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Endovascular middle cerebral artery occlusion in rats as a model for studying vascular dementia

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Abstract

Vascular dementia (VaD), incorporating cognitive dysfunction with vascular disease, ranks as the second leading cause of dementia in the United States, yet no effective treatment is currently available. The challenge of defining the pathological substrates of VaD is complicated by the heterogeneous nature of cerebrovascular disease and coexistence of other pathologies, including Alzheimer’s disease (AD) types of lesion. The use of rodent models of ischemic stroke may help to elucidate the type of lesions that are responsible for cognitive impairment in humans. Endovascular middle cerebral artery (MCA) occlusion in rats is considered to be a convenient and reliable model of human cerebral ischemia. Both sensorimotor and cognitive dysfunction can be induced in the rat endovascular MCA occlusion model, yet sensorimotor deficits induced by endovascular MCA occlusion may improve with time, whereas data presented in this review suggest that in rats this model can result in a progressive course of cognitive impairment that is consistent with the clinical progression of VaD. Thus far, experimental studies using this model have demonstrated a direct interaction of cerebral ischemic damage and AD-type neuropathologies in the primary ischemic area. Further, coincident to the progressive decline of cognitive function, a delayed neurodegeneration in a remote area, distal to the primary ischemic area, the hippocampus, has been demonstrated in a rat endovascular MCA occlusion model. We argue that this model could be employed to study VaD and provide insight into some of the pathophysiological mechanisms of VaD.

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References

  • An G, Lin TN, Liu JS, Xue JJ, He YY, Hsu CY (1993) Expression of c-fos and c-jun family genes after focal cerebral ischemia. Ann Neurol 33:457–464

    Article  PubMed  CAS  Google Scholar 

  • Bannerman DM, Rawlins JN, McHugh SB, Deacon RM, Yee BK, Bast T, Zhang WN, Pothuizen HH, Feldon J (2004) Regional dissociations within the hippocampus-memory and anxiety. Neurosci Biobehav Rev 28:273–283

    Article  PubMed  CAS  Google Scholar 

  • Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H (1986) Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17:472–476

    PubMed  CAS  Google Scholar 

  • Belayev L, Busto R, Zhao W, Fernandez G, Ginsberg MD (1999) Middle cerebral artery occlusion in the mouse by intraluminal suture coated with poly-L-lysine: neurological and histological validation. Brain Res 833:181–190

    Article  PubMed  CAS  Google Scholar 

  • Block F, Dihne M, Loos M (2005) Inflammation in areas of remote changes following focal brain lesion. Prog Neurobiol 75:342–365

    Article  PubMed  CAS  Google Scholar 

  • Cheng YD, Al-Khoury L, Zivin JA (2004) Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx 1:36–45

    Article  PubMed  Google Scholar 

  • Dahlqvist P, Ronnback A, Bergstrom SA, Soderstrom I, Olsson T (2004) Environmental enrichment reverses learning impairment in the Morris water maze after focal cerebral ischemia in rats. Eur J Neurosci 19:2288–2298

    Article  PubMed  Google Scholar 

  • DeVries AC, Nelson RJ, Traystman RJ, Hurn PD (2001) Cognitive and behavioral assessment in experimental stroke research: will it prove useful? Neurosci Biobehav Rev 25:325–342

    Article  PubMed  CAS  Google Scholar 

  • Dihne M, Block F (2001) Focal ischemia induces transient expression of IL-6 in the substantia nigra pars reticulata. Brain Res 889:165–173

    Article  PubMed  CAS  Google Scholar 

  • Dodd PR (2002) Excited to death: different ways to lose your neurones. Biogerontology 3:51–56

    Article  PubMed  CAS  Google Scholar 

  • Esiri MM, Nagy Z, Smith MZ, Barnetson L, Smith AD (1999) Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer’s disease. Lancet 354:919–920

    Article  PubMed  CAS  Google Scholar 

  • Fein G, Di Sclafani V, Tanabe J, Cardenas V, Weiner MW, Jagust WJ, Reed BR, Norman D, Schuff N, Kusdra L, Greenfield T, Chui H (2000) Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease. Neurology 55:1626–1635

