Acta Neuropathologica

, Volume 107, Issue 6, pp 532–538 | Cite as

Blood-brain barrier is impaired in the hippocampus of young adult spontaneously hypertensive rats

  • Masaki Ueno
  • Haruhiko Sakamoto
  • Hidekazu Tomimoto
  • Ichiro Akiguchi
  • Masayuki Onodera
  • Cheng-Long Huang
  • Kenji Kanenishi
Regular Paper


A causative role of blood-brain barrier (BBB) impairment is suggested in the pathogenesis of vascular dementia with leakage of serum components from small vessels leading to neuronal and glial damage. We examined the BBB function of young adult spontaneously hypertensive rats (SHR) in order to determine earlier changes in the BBB in chronic hypertension. SHR and stroke-prone SHR (SHRSP) were injected with horseradish peroxidase (HRP) as an indicator of BBB function and compared with Wistar Kyoto rats (WKY). The brain tissues were further examined with cationized ferritin, a marker for evaluating glycocalyx. The staining for HRP was distributed around the vessels in the hippocampal fissure of SHR and SHRSP, but not in WKY. With electron microscopy, the extravasated reaction product of HRP appeared in abluminal pits of the endothelial cells of arterioles and within the basal lamina in the hippocampus, but not the cerebral cortex, of SHR and SHRSP. On the contrary, the reaction product of HRP was never seen in the abluminal pits of the endothelial cells or the basal lamina of vessels in WKY. The number of cationized ferritin particles binding to the endothelial cells of capillaries was decreased in the hippocampus of SHR and SHRSP, while the number decreased in the cerebral cortex of SHRSP compared with those in WKY. However, the cationized ferritin binding was preserved in the endothelial cells of the arterioles with an increased vascular permeability. These findings suggest that the chronic hypertensive state induces BBB dysfunction in the hippocampus at an early stage.


Blood-brain barrier Hypertension Young adults Hippocampus SHR 



The authors wish to express their appreciation to Ms. C. Ishikawa for technical assistance and to Ms. Y. Fujiwara for editorial assistance. This research was supported by a budget from the Ministry of Education, Culture, Sports, Science and Technology, Japan.


