Anti-inflammatory effects of dopamine on microglia and a D1 receptor agonist ameliorates neuroinflammation of the brain in a rat delirium model.

Microglia play a central role in neuroinflammatory processes by releasing proinflammatory mediators. This process is tightly regulated along with neuronal activities, and neurotransmitters may link neuronal activities to the microglia. In this study, we showed that primary cultured rat microglia express the dopamine (DA) D1 receptor (D1R) and D4R, but not D2R, D3R, or D5R. In response to a D1R-specific agonist SKF-81297 (SKF), the cultured microglia exhibited increased intracellular cAMP levels. DA and SKF suppressed lipopolysaccharide (LPS)-induced expression of interleukin-1ß (IL-1ß) and tumor necrosis α (TNFα) in cultured microglia. Microglia in the normal mature rat prefrontal cortex (PFC) were sorted and significant expression of D1R, D2R, and D4R was observed. A delirium model was established by administering LPS intraperitoneally to mature male Wistar rats. The model also displayed sleep-wake disturbances as revealed by electroencephalogram and electromyogram recordings as well as increased expression of IL-1ß and TNFα in the PFC. DA levels were increased in the PFC 21 h after LPS administration. Increased cytokine expression was observed in sorted microglia from the PFC of the delirium model; however, TNFα, but not IL-1ß expression, was abruptly decreased 21 h after LPS administration in the delirium model, whereas DA levels were increased. A D1R antagonist SCH23390 partially abolished the TNFα expression change. This suggests that endogenous DA may play a role in suppressing neuroinflammation. Administration of the DA precursor L-DOPA or SKF to the delirium model rats inhibited the expression of IL-1ß and TNFα. The simultaneous administration of clozapine, a D4R antagonist, strengthened the suppressive effects of L-DOPA. These results suggest that D1R mediates the suppressive effects of LPS-induced neuroinflammation, in which microglia may play an important role. Agonists for D1R may be effective for treating delirium.

Chloride Intracellular Channel Protein 2 Promotes Microglial Invasion: A Link to Microgliosis in the Parkinson's Disease Brain.

Activated microglia potentially cause neurodegeneration in Parkinson's disease (PD). Matrix metalloproteinase (MMP)-9 plays a crucial role in the pathogenesis of PD, but the modulator of microglial release of MMP-9 remains obscure. Given the modulatory effect of chloride intracellular channel protein 2 (CLIC2) on MMPs, we aimed to determine the role of CLIC2 in regulating microglial MMP expression and activation. We found that CLIC2 is expressed in microglia and neurons in rat brain tissue and focused on the function of CLIC2 in primary cultured microglia. Exposure to recombinant CLIC2 protein enhanced microglial invasion activity, and its knockdown abolished this activity. Moreover, increased activation of MMP-9 was confirmed by the addition of the CLIC2 protein, and CLIC2 knockdown eliminated this activation. Additionally, increased expression of CLIC2 was observed in PD-modeled tissue. In conclusion, CLIC2 increases MMP-9 activity in the microglia, which are involved in PD pathogenesis.

Insomnia and depressive behavior of MyD88-deficient mice: Relationships with altered microglial functions.

Myeloid differentiation primary response gene 88 (MyD88) is essential for microglial activation. Despite the significant role of microglia in regulating sleep homeostasis, the contribution of MyD88 to sleep is yet to be determined. To address this, we performed electroencephalographic and electromyographic recordings on MyD88-KO mice and wild-type mice to investigate their sleep/wake cycles. In the daytime, MyD88-KO mice exhibited prolonged wakefulness and shorter non-rapid eye movement sleep duration. Tail suspension and sucrose preference tests revealed that MyD88-KO mice displayed a depressive-like phenotype. We determined monoamines in the prefrontal cortex (PFC) using high-performance liquid chromatography and observed a decreased content of serotonin in the PFC of MyD88-KO mice. Flow cytometry revealed that CD11b, CD45, and F4/80 expressions were elevated at Zeitgeber time (ZT) 1 compared to at ZT13 only in wild-type mice. Furthermore, MFG-E8 and C1qB-tagged synapses were enhanced at ZT1 in the PFC of wild-type mice but not in MyD88-KO mice. Primary cultured microglia from MyD88-KO mice revealed decreased phagocytic ability. These findings indicate that genetic deletion of MyD88 induces insomnia and depressive behavior, at least in part, by affecting microglial homeostasis functions and lowering the serotonergic neuronal output.