Studies on the white matter damage after ischemia of perforating brain artery.

• Project/Area Number: 17390392
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: The University of Tokyo (2006-2007); Gunma University (2005)
• Principal Investigator: SAITO Nobuhito The University of Tokyo, Department of Neurosurgery, Professor (60262002)
• Co-Investigator(Kenkyū-buntansha): IMAI Hideaki Gunma University, Department of Neurosurgery, Assistant Professor (70359587) ; KAZAMA Ken Gunma University, Department of Neurosurgery, Assistant Professor (30396626) ; TOSAKA Masahiko Gunma University, Department of Neurosurgery, Assistant Professor (40323357) ; KONNO Kenjiro Gunma University, Department of Neurosurgery, Assistant Professor (30323348) ; TAKAI Keisuke The University of Tokyo, Department of Neurosurgery, Assistant Professor (70376424) ; 平戸 政史 群馬大学, 大学院・医学系研究科, 助教授 (00173245)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥16,630,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥1,230,000); Fiscal Year 2007: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2006: ¥4,100,000 (Direct Cost: ¥4,100,000); Fiscal Year 2005: ¥7,200,000 (Direct Cost: ¥7,200,000)
• Keywords: cerebral ischemia / lacunar inarction / white matter / monitoring / miniature pig / axonal injury / animal model / 白質(内包)障害 / 運動障害 / 虚血後微小環境変化 / 再現性 / 低侵襲性

Research Abstract

There has been no previous animal model of lacunar infarction relevant to the lacunar infarction of human so far. In this study, we aimed to develop a new model of lacunar stroke in gyrencephalic brain as a result of in situ small perforating arterial occlusion of internal carotid artery, anterior choroidal artery (AchA) occlusion. Mexican hairless miniature pigs, weighing 19-42 kg, were undergone to AchA occlusion, using a modification of the permanent MCA occlusion method Animals were allowed to recover for 24 hours, 2 days, 1 week, 4 weeks and other days. The present protocol provided a 91.4% rate in successful production of the internal capsule. For MMEP results, internal capsule tissues that were exposed to ischemia between the first 6 - 15 minutes of AchA occlusion were considered penumbra zone. Lacunar infarction animal group usually displayed signs of neurological deficit after stroke onset. Although some degree of motor deficit remains to be unrecovered, the neurological deficit spontaneously recovered to became nearly same as to the control animals at 12 day after ischemia. On the other hand, histopathological study revealed that the lesion of internal capsule expands gradually as time dependent manner which is particularly attributed to significant expansion of the ischemic lesion during the first week after ischemia (P<0.05). Ultrastructural analysis unveiled the characteristics in terms of the mechanism of expansion in white matter ischemia. At peri-infarct zone the axon was initially swollen accompanied with the edema formation. Finally the axon was ireversiblly damaged presumably due to the Ca2+ overload in axons. This chain reaction might further increase the vulnarability of the exposed axon to induce the expansion of the ishemic lesion. The small vessels amount at internal capsule remains constant before and after ischemia, even in the chronic phase. This is probably attributed to the difference in cellular susceptibility.