  1. 1.
    Amano S (1977) Vascular changes in the brain of spontaneously hypertensive rats: hyaline and fibrinoid degeneration. J Pathol 121:119–128PubMedGoogle Scholar
  2. 2.
    Cavaglia M, Dombrowski SM, Drazba J, Vasanji A, Bokesch PM, Janigro D (2001) Regional variation in brain capillary density and vascular response to ischemia. Brain Res 910:81–93CrossRefPubMedGoogle Scholar
  3. 3.
    Cervos-Navarro J, Artigas J, Mrsulja BJ (1983) Morphofunctional aspects of the normal and pathological blood-brain barrier. Acta Neuropathol 8:1-19Google Scholar
  4. 4.
    Fredriksson K, Auer RN, Kalimo H, Nordborg C, Olsson Y, Johansson BB (1985) Cerebrovascular lesions in stroke-prone spontaneously hypertensive rats. Acta Neuropathol 68:284–294PubMedGoogle Scholar
  5. 5.
    Fredriksson K, Kalimo H, Westergren I, Kahrstrom J, Johansson BB (1987) Blood-brain barrier leakage and brain edema in the stroke-prone spontaneously hypertensive rats. Acta Neuropathol 74:259–268PubMedGoogle Scholar
  6. 6.
    Fredriksson K, Kalimo H, Nordborg C, Olsson Y, Johansson BB (1988) Cyst formation and glial response in the brain lesions of stroke-prone spontaneously hypertensive rats. Acta Neuropathol 76:441–450PubMedGoogle Scholar
  7. 7.
    Fredriksson K, Nordborg C, Kalimo H, Olsson Y, Johansson BB (1988) Cerebral microangiopathy in stroke-prone spontaneously hypertensive rats. An immunohistochemical and ultrastructural study. Acta Neuropathol 75:241–252PubMedGoogle Scholar
  8. 8.
    Hachinski VC, Potter P, Merskey H (1987) Leuko-araiosis. Arch Neurol 44:21–23PubMedGoogle Scholar
  9. 9.
    Hazama F, Amano S, Haebara H, Okamoto K (1975) Changes in vascular permeability in the brain of stroke-prone spontaneously hypertensive rats studied with peroxidase as a tracer. Acta Pathol Jap 25:565–574Google Scholar
  10. 10.
    Johansson BB (1977) The cerebrovascular permeability to protein after bicuculline and amphetamine administration in spontaneously hypertensive rats. Acta Neurol Scand 56:397–404PubMedGoogle Scholar
  11. 11.
    Johansson BB (1980) The blood-brain barrier in acute and chronic hypertension. Adv Exp Med Biol 131:211–226PubMedGoogle Scholar
  12. 12.
    Knox CA, Yates RD, Chen I-li, Klara PM (1980) Effects of aging on the structural and permeability characteristics of cerebrovasculature in normotensive and hypertensive strains of rats. Acta Neuropathol 51:1-13PubMedGoogle Scholar
  13. 13.
    Lindner JR, Ismail S, Spotnitz WD, Skyba DM, Jayaweera AR, Kaul S (1998) Albumin microbubble persistence during myocardial contrast echocardiography is associated with microvascular endothelial glycocalyx damage. Circulation 98:2187–2194PubMedGoogle Scholar
  14. 14.
    Mesulam M-M (1978) Tetramethyl benzidine for horseradish peroxidase neurohistochemistry: a non-carcinogenic blue reaction-product with superior sensitivity for visualizing neural afferents and efferents. J Histochem Cytochem 26:106–117PubMedGoogle Scholar
  15. 15.
    Miyamoto M, Kiyota Y, Yamazaki N, Nagaoka A, Matsuo T, Nagawa Y, Takeda T (1986) Age-related changes in learning and memory in the senescence-accelerated mouse (SAM). Physiol Behav 38:399–406CrossRefPubMedGoogle Scholar
  16. 16.
    Mueller SM (1982) The blood-brain barrier in young spontaneously hypertensive rats. Acta Neurol Scand 65:623–628PubMedGoogle Scholar
  17. 17.
    Nag S (1984) Cerebral endothelial surface charge in hypertension. Acta Neuropathol 63:276–281PubMedGoogle Scholar
  18. 18.
    Negishi H, Ikeda K, Nara Y, Yamori Y (2001) Increased hydroxyl radicals in the hippocampus of stroke-prone spontaneously hypertensive rats during transient ischemia and recirculation. Neurosci Lett 306:206–208CrossRefPubMedGoogle Scholar
  19. 19.
    Ogata J, Fujishima M, Tamaki K, Nakatomi Y, Ishitsuka T, Omae T (1981) Vascular changes underlying cerebral lesions in stroke-prone spontaneously hypertensive rats. Acta Neuropathol 54:183–188PubMedGoogle Scholar
  20. 20.
    Okamoto K, Aoki K (1963) Development of a strain of spontaneously hypertensive rats. Jap Circ J 27:282–293PubMedGoogle Scholar
  21. 21.
    Okamoto K, Yamori Y, Nagaoka A (1974) Establishment of the stroke-prone spontaneously hypertensive rat (SHR). Circ Res 34:143–153PubMedGoogle Scholar
  22. 22.
    Parnetti L, Mari D, Mecocci P, Senin U (1994) Pathogenetic mechanisms in vascular dementia. Int J Clin Lab Res 24:15–22PubMedGoogle Scholar
  23. 23.
    Reese TS, Karnovsky MJ (1967) Fine structural localization of blood-brain barrier to exogenous peroxidase. J Cell Biol 34:207–217PubMedGoogle Scholar
  24. 24.