    PubMed  CAS  Google Scholar 

  • Gainotti G, Acciarri A, Bizzarro A, Marra C, Masullo C, Misciagna S, Tartaglione T, Valenza A, Colosimo C (2004) The role of brain infarcts and hippocampal atrophy in subcortical ischaemic vascular dementia. Neurol Sci 25:192–197

    Article  PubMed  CAS  Google Scholar 

  • Gupta, YK, Sinha, K, Chaudhary, G (2002) Transient focal ischemia induces motor deficit but does not impair the cognitive function in middle cerebral artery occlusion model of stroke in rats. J Neurol Sci 203–204:267–271

    Article  PubMed  Google Scholar 

  • Hanz S, Fainzilber M (2004) Integration of retrograde axonal and nuclear transport mechanisms in neurons: implications for therapeutics. Neurosci 10:404–408

    Article  CAS  Google Scholar 

  • Hattori K, Lee H, Hurn PD, Crain BJ, Traystman RJ, DeVries AC (2000) Cognitive deficits after focal cerebral ischemia in mice. Stroke 31:1939–1944

    PubMed  CAS  Google Scholar 

  • Jin K, Mao XO, Eshoo MW, Nagayama T, Minami M, Simon RP, Greenberg DA (2001a) Microarray analysis of hippocampal gene expression in global cerebral ischemia. Ann Neurol 50:93–103

    Article  PubMed  CAS  Google Scholar 

  • Jin K, Minami M, Lan JQ, Mao XO, Batteur S, Simon RP, Greenberg DA (2001b) Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci U S A 98:4710–4715

    Article  PubMed  CAS  Google Scholar 

  • Jolkkonen J, Gallagher NP, Zilles K, Sivenius J (2003) Behavioral deficits and recovery following transient focal cerebral ischemia in rats: glutamatergic and GABAergic receptor densities. Behav Brain Res 138:187–200

    Article  PubMed  CAS  Google Scholar 

  • Kalaria RN, Kenny RA, Ballard CG, Perry R, Ince P, Polvikoski T (2004) Towards defining the neuropathological substrates of vascular dementia. J Neurol Sci 226:75–80

    Article  PubMed  Google Scholar 

  • Karhunen H, Pitkanen A, Virtanen T, Gureviciene I, Pussinen R, Ylinen A, Sivenius J, Nissinen J, Jolkkonen J (2003) Long-term functional consequences of transient occlusion of the middle cerebral artery in rats: a 1-year follow-up of the development of epileptogenesis and memory impairment in relation to sensorimotor deficits. Epilepsy Res 54:1–10

    Article  PubMed  Google Scholar 

  • Kitagawa K, Matsumoto M, Yang G, Mabuchi T, Yagita Y, Hori M, Yanagihara T (1998) Cerebral ischemia after bilateral carotid artery occlusion and intraluminal suture occlusion in mice: evaluation of the patency of the posterior communicating artery. J Cereb Blood Flow Metab 18:570–579

    Article  PubMed  CAS  Google Scholar 

  • Loeb C, Gandolfo C, Croce R, Conti M (1992) Dementia associated with lacunar infarction. Stroke 23:1225–1229

    PubMed  CAS  Google Scholar 

  • Loos M, Dihne M, Block F (2003) Tumor necrosis factor-alpha expression in areas of remote degeneration following middle cerebral artery occlusion of the rat. Neuroscience 122:373–380

    Article  PubMed  CAS  Google Scholar 

  • Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87–136

    Article  PubMed  CAS  Google Scholar 

  • Madureira S, Guerreiro M, Ferro JM (2001) Dementia and cognitive impairment three months after stroke. Eur J Neurol 8:621–627

    Article  PubMed  CAS  Google Scholar 

  • Markgraf CG, Green EJ, Hurwitz BE, Morikawa E, Dietrich WD, McCabe PM, Ginsberg MD, Schneiderman N (1992) Sensorimotor and cognitive consequences of middle cerebral artery occlusion in rats. Brain Res 575:238–246