Research Products

• [Journal Article] Experimental Model of Lacunar Infarction in the Gyrencephalic Brain of the Miniature Pig: Neurological Assessment and Histological, Immunohistochemical, and Physiological Evaluation of Dynamic Corticospinal Tract Deformation. (2008)
  • Author(s): Tanaka Y, Imai H, Konno K, Miyagishima T, Kubota C, Puentes S, Aoki T, Hata H, Takata K, Yoshimoto Y, Saito N.
  • Journal Title: Stroke 39 Pages: 205-212
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Experimental Model of Lacunar Infarction in the Gyrencephalic Brain of the Miniature Pig : Neurological Assessment and Histological, Immunohistochemical, and Physiological Evaluation of Dynamic Corticospinal Tract Deformation (2008)
  • Author(s): Tanaka Y, Imai H, Konno K, Miyagishima T, Kubota C, Puentes S, Aoki T, Hata H, Takata K, Yoshimoto Y, Saito N.
  • Journal Title: Stroke 39 Pages: 205-212
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Experimental Model of Lacunar Infarction in the Gyrencephalic Brain of the Miniature Pig:Neurological Assessment and Histological,Immunohistochemical, and Physiological Evaluation of Dynamic Corticospinal Tract Defromation (2008)
  • Author(s): Tanaka Y, Imai H, Konno K, Miyagishima T, Kubota C, Puentes S, Aoki T, Hata H, Takata K, Yoshimoto Y, Saito N.
  • Journal Title: Stroke 39 Pages: 205-212
  • Peer Reviewed
• [Journal Article] Vasorelaxing effect of the Rho-kinase inhibitor, Y-27632, in isolated caninebasilar arteries. (2007)
  • Author(s): Hashiba Y, Tosaka M, Saito N, Imai H, Shimizu T, Sasaki T.
  • Journal Title: Neurol Res. 29 Pages: 458-489
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] New Model of Focal Cerebral Ischemia in the Miniature Pig.. (2006)
  • Author(s): H Imai, K Konno, M Nakamura, TShimizu, C Kubota, K Seki, F Honda, S Tomizawa, Y Tanaka, H Hata, N Saito.
  • Journal Title: J. Neurosurg (2 Suppl Pediatrics) 104 Pages: 123-132
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Nestin expression in vascular malformations: a novel marker forproliferative endothelium. (2006)
  • Author(s): Shimizu T, Sugawara K, Tosaka M, Imai H, Hoya K, Takeuchi T, Sasaki T, Saito N.
  • Journal Title: Neurol Med Chir (Tokyo). 46 Pages: 111-117
  • NAID: 110004656790
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cilostazol Attenuates Both Gray and White Matter Damage in a Rodent Model of Focal Cerebral Ischemia. (2006)
  • Author(s): F Honda, H Imai, M Ishikawa, CKubota, T Shimizu, M Fukunaga, N Saito.
  • Journal Title: Stroke 37 Pages: 223-228
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A new model of focal cerebral ischemia in the miniature pig (2006)
  • Author(s): Imai H, Konno K, Nakamura M, Shimizu T, Kubota C, Seki K, Honda F, Tomizawa S, Tanaka Y, Hata H, Saito N.
  • Journal Title: J Neurosurg 104(2 Suppl) Pages: 123-132
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cilostazol attenuates both gray and white matter damage in a rodent model of focal cerebral ischemia (2006)
  • Author(s): Honda F, Imai H, Ishikawa M, Kubota C, Shimizu T, Fukunaga M, Saito N.
  • Journal Title: Stroke 37 Pages: 223-228
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A new model of focal cerebral ischemia in the miniature pig. J Neurosurg. 104 (2 Suppl):123-132,2006 (2006)
  • Author(s): Imai H, Konno K, Nakamura M, Shimizu T, Kubota C, Seki K, Honda F, Tomizawa S, Tanaka Y, Hata H, Saito N.
  • Journal Title: J Neurosurg 104(2 Suppl) Pages: 123-132
• [Journal Article] New Model of Focal Cerebral Ischemia in the Miniature Pig. (2006)
  • Author(s): H Imai, K Konno, M Nakamura, T Shimizu, C Kubota, K Seki, F Honda, S Tomizawa, Y Tanaka, H Hata, N Saito.
  • Journal Title: J Neurosurg (2 Suppl Pediatrics) 104 Pages: 123-132
• [Journal Article] Cilostazol Attenuates Both Gray and White Matter Damage in a Rodent Model of Focal Cerebral Ischemia. (2006)
  • Author(s): F Honda, H Imai, M Ishikawa, C Kubota, T Shimizu, M Fukunaga, N Saito.
  • Journal Title: Stroke 37 Pages: 223-228
• [Journal Article] The detection and quantification of highly reactive oxygen species using the novel HPF fluorescence probe in a rat model of focal cerebral ischemia. (2005)
  • Author(s): Tomizawa, S, Imai H, Tsukada S, Simizu T, Honda F, Nakamura M, Nagano T, Urano Y, Matsuoka Y, Fukasaku N, Saito N.
  • Journal Title: Neurosci. Res. 53 Pages: 304-313
  • NAID: 10017131014
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cyclophilin C-associated protein and cyclophilin C mRNA are up-regulatedin penumbral neurons and microglia after focal cerebral ischemia (2005)
  • Author(s): Shimizu T, Imai H, Seki K, Tomizawa S, Nakamura M, Honda F, Kawahara N, Saito N.
  • Journal Title: J. Cereb Blood Flow Metab 25 Pages: 325-337
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cyclophilin C-associated protein and cyclophilin C mRNA are upregulated in penumbral neurons and microglia after focal cerebral ischemia. (2005)
  • Author(s): T Shimizu, H Imai, K Seki, S Tomizawa, M Nakamura, F Honda, N Kawahara, N Saito.
  • Journal Title: J Cereb Blood Flow Metab 25(3) Pages: 325-337
• [Journal Article] The detection and quantification of highly reactive oxygen species using the novel HPF fluorescence probe in a rat model of focal cerebral ischemia. (2005)
  • Author(s): S Tomizawa, H Imai, S Tsukada, T Simizu, F Honda, M Nakamura, T Nagano, Y Urano, Y Matsuoka, N Fukasaku, N Saito.
  • Journal Title: Neuroscience Research 53 Pages: 304-313
  • NAID: 10017131014
• [Journal Article] Focal Cerebral ischemia increases type2 iodothyronine deiodinase. (2005)
  • Author(s): K Seki, H Imai, T Shimizu, K Tsunekawa, T Kasahara, T Ogiwara, N Saito, M Murakami.
  • Journal Title: J Cereb Blood Flow Metab. 25
• [Presentation] Expression of Cyclophilin C-associated protein in focal cerebral ischemia in the rat. (2007)
  • Author(s): Yamaguchi R, Imai H, Hosaka M, Takeuchi T, Yoshimoto Y, Saito N.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, Metabolism & Function.
  • Place of Presentation: Osaka
  • Year and Date: 2007-05-24
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Expression of Cyclophilin C-associated protein in focal cerebral ischemia in the rat (2007)
  • Author(s): Yamaguchi R, Imai H, Hosaka M, Takeuchi T, Yoshimoto Y, Saito N.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Osaka
  • Year and Date: 2007-05-24
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] A New Model of Lacunar Infarction in the Miniature Pig: Comprehensive Evaluation for the Pure White Matter Ischemia (2007)
  • Author(s): Tanaka Y, Imai H, Konno K, Miyagishima T, Kubota C, Puentes S, Aoki T, Hata H, Takata K, Yoshimoto Y, Saito N.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Osaka
  • Year and Date: 2007-05-23
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] A New Model of Lacunar Infarction in the Miniature Pig : Comprehensive Evaluation for the Pure White Matter Ischemia (2007)
  • Author(s): Tanaka Y, Imai H, Konno K, Miyagishima T, Kubota C, Puentes S, Aoki T, Hata H, Takata K, Yoshimoto Y, Saito N.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, Metabolism & Function
  • Place of Presentation: Osaka
  • Year and Date: 2007-05-23
  • Description: 「研究成果報告書概要(欧文)」より