Study of the molecular mechanism by which microglia are activated in the brain

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Since the activation of microglia in vivo has been believed to affect largely the state of neuronal degeneration and/or regeneration, we analyzed the mechanism by which microglia are activated in the brain.(1) Brain-derived neurotrophic factor (BDNF) and ATP were selected as candidates for neuron-derived microglial activation factors from the observation of rat facial nerve transection model. The in vitro study revealed that BDNF enhanced the secretion of plasminogen (PGn) and urokinase (UK), and ATP induced morphological change and enhanced the secretion of PGn and tumor necrosis factor α (TNFα) from microglia. Therefore, it is suggested that neurotrophins and/or ATP are released to extracellular spaces from injured neurons and activate microglia in vivo.(2) Among factors which can suppress microglial functions, glial cell line-derived neurotrophic factor (GDNF) was found to show the strongest activity. This factor did not affect survival, morphology and proliferative activity, but suppressed the secretion of PGn and UK from microglia. GDNF was considered to play a role on the suppression of microglial activation which was observed in later stage of brain injury including facial nerve transection.(3) To analyze the signal transduction mechanism in the induction of microglial activation, lipopolysaccharide (LPS)-stimulating system was used for in vitro model. LPS induced the release of nitric oxide (NO) and TNFα in microglia. These secretions were suppressed by the pretreatment with specific protein kinase C (PKC) inhibitor, suggesting the strong association of PKC with NO and TNFα releases. Although MAP kinases including ERK, JNK and p38 were all activated by the stimulation with LPS, specific inhibitor of p38 inhibited strongly the release of TNFα, suggesting the association of p38 with TNFα release. The release of these cytotoxic factors from activated microglia was suggested to be regulated by PKC signaling pathway and the associated MAP kinase activity.