    Article  PubMed  CAS  Google Scholar 

  • Markgraf CG, Green EJ, Watson B, McCabe PM, Schneiderman N, Dietrich WD, Ginsberg MD (1994) Recovery of sensorimotor function after distal middle cerebral artery photothrombotic occlusion in rats. Stroke 25:153–159

    PubMed  CAS  Google Scholar 

  • Markgraf CG, Johnson MP, Braun DL, Bickers MV (1997) Behavioral recovery patterns in rats receiving the NMDA receptor antagonist MDL 100,453 immediately post-stroke. Pharmacol Biochem Behav 56:391–397

    Article  PubMed  CAS  Google Scholar 

  • McColl BW, Carswell HV, McCulloch J, Horsburgh K (2004) Extension of cerebral hypoperfusion and ischaemic pathology beyond MCA territory after intraluminal filament occlusion in C57Bl/6J mice. Brain Res 997:15–23

    Article  PubMed  CAS  Google Scholar 

  • Modo M, Stroemer RP, Tang E, Veizovic T, Sowniski P, Hodges H (2000) Neurological sequelae and long-term behavioural assessment of rats with transient middle cerebral artery occlusion. J Neurosci Methods 104:99–109

    Article  PubMed  CAS  Google Scholar 

  • Modo M, Stroemer RP, Tang E, Patel S, Hodges H (2002) Effects of implantation site of stem cell grafts on behavioral recovery from stroke damage. Stroke 33:2270–2278

    Article  PubMed  Google Scholar 

  • Mungas D, Jagust WJ, Reed BR, Kramer JH, Weiner MW, Schuff N, Norman D, Mack WJ, Willis L, Chui HC (2001) MRI predictors of cognition in subcortical ischemic vascular disease and Alzheimer’s disease. Neurology 57:2229–2235

    PubMed  CAS  Google Scholar 

  • Nihashi T, Inao S, Kajita Y, Kawai T, Sugimoto T, Niwa M, Kabeya R, Hata N, Hayashi S, Yoshida J (2001) Expression and distribution of beta amyloid precursor protein and beta amyloid peptide in reactive astrocytes after transient middle cerebral artery occlusion. Acta Neurochir (Wien) 143:287–295

    Article  CAS  Google Scholar 

  • Ozdemir YG, Bolay H, Erdem E, Dalkara T (1999) Occlusion of the MCA by an intraluminal filament may cause disturbances in the hippocampal blood flow due to anomalies of circle of Willis and filament thickness. Brain Res 822:260–264

    Article  PubMed  CAS  Google Scholar 

  • Phipps MA (1991) Assessment of neurologic deficits in stroke. Acute-care and rehabilitation implications. Nurs Clin North Am 26:957–970

    PubMed  CAS  Google Scholar 

  • Pohjasvaara T, Erkinjuntti T, Ylikoski R, Hietanen M, Vataja R, Kaste M (1998) Clinical determinants of poststroke dementia. Stroke 29:75–81

    PubMed  CAS  Google Scholar 

  • Pohjasvaara T, Mantyla R, Ylikoski R, Kaste M, Erkinjuntti T (2000) Comparison of different clinical criteria (DSM-III, ADDTC, ICD-10, NINDS-AIREN, DSM-IV) for the diagnosis of vascular dementia. National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences. Stroke 31:2952–2957

    PubMed  CAS  Google Scholar 

  • Puurunen K, Jolkkonen J, Sirvio J, Haapalinna A, Sivenius J (2001) Selegiline combined with enriched-environment housing attenuates spatial learning deficits following focal cerebral ischemia in rats. Exp Neurol 167:348–355.

