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Background: Mast cells play an important role in early immune reactions in the brain by degranulation and the consequent inflammatory response. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a germinal matrix hemorrhage (GMH) rat model., Methods: One hundred seventy-three P7 rat pups were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 h prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 h and 13 h after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injection. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and toluidine blue staining., Results: Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus (PHH) after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6, and TNF-α. However, knockdown of RXFP1 and PI3K inhibition abolished the protective effects of rh-relaxin-2., Conclusions: Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes, and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

Background : Mast cells (MCs) are perivascularly located immune cells of haematopoietic origin. Emerging evidences suggest that the activation of MCs play important roles in the pathogenesis of blood brain barrier disruption, neuroinflammation, and neurodegeneration. Objectives : In this review, we aimed to discuss the detrimental effects of MCs in response to various types of brain injury, as well as the therapeutic potential and neuroprotective effects of targeting the activation and degranulation of MCs, particularly in the management of the acute phase. Methods : An extensive online literature search was conducted through Pubmed/Central on March 2018. Then, we comprehensively summarized the effects of the activation of brain MCs in acute brain injury along with current pharmacological strategies targeting at the activation of MCs. Results : The review of the current literature indicated that the activation and degranulation of brain MCs significantly contribute to the acute pathological process following different types of brain injury including focal and global cerebral ischaemia, intracerebral haemorrhage, subarachnoid haemorrhage, and traumatic brain injury. Conclusions : Brain MCs significantly contribute to the acute pathological processes following brain injury. In that regard, targeting brain MCs may provide a novel strategy for neuroprotection.

Mast cells (MCs) has been recognized as an effector of inflammation or a trigger of inflammatory factors during stroke. LJ529 was reported to attenuate inflammation through a Gi protein-coupled Adenosine A3 receptor (A 3 R) after ischemia. Here, we aim to study the protective effect and its mechanism of LJ529 in subarachnoid hemorrhage (SAH) rat model for mast cell-related inflammation. 155 Sprague–Dawley adult male rats were used in experiments. Endovascular perforation was used for SAH model. Intraperitoneal LJ529 was performed 1 h after SAH. Neurological scores were measured 24 h after SAH. Rotarod and morris water maze tests were evaluated for 21 days after SAH. Mast cell degranulation was assessed with Toluidine blue staining and Chymase/Typtase protein expressions. Mast cell-related inflammation was evaluated using IL-6, TNF-α and MCP-1 protein expressions. MRS1523, inhibitor of GPR18 and ε-V1-2, inhibitor of PKCε were respectively given intraperitoneally (i.p.) 1 h and 30 min before SAH for mechanism studies. Pathway related proteins were investigated with western blot and immunofluorescence staining. Expression of A 3 R, PKCε increased after SAH. LJ529 treatment attenuated mast cell degranulation and inflammation. Meanwhile, both short-term and long-term neurological functions were improved after LJ529 treatment. Administration of LJ529 resulted in increased expressions of A 3 R, PKCε, ALDH2 proteins and decreased expressions of Chymase, Typtase, IL-6, TNF-α and MCP-1 proteins. MRS1523 abolished the treatment effects of LJ529 on neurobehavior and protein levels. ε-V1-2 also reversed the outcomes of LJ529 administration through reduction in protein expressions downstream of PKCε. LJ529 attenuated mast cell-related inflammation through inhibiting degranulation via A3R-PKCε-ALDH2 pathway after SAH. LJ529 may serve as a potential treatment strategy to relieve post-SAH brain injury. Degranulation of mast cells with Chymase, Tryptase, IL-6, TNF-α and MCP-1 release led to inflammation after SAH. With LJ529 administration, Adenosine A3 receptor was activated, and then attenuate mast cell-related inflammation through PKCε and ALDH2. LJ529 treatment pathway was indicated by green arrows (activation) and red arrows (inhibition). [Display omitted] • Adenosine A3 receptor (A3R) agonist LJ529 is proved to play a protective role following early brain injury (EBI) after subarachnoid hemorrhage (SAH). • Mast cell degranulation wildly exists and related to inflammatory cytokines after SAH. • The mechanism of LJ529 treatment attenuating SAH-induced mast cell-related inflammation was associated with A3R-PKCε-ALDH2 pathway. [ABSTRACT FROM AUTHOR]