Background and Purpose Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced secondary brain injury. Recently, Dopamine D2 receptor (DRD2) is identified an important component controlling innate immunity and inflammatory response in central nervous system and αB-crystallin (CRYAB) is a potent negative regulator on inflammatory pathways. Here, we sought to investigate the role of DRD2 on neuroinflammation after experimental ICH, and the potential mechanism mediated by CRYAB. Methods Two hundred and twenty-four (224) male CD-1 mice were subjected to intrastriatal infusion of bacterial collagenase or autologous blood. Two DRD2 agonists Quinpirole and Ropinirole were administrated by daily intraperitoneal injection starting at 1 hour post-ICH. DRD2 and CRYAB in vivo knockdown was performed 48 hour before ICH insult. Behavioral deficits and brain water content, western blots, immunofluorescence staining, co-immunoprecipitation assay and proteome cytokine array were evaluated. Results Endogenous DRD2 and CRYAB expression were increased after ICH. DRD2 knockdown aggravated the neurobehavioral deficits and the pronounced cytokines expression. DRD2 activation by Quinpirole and Ropinirole ameliorated neurological outcome, brain edema, IL-1β and MCP-1 expression, as well as microglia/macrophages activation in the perihematomal region. These effects were abolished by pretreated with CRYAB siRNAs. Quinpirole enhanced cytoplasmic binding activity between CRYAB and NF-κB, and decreased nuclear NF-κB expression. Similar therapeutic benefits were observed using autologous blood injection model and intranasal delivery of Quinpirole. Conclusions DRD2 may have anti-inflammatory effects after ICH. DRD2 agonists inhibited neuroinflammation and attenuated brain injury after ICH, which is probably mediated by CRYAB and enhanced cytoplasmic binding activity with NF-κB.
Background and Purpose Norrin and its receptor Frizzled 4 have important roles in the blood-brain barrier (BBB) development. This study is to investigate a potential role and mechanism of Norrin/Frizzled 4 on protecting BBB integrity after subarachnoid hemorrhage (SAH). Methods One hundred and seventy-eight male Sprague-Dawley rats were used. SAH model was induced by endovascular perforation. Frizzled 4 small interfering RNA (siRNA) was injected intracerebroventricularly 48 hours before SAH. Norrin was administrated intracerebroventricularly 3 hours after SAH. SAH grade, neurologic scores, brain water content, Evans blue extravasation, western blots and immunofluorescence were employed to study the mechanisms of Norrin and its receptor regulation protein TSPAN12, as well as neurological outcome. Results Endogenous Norrin and TSPAN12 expression were increased after SAH, and Norrin was colocalizated with astrocytes marker GFAP in cortex. Exogenous Norrin treatment significantly alleviated neurobehavioral dysfunction, reduced brain water content and Evans blue extravasation, promoted β-catenin nuclear translocation and increased Occludin, VE-Cadherin and ZO-1 expressions. These effects were abolished by Frizzled 4 siRNA pretreated before SAH. Conclusions Norrin protected BBB integrity and improved neurological outcome after SAH, and the action of Norrin seemed mediated by Frizzled 4 receptor activation which promoted β-catenin nuclear translocation, which then enhanced Occludin, VE-Cadherin and ZO-1 expression. Norrin might have potential to protect BBB after SAH.
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