    Article  PubMed  CAS  Google Scholar 

  • Que M, Schiene K, Witte OW, Zilles K (1999) Widespread up-regulation of N-methyl-D-aspartate receptors after focal photothrombotic lesion in rat brain. Neurosci Lett 273:77–80

    Article  PubMed  CAS  Google Scholar 

  • Redecker C, Wang W, Fritschy JM, Witte OW (2002) Widespread and long-lasting alterations in GABA(A)-receptor subtypes after focal cortical infarcts in rats: mediation by NMDA-dependent processes. J Cereb Blood Flow Metab 22:1463–1475

    Article  PubMed  CAS  Google Scholar 

  • Reep, RL, Corwin, JV, Cheatwood, JL, Van Vleet, TM, Heilman, KM, Watson, RT (2004) A rodent model for investigating the neurobiology of contralateral neglect. Cog Behav Neurol 17:191–194

    CAS  Google Scholar 

  • Roman GC, Sachdev P, Royall DR, Bullock RA, Orgogozo JM, Lopez-Pousa S, Arizaga R, Wallin A (2004) Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci 226:81–87

    Article  PubMed  Google Scholar 

  • Roof RL, Schielke GP, Ren X, Hall ED (2001) A comparison of long-term functional outcome after 2 middle cerebral artery occlusion models in rats. Stroke 32:2648–2657

    PubMed  CAS  Google Scholar 

  • Ross DT, Ebner FF (1990) Thalamic retrograde degeneration following cortical injury: an excitotoxic process? Neuroscience 35:525–550

    Article  PubMed  CAS  Google Scholar 

  • Saido TC, Yokota M, Maruyama K, Yamao-Harigaya W, Tani E, Ihara Y, Kawashima S (1994) Spatial resolution of the primary beta-amyloidogenic process induced in postischemic hippocampus. J Biol Chem 269:15253–15257

    PubMed  CAS  Google Scholar 

  • Saji M, Reis DJ (1987) Delayed transneuronal death of substantia nigra neurons prevented by gamma-aminobutyric acid agonist. Science 235:66–69

    Article  PubMed  CAS  Google Scholar 

  • Sarti C, Pantoni L, Bartolini L, Inzitari D (2002) Cognitive impairment and chronic cerebral hypoperfusion: what can be learned from experimental models. J Neurol Sci 203–204:263–266

    Article  PubMed  Google Scholar 

  • Shi J, Yang SH, Stubley L, Day AL, Simpkins JW (2000) Hypoperfusion induces overexpression of beta-amyloid precursor protein mRNA in a focal ischemic rodent model. Brain Res 853:1–4

    Article  PubMed  CAS  Google Scholar 

  • Sinigaglia-Coimbra R, Cavalheiro EA, Coimbra CG (2002) Postischemic hyperthermia induces Alzheimer-like pathology in the rat brain. Acta Neuropathol (Berl) 103:444–452

    Article  CAS  Google Scholar 

  • Smith SE, Hodges H, Sowinski P, Man CM, Leach MJ, Sinden JD, Gray JA, Meldrum BS (1997) Long-term beneficial effects of BW619C89 on neurological deficit, cognitive deficit and brain damage after middle cerebral artery occlusion in the rat. Neuroscience 77:1123–1135

    Article  PubMed  CAS  Google Scholar 

  • Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR (1997) Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. Jama 277:813–817

    Article  PubMed  CAS  Google Scholar 

  • Sopala M, Frankiewicz T, Parsons C, Danysz W (2000) Middle cerebral artery occlusion produces secondary, remote impairment in hippocampal plasticity of rats - involvement of N-methyl-D-aspartate receptors? Neurosci Lett 281:143–146

    Article  PubMed  CAS  Google Scholar 

  • Stapf C, Mohr JP (2002) Ischemic stroke therapy. Annu Rev Med 53:453–475

    Article  PubMed  CAS  Google Scholar 

  • Stroemer RP, Kent TA, Hulsebosch CE (1998) Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. Stroke 29:2381–2393; discussion 2393–2385.

