain. Arch Neurol. 2011;68:1049–56.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Schneider JA et al. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69:2197–204.

    Article  PubMed  Google Scholar 

  26. Bueche CZ et al. Hypertension drives parenchymal beta-amyloid accumulation in the brain parenchyma. Ann Clin Transl Neurol. 2014;1:124–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Schreiber S et al. The pathologic cascade of cerebrovascular lesions in SHRSP: is erythrocyte accumulation an early phase? J Cereb Blood Flow Metab. 2012;32:278–90.

    Article  CAS  PubMed  Google Scholar 

  28. Greenberg SM et al. Outcome markers for clinical trials in cerebral amyloid angiopathy. Lancet Neurol. 2014;13:419–28.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Okamoto Y et al. Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol. 2012;123:381–94.

    Article  CAS  PubMed  Google Scholar 

  30. Kruyer A et al. Chronic hypertension leads to neurodegeneration in the TgSwDI mouse model of Alzheimer’s disease. Hypertension. 2015;66:175–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shibata M et al. Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion. Stroke. 2007;38:2826–32.

    Article  PubMed  Google Scholar 

  32. Wakita H et al. Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study. Acta Neuropathol (Berl). 1994;87:484–92.

    Article  CAS  Google Scholar 

  33. Yamada M et al. The influence of chronic cerebral hypoperfusion on cognitive function and amyloid beta metabolism in APP overexpressing mice. PLoS One. 2011;6, e16567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Farkas E, Luiten PG, Bari F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev. 2007;54:162–80.

    Article  CAS  PubMed  Google Scholar 

  35. Kitamura A et al. Selective white matter abnormalities in a novel rat model of vascular dementia. Neurobiol Aging. 2012;33(1012):e25–35.

    PubMed  Google Scholar 

  36. Schmidt-Kastner R et al. Astrocytes react to oligemia in the forebrain induced by chronic bilateral common carotid artery occlusion in rats. Brain Res. 2005;1052:28–39.

    Article  CAS  PubMed  Google Scholar 

  37. Ueno M et al. Blood–brain barrier disruption in white matter lesions in a rat model of chronic cerebral hypoperfusion. J Cereb Blood Flow Metab. 2002;22:97–104.

    Article  PubMed  Google Scholar 

  38. Nakaji K et al. Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents. Stroke. 2006;37:2816–23.

    Article  CAS  PubMed  Google Scholar 

  39. Ihara M et al. Chronic cerebral hypoperfusion induces MMP-2 but not MMP-9 expression in the microglia and vascular endothelium of white matter. J Cereb Blood Flow Metab. 2001;21:828–34.

    Article  CAS  PubMed  Google Scholar 

  40. Sood R et al. Increased apparent diffusion coefficients on MRI linked with matrix metalloproteinases and edema in white matter after bilateral carotid artery occlusion in rats. J Cereb Blood Flow Metab. 2009;29:308–16.

    Article  CAS  PubMed  Google Scholar 

  41. Jalal FY et al. Myelin loss associated with neuroinflammation in hypertensive rats. Stroke. 2012;43:1115–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. de la Torre JC. Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol. 2004;3:184–90.

    Article  PubMed  Google Scholar 

  43. Ohtani K et al. Blocking the glycine-binding site of NMDA receptors prevents the progression of ischemic pathology induced by bilateral carotid artery occlusion in spontaneously hypertensive rats. Brain Res. 2000;871:311–8.

    Article  CAS  PubMed  Google Scholar 

  44. Magnoni S et al. Differential alterations in the expression and activity of matrix metalloproteinases 2 and 9 after transient cerebral ischemia in mice. Neurobiol Dis. 2004;17:188–97.

