Establishment of new kinin-network via microglia in the central nervous system

通过中枢神经系统中的小胶质细胞建立新的激肽网络

• 批准号: 16590051
• 负责人: NODA Mami
• 金额: $ 2.24万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590051/
• 关键词: 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

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 … More 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

缓激肽（BK）已被报道为急性脑损伤的介质。我们已经发现BK的受体在小胶质细胞上被鉴定，小胶质细胞是大脑的病理传感器（Noda等人，2003年）。在这里，我们报告BK通过小胶质细胞具有两种功能：意想不到的神经保护作用和化学吸引作用。1）BK通过小胶质细胞的神经保护作用。BK可减弱LPS诱导的TNF-α和IL-1β的释放，从而起到抗炎介质的作用。这种效应通过提高细胞内cAMP来模拟。增加细胞内cAMP的机制是通过激活前列腺素受体。我们发现BK可增加前列腺素E_2的释放，增加微粒体前列腺素E合成酶和前列腺素受体EP_2和EP_4的表达，表明存在一个自分泌放大环。BK对LPS诱导的TNF-α释放的抑制作用被EP 2/EP 4激动剂模拟，而cAMP拮抗剂则消除，这一观察结果支持了这一观点 ...更多信息 nist，前列腺素类受体拮抗剂或诱导型环氧合酶（考克斯-2）抑制剂。后一种效应可以通过我们观察到mPGES的表达被考克斯-2的阻断剂抑制来解释。由于LPS和BK均增加了B_1和B_2受体的表达，这一信号级联反应被进一步放大。使用生理技术，我们确定了功能BK受体不仅在文化，而且在小胶质细胞从急性脑切片。为了研究BK的抗炎作用的影响，我们将LPS应用于神经元-小胶质细胞共培养物：BK减弱了神经元死亡。另一方面，在纯神经元培养物中，BK不影响TNF-□诱导的神经元死亡。提示BK通过调节小胶质细胞的功能发挥抗炎和神经保护作用。2）BK诱导的小胶质细胞迁移。在中枢神经系统中，小胶质细胞向受损组织的迁移在病理条件下的再生中起作用。在本研究中，我们发现缓激肽（BK）可诱导培养的小胶质细胞迁移，这种迁移可被大电导Ca^2+依赖性K^+通道阻断剂-Charybdotoxin阻断，但不能被百日咳毒素（PTX）阻断。这些结果表明，BK诱导的小胶质细胞迁移需要激活大电导Ca^2+激活的K^+通道，而PTX敏感的G蛋白的激活不是必需的。我们的研究结果可能有助于了解激肽在脑中的功能以及小胶质细胞在脑损伤中的作用。少

项目成果

Asian Symposium for Pharmaceutical Science in JSPS Asian Core Program

JSPS 亚洲核心计划亚洲药学研讨会

• 发表时间: 2006
• 作者: Noda;M.;Ifuku;M.;Farber;K.;Seike;T.;Wang;B.;Kettenmann;H.;Wada;K.
• 通讯作者: K.

Kinin-induced microglial migration and anti-inflammatory effects in the central nervous system.

激肽诱导的小胶质细胞迁移和中枢神经系统的抗炎作用。

• 发表时间: 2006
• 期刊: Journal of Neurochemistry 96(1)
• 作者: Noda;M.;Ifuku;M.;Farber;K.;Kettenmann;H.;Wada;K.
• 通讯作者: K.

Potentiation of ATP‐induced currents due to the activation of P2X receptors by ubiquitin carboxy‐terminal hydrolase L1

• DOI: 10.1111/j.1471-4159.2004.02963.x
• 发表时间: 2005-03
• 期刊: Journal of Neurochemistry
• 影响因子: 4.7
• 作者: Yoshimasa Manago;Yoshiko Kanahori;Aki Shimada;Ayumi Sato;Taiju Amano;Yae Sato-Sano;Rieko Setsuie;Mikako Sakurai;S. Aoki;Yu-Lai Wang;H. Osaka;K. Wada;M. Noda

Two closely related ubiquitin C-terminal hydrolase isozymes function as reciprocal modulators of germ cell apoptosis in cryptorchid testes.

两种密切相关的泛素 C 末端水解酶同工酶在隐睾睾丸中充当生殖细胞凋亡的相互调节剂。

• 发表时间: 2004
• 期刊: Am. J. Pathol. 165・4
• 作者: Kwon;J. et al.
• 通讯作者: J. et al.

Potentiation of ATP-induced currents due to the activation by ubiquitin carboxy-terminal hydrolase L1.

由于泛素羧基末端水解酶 L1 的激活，ATP 诱导电流增强。

• 发表时间: 2005
• 期刊: J.Neurochemistry 92
• 作者: ManagoY(他11名);Noda M.
• 通讯作者: Noda M.