Establishment of new kinin-network via microglia in the central nervous system
| Project/Area Number |
16590051
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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 |
Biological pharmacy
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
NODA Mami Kyushu University, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学研究院, 助教授 (80127985)
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| Co-Investigator(Kenkyū-buntansha) |
WADA Keiji National Center of Neurology and Psychiatry, National Institute of Neuroscience, Head, 神経研究所・疾病研究第4部, 部長 (70250222)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | inflammation / bradykinin / microglia / neuroprotection / motility / chemotaxis / B1 receptor / cytokine / パッチクランプ / 腫瘍壊死因子 / プロスタグランジン / 一酸化窒素 |
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| Research Abstract |
Bradykinin (BK) has been reported as a mediator of brain damage in acute insults. We had found that receptors for BK were identified on microglia, the pathologic sensors of the brain (Noda et al., 2003). Here we report that BK has two functions via microglia ; unexpected neuroprotective effects and chemoattracting effect.
1)Neuroprotective effects of BK via microelia. BK attenuated LPS-induced release of TNF-α and IL-1β, thus acting as an anti-inflammatory mediator. This effect was mimicked by raising intracellular cAMP. A mechanism to increase intracellular cAMP is via activation of prostanoid receptors. Indeed we found that BK increased the release of prostaglandin E_2, enhanced the expression of microsomal prostaglandin E synthase and the prostanoid receptors EP2 and EP4 indicating an autocrine amplification loop. This is supported by the observation that the inhibitory effect of BK on LPS-induced TNF-α release was mimicked by EP2/EP4 agonists, while it was abolished by a cAMP antago
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nist, a prostanoid receptor antagonist or an inhibitor of inducible type of cyclooxygenase (COX-2). The latter effect is explained by our observation that expression of mPGES was inhibited by a blocker of COX-2. This signaling cascade was further amplified since both LPS and BK increased expression of B_1 and B_2 receptors. Using physiological techniques we identified functional BK receptors not only in culture, but also in microglia from acute brain slices. To study the impact of the anti-inflammatory effect of BK, we applied LPS to neuron-microglia co-cultures : neuronal death was attenuated by BK. On the other hand, TNF-□-induced neuronal death was not affected by BK in pure neuronal cultures. Our data imply that BK has anti-inflammatory and neuroprotective effects in the CNS by modulating microglial function.
2)BK-induced micrglial migration. In the central nervous system, migration of microglia towards damaged tissue plays a role in regeneration under pathological condition. In the present study, we found that bradykinin (BK) induced migration of cultured microglia, which was blocked by charybdotoxin, a blocker of large conductance Ca^<2+>-dependent K^+ channels, but not by pertussis toxin (PTX). These results indicate that activation of large conductance Ca^<2+> -activated K^+ channel is required for BK-induced microglial migration, while activation of PTX-sensitive G protein is not. Our findings may help to understand the function of kinins in the brain and the role of microglia in response to brain injury. Less
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Report
(3 results)
Research Products
(22 results)
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[Journal Article] Potentiation of ATP-induced currents due to the activation of P2X receptors by ubiquitin carboxy-terminal hydrolase L1.2005
Author(s)
Manago Y, Kanahori Y, Shimada A, Sato A, Amano T, Sano-Sato Y, Setsuie R, Sakurai M, Aoki S, WangY, Osaka H, Wada K, Noda M
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Journal Title
J.Neurochemistry 92
Pages: 1061-1072
Description
「研究成果報告書概要(欧文)」より
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[Book] Asian Symposium for Pharmaceutical Science in JSPS Asian Core Program2006
Author(s)
Noda, M., Ifuku, M., Farber, K., Seike, T., Wang, B., Kettenmann, H., Wada, K.
Total Pages
3
Publisher
Kyushu University
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