Pharmacological investigation for mechanisms of cerebral hemorrhage induced by anti-thrombotic agents

• Project/Area Number: 15390173
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: UMEMURA Kazuo Hamamatsu University School of Medicine, Professor, 医学部, 教授 (40232912)
• Co-Investigator(Kenkyū-buntansha): SUZUKI Yasuhiro Hamamatsu University School or Medicine, Assistant Professor, 医学部, 助手 (00324343) ; 池田 康彦 浜松医科大学, 医学部, 助手 (50293618)
• Project Period (FY): 2003 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥9,900,000 (Direct Cost: ¥9,900,000); Fiscal Year 2005: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2004: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2003: ¥3,500,000 (Direct Cost: ¥3,500,000)
• Keywords: stroke / cerebral hemorrhage / heparin / tPA / MMP-9

Research Abstract

Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke is a major clinical problem. We investigated the roles of endogenous tPA and MMPs in hemorrhagic cerebral infarction associated with heparin. We demonstrated that heparin administration caused cerebral hemorrhage in WT but not in KO. Heparin administration increased tPA activity and its mRNA expression in WT. We also observed an induction of MMP9 and its mRNA expression by heparin administration in WT but not in KO. Our findings suggest that endogenous tPA plays an important role in heparin-produced cerebral hemorrhage via MMP9 induction and activation.

Research Products

• [Journal Article] Positron Emission Tomographic Study of the Neuroprotective Effect of TRA-418, an Anti-Platelet Agent, in a Monkey Model of Stroke. (2005)
  • Author(s): Umemura, K., Tsukada, H., Kakiuchi, T., Yamada, N., Matsuura, N.
  • Journal Title: J Nucl Med 46 Pages: 1931-1936
• [Journal Article] Neuroprotective effects of KCL-440, a new poly(ADP-ribose)polymerase inhibitor, in the rat middle cerebral artery occlusion model. (2005)
  • Author(s): Ikeda, Y., Hokamura, K., Kawai, T., Ishiyama, J., Ishikawa, K., Anraku, T., Uno, T., Umemura, K.
  • Journal Title: Brain Res 1060 Pages: 73-80
• [Journal Article] Experimental study on the pro tective effects of edaravone against ischemic spinal cord injury.J (2005)
  • Author(s): Suzuki, K., Kazui, T., Terada, H., Umemura, K., Ikeda, Y., Bashar, A.H.M., Yamashita, K., Washiyama, N., Suzuki, T., Ohkura, K., Yasuike, J.
  • Journal Title: Thorac Cardiov Sur 130 Pages: 1586-1592
• [Journal Article] Essential role of endogenous tissue plasminogen activator via matrix metallop roteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice. (2004)
  • Author(s): Zhao B.Q., Ikeda Y., Ihara H., Urano T., Fan W.Y., Mikawa S., Suzuki Y., Kondo K., Sato K., Nagai N., Umemura K.
  • Journal Title: Blood 103 Pages: 2610-2616
• [Journal Article] A Na^+/H^+ exchanger inhibitor, SM-20220, is protective against excitotoxicity in cultured cortical neurons. (2004)
  • Author(s): Matsumoto Y., Yamamoto S., MD, Suzuki Y., Tsuboi, T., Terakawa S.Ohashi N., Umemura K.
  • Journal Title: Stroke 35 Pages: 185-190
• [Journal Article] Neuroprotective effects of ONO-1924H, an inhibitor of poly ADP-ribose polymerase (PARP), on cytotoxicity of PC12 cells and ischemic cerebral damage. (2004)
  • Author(s): Kamanaka Y., Kondo K., Ikeda Y., Kamoshimo W., Kitajima T., Suzuki Y., Nakamura Y., Umemura K
  • Journal Title: Life Sciences 76 Pages: 151-162
• [Publications] Suzuki Y., Takagi Y., Nakamura R., Hashimoto K., Umemura K.: "Ability of NMDA and non-NMDA receptor antagonists to inhibit cerebral ischemic damage in aged rats."Brain Res. 964. 116-120 (2003)
• [Publications] Yamada N., Miyamoto M., Isogaya M., Suzuki M., Ikezawa S., Hoshi K., Ohno M., Takeda T., Otake A., Umemura K.: "TRA-418, a novel compound having both thromboxane A_2 receptor antagonistic and prostaglandin I_2 receptor agonistic activities : its antiplatelet effects in human and animal platelets."J Thromb Haemostasis. 1. 1813-1819 (2003)
• [Publications] Katsuta K., Umemura K., Ueyama N., Matsuoka N.: "Pharmacological evidence for a correlation between hippocampal CA1 cell damage and hyperlocomotion following global cerebral ischemia in gerbils."Eur J Pharmacol. 467. 103-109 (2003)
• [Publications] Miyamoto M., Yamada N., Ikezawa S., Ohno M., Otake A., Umemura K., Matsushita T.: "Effects of TRA-418, a novel TP-receptor antagonist, and IP-receptor agonist, on human platelet activation and aggregation."Bri J Pharmacol. 140. 889-894 (2003)
• [Publications] Yamamoto S., Matsumoto Y., Suzuki Y., Tsuboi T., Terakawa S., Ohashi N., Umemura K.: "An Na+/H+ exchanger inhibitor suppresses cellular swelling and neuronal death induced by glutamate in cultured cortical neurons."Acta Neurochir Suppl.. 86. 223-226 (2003)