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New therapeutic strategy for brain ischemic cellular edema according to the opening mechanism of water channel

Research Project

Project/Area Number 13671467
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionJuntendo University

Principal Investigator

MORI kentaro  Juntendo University, Neurosurgery, Associate Professor, 医学部, 助教授 (30200364)

Co-Investigator(Kenkyū-buntansha) YAMAMOTO takuji  Juntendo University, Neurosurgery, Assistant, 医学部, 助手 (50255684)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
Keywordsbrain edema / aquaporin / Na^+ / H^+ exchanger / phorbol estel / SM-20220 / protein kinase C
Research Abstract

Cellular swelling associated with cerebral ischemia occurs primarily in astrocytes. Our previous study demonstrated that ischemic cellular swelling occurs concomitantly with the increase in extracellular K^+ concentration but preceded the disruption of ionic membrane homeostasis. Presumably cerebral energy failure causes intracellular lactic acidosis which in turn stimulates the Na^+/H^+ exchanger and increases the intracellular Na^+ concentration. The increased osmotic pressure then causes water influx into the astrocyte through the water channel Aquaporin 4 (AQP4). The effects of SM-20220, a potent inhibitor of the Na^+/H^+ exchanger, and phorbol ester, an activator of protein kinase C which causes closing of AQP4 by phosphorylation, were investigated on astrocyte swelling in vitro and in vivo. Astrocytes in cultures expressed both AQP4 mRNA and AQP4 protein. The change in cellular diameter was evaluated after lactic acidosis of the culture medium (pH 4.5) using a Coulter flow cytometer. Astrocytes cultured without agents showed a 5.4 ± 1.5% increase in diameter. Astrocytes cultured with SM-20220 showed a significantly smaller diameter change (2.3 ± 0.8%, P < 0.05). Astrocytes cultured with phorbol ester also showed a smaller diameter change (9.97 ± 0.008%, P = 0.06). Both the Na^+/H^+ exchanger and AQP4 are important in the mechanism of cytotoxic brain edema. The effect of these two agents was examined on in vivo rat brain after water intoxication and metabolic suppressant administration (6-aminonicotinamide) with hypoxia. The agents were delivered into the rat cortex using a micro-dialysis tube and cellular swelling was measured by the impedance method. Neither agent effectively suppressed the cellular swelling. A more effective drug delivery system is needed to treat cellular swelling.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Kentaro Mori: "Temporal profile of changes in brain tissue extracellular space and extracellular ion (Na^+, K^+) concentrations after cerebral ischemia and the effects of mild cerebral hypothermia"J Neurotrauma. 19. 1261-1270 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takuji Yamamoto: "Assessment of prognostic factors in severe traumatic brain injury patients treated by mild therapeutic cerebral hypothermia therapy"Neurol Res. 24. 789-795 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Aya Aoki: "Adequate cerebral perfusion pressure during rewarming to prevent ischemic deterioration after therapeutic hypothermia"Neurol Res. 24. 271-280 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kentaro Mori: "Quantitative local cerebral blood flow change after cerebrospinal fluid removal in patients with normal pressure hydrocephalus measured by a double injection method with N-isopropyl-p-[^<123>I] iodoamphetamine"Acta Neurochir (Wien). 144. 255-263 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Aya Aoki: "Appropriate cerebral perfusion pressure during rewarming after therapeutic hypothermia"Acta Neurochir. 81. 237-239 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 森 健太郎: "脳虚血性細胞性浮腫の発生メカニズムと軽度脳低温の効果(水チャネルAquaporinの虚血性細胞性浮腫への関与の可能性について)。"Progress in Reserch on Brain Edema and ICP. 27-33 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K Mori, M Miyazaki, H Iwase, M Maeda: "Temporal profile of changes in brain tissue extracellular space and extracellular ion (Na^+, K^+) concent rations after cerebral ischemia and the effects of mild cerebral hypothermia"J Neurotrauma. 19. 1261-1270 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] T Yamamoto, K Mori, M Maeda: "Assessment of prognostic factors in severe traumatic brain injury patients treated by mild therapeutic cerebral hypothermia therapy"Neurol Res. 24. 789-795 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] A Aoki, K Mori, M Maeda, M Miyazaki, H Iwase: "Adequate cerebral perfusion pressure during rewarming to prevent ischemic deterioration after therapeutic hypothermia"Neurol Res. 24. 271-280 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K Mori, M Maeda, S Asegawa, J Iwata: "Quantitative local cerebral blood flow change after cerebrospinal fluid removal in patients with normal pressure hydrocephalus measured by a double injection method with N-isopropyl-p-[^<123>I]iodoamphetamine"Acta Neurochir (Wien). 144. 255-263 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kentaro Mori: "Temporal profile of changes in brain tissue extracellular space and extracellular ion (Na^+, K^+) concentrations after cerebral ischemia and the effects of mild cerebral hypothermia"J Neurotrauma. 19. 1261-1270 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takuji Yamamoto: "Assessment of prognostic factors in sever traumatic brain injury patients treated by mild therapeutic cerebral hypothermia therapy"Neurol Res. 24. 789-795 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Aya Aoki: "Adequate cerebral perfusion pressure during rewarming to prevent ischemic deterioration after therapeutic hypothermia"Neurol Res. 24. 271-280 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kentaro Mori: "Quantitative local cerebral blood flow change after cerebrospinal fluid removal in patients with normal pressure hydrocephalus measured by a double injection method with N-isopropyl-p-[^<123>I]iodoamphetamine"Acta Neurochir (Wien). 144. 255-263 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Aya Aoki: "Appropriate cerebral perfusion pressure during rewarming after therapeutic hypothermia"Acta Neurochir. 81. 237-239 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 森 健太郎: "脳虚血性細胞性浮腫の発生メカニズムと軽度脳低温の効果(水チャネルAquaporinの虚血性細胞性浮腫への可能性について)"Progress in Reserch on Brain Edema and ICP. 27-33 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mori K., Miyazaki M., Iwase H., Maeda M.: "Temporal profile of changes in brain extracellular ion (Na^+,K^+) concentrations after cerebral ischemia and the effects of mild cerebral hypothermia"J Neurotrauma. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 森 健太郎, 前田 稔: "脳虚血性細胞性浮腫の発生メカニズムと軽度脳低温の効果(水チャネルAquaporinの虚血性細胞性浮腫への関与の可能性について)"脳浮腫、頭蓋内圧研究会報告集. (in press). (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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