    Article  CAS  PubMed  Google Scholar 

  45. Shibata M et al. White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion. Stroke. 2004;35:2598–603.

    Article  PubMed  Google Scholar 

  46. Hattori Y et al. A novel mouse model of subcortical infarcts with dementia. J Neurosci. 2015;35:3915–28.

    Article  CAS  PubMed  Google Scholar 

  47. Iadecola C. The pathobiology of vascular dementia. Neuron. 2013;80:844–66.

    Article  CAS  PubMed  Google Scholar 

  48. Yamori Y. Overview: studies on spontaneous hypertension-development from animal models toward man. Clin Exp Hypertens A. 1991;13:631–44.

    CAS  PubMed  Google Scholar 

  49. Yamori Y et al. Pathogenetic similarity of strokes in stroke-prone spontaneously hypertensive rats and humans. Stroke. 1976;7:46–53.

    Article  CAS  PubMed  Google Scholar 

  50. Gianella A et al. Rosuvastatin treatment prevents progressive kidney inflammation and fibrosis in stroke-prone rats. Am J Pathol. 2007;170:1165–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ballerio R et al. Gender differences in endothelial function and inflammatory markers along the occurrence of pathological events in stroke-prone rats. Exp Mol Pathol. 2007;82:33–41.

    Article  CAS  PubMed  Google Scholar 

  52. Rosenberg GA et al. Consensus statement for diagnosis of subcortical small vessel disease. J Cereb Blood Flow Metab. 2016;36:6–25.

    PubMed  Google Scholar 

  53. Sironi L et al. Analysis of pathological events at the onset of brain damage in stroke-prone rats: a proteomics and magnetic resonance imaging approach. J Neurosci Res. 2004;78:115–22.

    Article  CAS  PubMed  Google Scholar 

  54. Lan LF et al. Peroxisome proliferator-activated receptor-gamma agonist pioglitazone ameliorates white matter lesion and cognitive impairment in hypertensive rats. CNS Neurosci Ther. 2015;21:410–6.

  55. Tayebati SK et al. Neuroprotective effect of treatment with galantamine and choline alphoscerate on brain microanatomy in spontaneously hypertensive rats. J Neurol Sci. 2009;283:187–94.

  56. Amenta F, Tomassoni D. Treatment with nicardipine protects brain in an animal model of hypertension-induced damage. Clin Exp Hypertens. 2004;26:351–61.

  57. Jalal FY et al. Hypoxia-induced neuroinflammatory white-matter injury reduced by minocycline in SHR/SP. J Cereb Blood Flow Metab. 2015;35:1145–53.

  58. Kondo Y et al. Preventive effects of bifemelane hydrochloride on decreased levels of muscarinic acetylcholine receptor and its mRNA in a rat model of chronic cerebral hypoperfusion. Neurosci Res. 1996;24:409–14.

  59. Kwon KJ et al. Effects of donepezil, an acetylcholinesterase inhibitor, on neurogenesis in a rat model of vascular dementia. J Neurol Sci. 2014;347:66–77.

  60. Stasiak K et al. A pilot double blind randomized placebo controlled trial of a prototype computer-based cognitive behavioural therapy program for adolescents with symptoms of depression. Behav Cogn Psychother. 2014;42:385–401.

  61. Ozkul A et al. Effects of lithium and lamotrigine on oxidative-nitrosative stress and spatial learning deficit after global cerebral ischemia. Neurochem Res. 2014;39:853–61.

  62. Dong YF et al. Attenuation of brain damage and cognitive impairment by direct renin inhibition in mice with chronic cerebral hypoperfusion. Hypertension. 2011;58:635–42.

  63. Farkas E et al. Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion. Brain Res. 2004;1008:252–60.

  64. Gupta S, Sharma B. Pharmacological modulation of I(1)-imidazoline and alpha2-adrenoceptors in sub acute brain ischemia induced vascular dementia. Eur J Pharmacol. 2014;723:80–90.

  65. Kim JS et al. Ramipril protects from free radical induced white matter damage in chronic hypoperfusion in the rat. J Clin Neurosci. 2008;15:174–8.

