White Matter Damage and Hippocampal Neurodegeneration Induced by Permanent Bilateral Occlusion of Common Carotid Artery in the Rat: Comparison between Wistar and Sprague-Dawley Strain

  • Kim, Seul-Ki (Department of Pharmacology, Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea) ;
  • Cho, Kyung-Ok (Department of Pharmacology, Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea) ;
  • Kim, Seong-Yun (Department of Pharmacology, Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea)
  • Published : 2008.06.30


In order to reproduce chronic cerebral hypoperfusion as it occurs in human aging and Alzheimer's disease, we introduced permanent, bilateral occlusion of the common carotid arteries (BCCAO) in rats (Farkas et al, 2007). Here, we induced BCCAO in two different rat strains in order to determine whether there was a strain difference in the pathogenic response to BCCAO. Male Wistar and Sprague-Dawley (SD) rats (250-270 g) were subjected to BCCAO for three weeks. Kluver-Barrera and cresyl violet staining were used to evaluate white matter and gray matter damage, respectively. Wistar rats had a considerably higher mortality rate (four of 14 rats) as compared to SD rats (one of 15 rats) following BCCAO. Complete loss of pupillary light reflex occurred in all Wistar rats that survived, but loss of pupillary light reflex did not occur at all in SD rats. Moreover, BCCAO induced marked vacuolation in the optic tract of Wistar rats as compared to SD rats. In contrast, SD rats showed fewer CA1 hippocampal neurons than Wistar rats following BCCAO. These results suggest that the neuropathological process induced by BCCAO takes place in a region-specific pattern that varies according to the strain of rat involved.


