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

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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