  66. Xie W et al. Angiotensin-(1-7) improves cognitive function in rats with chronic cerebral hypoperfusion. Brain Res. 2014;1573:44–53.

  67. Yamada K et al. Effect of a centrally active angiotensin converting enzyme inhibitor, perindopril, on cognitive performance in chronic cerebral hypo-perfusion rats. Brain Res. 2011;1421:110–20.

  68. Takizawa S, Fukuyama N, Hirabayashi H, Kohara S, Kazahari S, Shinohara Y et al. Quercetin, a natural flavonoid, attenuates vacuolar formation in the optic tract in rat chronic cerebral hypoperfusion model. Brain Res. 2003;980:156–60.

  69. Li H, Wang J, Wang P, Rao Y, Chen L. Resveratrol reverses the synaptic plasticity deficits in a chronic cerebral hypoperfusion rat model. J Stroke Cerebrovasc Dis. 2016;25:122–28.

  70. Wakita H, Ruetzler C, Illoh KO, Chen Y, Takanohashi A, Spatz M et al. Mucosal tolerization to E-selectin protects against memory dysfunction and white matter damage in a vascular cognitive impairment model. J Cereb Blood Flow Metab. 2008;28:341–53.

  71. Cho KO, La HO, Cho YJ, Sung KW, Kim SY. Minocycline attenuates white matter damage in a rat model of chronic cerebral hypoperfusion. J Neurosci Res. 2006;83:285–91.

  72. Liu C, Wu J, Gu J, Xiong Z, Wang F, Wang J et al. Baicalein improves cognitive deficits induced by chronic cerebral hypoperfusion in rats. Pharmacol Biochem Behav. 2007;86:423–30.

  73. Nakaji K, Ihara M, Takahashi C, Itohara S, Noda M, Takahashi R et al. Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents. Stroke. 2006;37:2816–23.

  74. Yang S, Zhou G, Liu H, Zhang B, Li J, Cui R et al. Protective effects of p38 MAPK inhibitor SB202190 against hippocampal apoptosis and spatial learning and memory deficits in a rat model of vascular dementia. BioMed Res Int. 2013;2013:215798.

  75. Choi BR et al. Characterization of white matter injury in a rat model of chronic cerebral hypoperfusion. Stroke. 2016;47:542–7.

  76. Wakita H, Tomimoto H, Akiguchi I, Lin JX, Ihara M, Ohtani R et al. Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat. Brain Res. 2003;992:53–9.

  77. Tanaka K, Hori K, Wada-Tanaka N, Nomura M, Ogawa N. FK506 ameliorates the discrimination learning impairment due to preventing the rarefaction of white matter induced by chronic cerebral hypoperfusion in rats. Brain Res. 2001;906:184–9.

  78. Ueno Y et al. L-carnitine enhances axonal plasticity and improves white-matter lesions after chronic hypoperfusion in rat brain. J Cereb Blood Flow Metab. 2015;35:382–91.

  79. Pedder H et al. Systematic review and meta-analysis of interventions tested in animal models of lacunar stroke. Stroke. 2014;45:563–70.

    Article  PubMed  Google Scholar 

  80. Bell RD et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012;485:512–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gary A. Rosenberg.

Ethics declarations

Funding

Studies are supported by NIH grants (RO1 NS045847). Yi Yang has received research grants from NIH and the American Heart Association. Gary Rosenberg has received research grants from NIH, the US-Israeli Binational Foundation, and Bayer Pharmaceutical.

Conflict of Interest

Shihoko Kimura and Jeffrey Thompson have no conflicts of interest.

Human and Animal Rights and Informed Consent

All animal studies were approved by the UNM Animal Resource Committee and followed NIH Guidelines for care of research animals.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Y., Kimura-Ohba, S., Thompson, J. et al. Rodent Models of Vascular Cognitive Impairment. Transl. Stroke Res. 7, 407–414 (2016). https://doi.org/10.1007/s12975-016-0486-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-016-0486-2

Keywords

Navigation