  1. Butte DM, Fortin T, Pappas BA. Pinealectomy: behavioral and neuropathological consequences in a chronic cerebral hypoperfusion model. Neurobiol Aging 23: 309-317, 2002 https://doi.org/10.1016/S0197-4580(01)00277-9
  2. Bennett SA, Tenniswood M, Chen JH, Davidson CM, Keyes MT, Fortin T, Pappas A. Chronic cerebral hypoperfusion elicits neuronal apoptosis and behavioral impairment. Neuroreport 9: 164-166, 1998
  3. 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 83: 285-291, 2006 https://doi.org/10.1002/jnr.20727
  4. Davidson CM, Pappas BA, Stevens WD, Fortin T, Bennett SAL. Chronic cerebral hypoperfusion: loss of pupillary reflex, visual impairment and retinal neurodegeneration. Brain Res 859: 96-103, 2000 https://doi.org/10.1016/S0006-8993(00)01937-5
  5. Farkas E, Institoris A, Domoki F, Mihaly A, Bari F. The effect of pre- and post-treatment with diazoxide on the early phase of chronic cerebral hypoperfusion in the rat. Brain Res 1087: 168-174, 2006 https://doi.org/10.1016/j.brainres.2006.02.134
  6. 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 54: 162-180, 2007 https://doi.org/10.1016/j.brainresrev.2007.01.003
  7. Hirabayashi H, Kurita D, Takizawa S, Shinohara Y. Phosphate-related energy compounds are not exhausted in chronically hypoperfused rat brain cortex after cortical spreading depression. J Stroke Cerebrovasc Dis 3: 271-279, 2004
  8. Jellinger KA. The enigma of vascular cognitive disorder and vascular dementia. Acta Neuropathol 113: 349-388, 2007 https://doi.org/10.1007/s00401-006-0185-2
  9. Kuang X, Du JR, Liu YX, Zhang GY, Peng HY. Postischemic administration of Z-Ligustilide ameliorates cognitive dysfunction and brain damage induced by permanent forebrain ischemia in rats. Pharmacol Biochem Behav 88: 213-221, 2008 https://doi.org/10.1016/j.pbb.2007.08.006
  10. Lavinsky D, Arterni NS, Achaval M, Netto CA. Chronic bilateral common carotid artery occlusion: a model for ocular ischemic syndrome in the rat. Graefes Arch Clin Exp Ophthalmol 244: 199−204, 2006
  11. Liu C, Wu J, Gu J, Xiong Z, Wang F, Wang J, Wang W, Chen J. Baicalein improves cognitive deficits induced by chronic cerebral hypoperfusion in rats. Pharmacol Biochem Behav 86: 423−430, 2007
  12. Liu HX, Zhang JJ, Zheng P, Zhang Y. Altered expression of MAP-2, GAP-43, and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment. Brain Res Mol Brain Res 139: 169−177, 2005
  13. Nakaji K, Ihara M, Takahashi C, Itohara S, Noda M, Takahashi R, Tomomoto H. Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents. Stroke 37: 2816−2823, 2006
  14. Ni JW, Matsumoto K, Li HB, Murakami Y, Watanabe H. Neuronal damage and decrease of centeral acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat. Brain Res 673: 290−296, 1995
  15. Ni JW, Ohta H, Matsumoto K, Watanabe H. Progressive cognitive impairment following chronic cerebral hypoperfusion induced by permanent occlusion of bilateral carotid arteries in rats. Brain Res 653: 231−236, 1994
  16. Ohta H, Nishikawa H, Kimura H, Anayama H, Miyamoto M. Chronic cerebral hypoperfusion by permanent internal carotid ligation produces learning impairment without brain damage in rat. Neuroscience 79: 1039−1050, 1997
  17. Pantoni L, Garcia JH, Gutierrez JA. Cerebral white matter is highly vulnerable to ischemia. Stroke 27: 1641−1646, 1996
  18. Pappas BA, Torre JC, Davidson CM, Keyes MT, Fortin T. Chronic reduction of cerebral blood flow in the adult rat: late-emerging CA1 cell loss and memory dysfunction. Brain Res 708: 50−58, 1996
  19. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 6th ed. Academic Press, Burlington, 2007
  20. Rockwood K, Wentzel C, Hachinski V, Hogan DB, MacKnight C, McDowell I. Prevalence and outcomes of vascular cognitive impairment. Neurology 54: 447−451, 2000 https://doi.org/10.1212/WNL.54.10.2000
  21. Román GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol 1: 426−436, 2002
  22. Sarti C, Pantoni L, Bartolini L, Inzitari D. Cognitive impairment and chronic cerebral hypoperfusion: what can be learned from experimental models. J Neurol Sci 203−204: 263−266, 2002
  23. Schmidt-Kastner R, Aguirri-Chen C, Saul I, Yick L, Hamasaki D, Busto R, Ginsberg MD. Astrocytes react to oligemia in the forebrain induced by chronic bilateral common carotid artery occlusion in rat. Brain Res 1052: 28−39, 2005
  24. Sopala M, Danysz W. Chronic cerebral hypoperfusion in the rat enhances age-related deficits in spatial memory. J Neural Transm 108: 1445−1456, 2001
  25. Stevens WD, Fortin T, Pappas BA. Retinal and optic nerve degeneration after chronic carotid ligation: time course and role of light exposure. Stroke 33: 1107−1112, 2002
  26. Tsuchiya M, Sako K, Yura S, Yonemasu Y. Local cerebral glucose utilization following acute and chronic bilateral carotid artery ligation in Wistar rat: relation to change in local cerebral blood flow. Exp Brain Res 95: 1−7, 1993
  27. Wakita H, Tomimoto H, Akiguchi I, Kimura J. Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study. Acta Neuropathol 87: 484−492, 1994
  28. Wakita H, Tomimoto H, Akiguchi I, Kimura J. Dose-dependent, protective effect of FK506 against white matter changes in the rat brain after chronic cerebral ischemia. Brain Res 792: 105−113, 1998
  29. Wakita H, Tomimoto H, Akiguchi I, Matsuo A, Lin JX, Ihara M, McGeer PL. Axonal damage and demyelination in the white matter after chronic cerebral hypoperfusion in the rat. Brain Res 924: 63−70, 2002
  30. Watanabe T, Zhang N, Liu M, Tanaka R, Mizuno Y, Urabe T. Cilostazol protects against brain white matter damage and cognitive impairment in a rat model of chronic cerebral hypoperfusion. Stroke 37: 1539−1545, 2006