    Ritter S, Dinh TT (1986) Progressive postnatal dilatation of brain ventricles in spontaneously hypertensive rats. Brain Res 370:327–332CrossRefPubMedGoogle Scholar
  25. 25.
    Roman GC (1996) From UBOs to Binswanger’s disease: impact of magnetic resonance imaging on vascular dementia research. Stroke 27:1269–1273PubMedGoogle Scholar
  26. 26.
    Sabbatini M, Strocchi P, Vitaioli L, Amenta F (2000) The hippocampus in spontaneously hypertensive rats: A quantitative microanatomical study. Neuroscience 100:251–258CrossRefPubMedGoogle Scholar
  27. 27.
    Sabbtini M, Catalani A, Consoli C, Marletta N, Tomassoni D, Avola R (2002) The hippocampus in spontaneously hypertensive rats: an animal model of vascular dementia. Mech Ageing Dev 123:547–559CrossRefPubMedGoogle Scholar
  28. 28.
    Schmidt-Kastner R, Szymas J, Hossmann K-A (1990) Immunohistochemical study of glial reaction and serum-protein extravasation in relation to neuronal damage in the rat hippocampus after ischemia. Neuroscience 38:527–540CrossRefPubMedGoogle Scholar
  29. 29.
    Shinnou M, Ueno M, Sakamoto H, Ide M (1998) Blood-brain barrier damage in reperfusion following ischemia in the hippocampus of the Mongolian gerbil brain. Acta Neurol Scand 98:406–411PubMedGoogle Scholar
  30. 30.
    Takeda T, Hosokawa M, Takeshita S, Irino M, Higuchi K, Matsushita T, Tomita Y, Yasuhira K, Hanamoto H, Shimizu K, Ishii M, Yamamuro T (1981) A new murine model of accelerated senescence. Mech Ageing Dev 17:183–194CrossRefPubMedGoogle Scholar
  31. 31.
    Thurauf N, Dermietzel R, Kalweit P (1983) Surface charges associated with fenestrated brain capillaries. I. In vitro labeling of anionic sites. J Ultrastruct Res 84:103–110PubMedGoogle Scholar
  32. 32.
    Ueno M, Akiguchi I, Hosokawa M, Yagi H, Takemura M, Kimura J, Takeda T (1994) Accumulation of blood-borne horseradish peroxidase in medial portions of the mouse hippocampus. Acta Neurol Scand 90:400–404PubMedGoogle Scholar
  33. 33.
    Ueno M, Akiguchi I, Hosokawa M, Shinnou M, Sakamoto H, Takemura M, Higuchi K (1997) Age-related changes in the brain transfer of blood-borne horseradish peroxidase in the hippocampus of senescence-accelerated mouse. Acta Neuropathol 93:233–240CrossRefPubMedGoogle Scholar
  34. 34.
    Ueno M, Akiguchi I, Hosokawa M, Kotani H, Kanenishi K, Sakamoto H (2000) Blood-brain barrier permeability in the periventricular areas of the normal mouse brain. Acta Neuropathol 99:385–392CrossRefPubMedGoogle Scholar
  35. 35.
    Ueno M, Sakamoto H, Kanenishi K, Onodera M, Akiguchi I, Hosokawa M (2001) Ultrastructural and permeability features of microvessels in the hippocampus, cerebellum and pons of senescence-accelerated mice (SAM). Neurobiol Aging 22:469–478CrossRefPubMedGoogle Scholar
  36. 36.
    Ueno M, Tomimoto H, Akiguchi I, Wakita H, Sakamoto H (2002) Blood-brain barrier disruption in white matter of chronic cerebral hypoperfusion. J Cereb Blood Flow Metab 22:97–104CrossRefPubMedGoogle Scholar
  37. 37.
    Vorbrodt AW, Lossinsky AS, Dobrogowska DH, Wisniewski HM (1986) Distribution of anionic sites and glycoconjugates on the endothelial surfaces of the developing blood-brain barrier. Dev Brain Res 29:69–79CrossRefGoogle Scholar
  38. 38.
    Wallin A, Blennow K (1993) Heterogeneity of vascular dementia: mechanisms and subgroups. J Geriatr Psychiatr Neurol 6:177–188Google Scholar
  39. 39.
    Wardlaw JM, Sandercock PAG, Dennia MS, Starr J (2003) Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke 34:806–812CrossRefGoogle Scholar
  40. 40.
    Westergaard RD, Brightman MW (1973) Transport of proteins across normal cerebral arterioles. J Comp Neurol 152:17–44PubMedGoogle Scholar
  41. 41.
    Yamori Y, Horie R, Sato M, Sasagawa S, Okamoto K (1975) Experimental studies on the pathogenesis and prophylaxis of stroke-prone spontaneously hypertensive rats (SHR). (1) Quantitative estimation of cerebrovascular permeability. Jpn Circ J 39:611–615PubMedGoogle Scholar
  42. 42.
    Yoshida T, Tanaka M, Okamoto K (2002) Immunoglobulin G induces microglial superoxide production. Neurol Res 24(4): 361–364PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Masaki Ueno
    • 1
  • Haruhiko Sakamoto
    • 1
  • Hidekazu Tomimoto
    • 2
  • Ichiro Akiguchi
    • 2
  • Masayuki Onodera
    • 1
  • Cheng-Long Huang
    • 3
  • Kenji Kanenishi
    • 4
  1. 1.Department of Pathology and Host DefenseFaculty of Medicine, Kagawa UniversityKita-gunJapan
  2. 2.Department of NeurologyGraduate School of Medicine, Kyoto UniversityKyotoJapan
  3. 3.Department of SurgeryFaculty of Medicine, Kagawa UniversityJapan
  4. 4.Department of PerinatologyFaculty of Medicine, Kagawa UniversityJapan

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