    Google Scholar 

  • Takasawa K, Kitagawa K, Yagita Y, Sasaki T, Tanaka S, Matsushita K, Ohstuki T, Miyata T, Okano H, Hori M, Matsumoto M (2002) Increased proliferation of neural progenitor cells but reduced survival of newborn cells in the contralateral hippocampus after focal cerebral ischemia in rats. J Cereb Blood Flow Metab 22:299–307

    Article  PubMed  Google Scholar 

  • Tamura A, Graham DI, McCulloch J, Teasdale GM (1981) Focal cerebral ischaemia in the rat: 1. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab 1:53–60

    PubMed  CAS  Google Scholar 

  • Tamura A, Kirino T, Sano K, Takagi K, Oka H (1990) Atrophy of the ipsilateral substantia nigra following middle cerebral artery occlusion in the rat. Brain Res 510:154–157

    Article  PubMed  CAS  Google Scholar 

  • Tanaka K, Nogawa S, Nagata E, Ito D, Suzuki S, Dembo T, Kosakai A, Fukuuchi Y (2000) Persistent CREB phosphorylation with protection of hippocampal CA1 pyramidal neurons following temporary occlusion of the middle cerebral artery in the rat. Exp Neurol 161:462–471

    Article  PubMed  CAS  Google Scholar 

  • Traystman RJ (2003) Animal models of focal and global cerebral ischemia. Ilar J 44:85–95

    PubMed  CAS  Google Scholar 

  • Wahl F, Allix M, Plotkine M, Boulu RG (1992) Neurological and behavioral outcomes of focal cerebral ischemia in rats. Stroke 23:267–272

    PubMed  CAS  Google Scholar 

  • Wang W, Redecker C, Bidmon HJ, Witte OW (2004) Delayed neuronal death and damage of GDNF family receptors in CA1 following focal cerebral ischemia. Brain Res 1023:92–101

    Article  PubMed  CAS  Google Scholar 

  • Wen Y, Onyewuchi O, Yang S, Liu R, Simpkins JW (2004a) Increased beta-secretase activity and expression in rats following transient cerebral ischemia. Brain Res 1009:1–8

    Article  PubMed  CAS  Google Scholar 

  • Wen Y, Yang S, Liu R, Brun-Zinkernagel AM, Koulen P, Simpkins JW (2004b) Transient cerebral ischemia induces aberrant neuronal cell cycle re-entry and Alzheimer’s disease-like tauopathy in female rats. J Biol Chem 279:22684–22692

    Article  PubMed  CAS  Google Scholar 

  • Wu YP, Ling EA (1998) Transsynaptic changes of neurons and associated microglial reaction in the spinal cord of rats following middle cerebral artery occlusion. Neurosci Lett 256:41–44

    Article  PubMed  CAS  Google Scholar 

  • Yonemori F, Yamada H, Yamaguchi T, Uemura A, Tamura A (1996) Spatial memory disturbance after focal cerebral ischemia in rats. J Cereb Blood Flow Metab 16:973–980

    Article  PubMed  CAS  Google Scholar 

  • Yonemori F, Yamaguchi T, Yamada H, Tamura A (1999) Spatial cognitive performance after chronic focal cerebral ischemia in rats. J Cereb Blood Flow Metab 19:483–494

    Article  PubMed  CAS  Google Scholar 

  • Zekry D, Duyckaerts C, Moulias R, Belmin J, Geoffre C, Herrmann F, Hauw JJ (2002) Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol (Berl) 103:481–487

    Article  CAS  Google Scholar 

  • Zhu DY, Lau L, Liu SH, Wei JS, Lu YM (2004) Activation of cAMP-response-element-binding protein (CREB) after focal cerebral ischemia stimulates neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A 101:9453–9457

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Supported by National Institutes of Health grants AG10485, AG22550, and a grant from American Heart Association (Texas Affiliate).

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  1. Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA

    Shao-Hua Yang, Ritu A. Shetty, Ran Liu, Nathalie Sumien, Kevin R. Heinrich, Margaret Rutledge, Nopporn Thangthaeng, Anne-Marie Brun-Zinkernagel & Michael J. Forster

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  1. Shao-Hua Yang
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  2. Ritu A. Shetty
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  3. Ran Liu
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Correspondence to Shao-Hua Yang.

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Yang, SH., Shetty, R.A., Liu, R. et al. Endovascular middle cerebral artery occlusion in rats as a model for studying vascular dementia. AGE 28, 297–307 (2006). https://doi.org/10.1007/s11357-006-9026-4

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