New therapeutic strategy for brain ischemic cellular edema according to the opening mechanism of water channel
| Project/Area Number |
13671467
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | Juntendo University |
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Principal Investigator |
MORI kentaro Juntendo University, Neurosurgery, Associate Professor, 医学部, 助教授 (30200364)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO takuji Juntendo University, Neurosurgery, Assistant, 医学部, 助手 (50255684)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| 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)
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| Keywords | brain edema / aquaporin / Na^+ / H^+ exchanger / phorbol estel / SM-20220 / protein kinase C |
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| 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.
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Report
(3 results)
Research Products
(18 results)
