Macrophage stimulating protein preserves blood brain barrier integrity after intracerebral hemorrhage through recepteur d'origine nantais dependent GAB1/Src/ß-catenin pathway activation in a mouse model.

Blood brain barrier (BBB) disruption is an important contributor to brain edema and neurological deficits following intracerebral hemorrhage (ICH). Macrophage stimulating protein (MSP) is a hepatocyte growth factor-like protein that mediates its functions via activating receptor tyrosine kinase recepteur d'origine nantais (RON). Grb2-associated binder 1 (GAB1) is a docking protein that mediates downstream receptor signal transduction pathways. This study aimed to evaluate the role of MSP and RON activated signaling pathway in preserving BBB integrity after collagenase-induced ICH. ICH mice received recombinant human MSP (rhMSP) or rhMSP combined with siRNA knockdown of RON or GAB1. rhMSP was administered by intranasal route 1 h after ICH. Brain edema, neurobehavior, BBB tight junction protein expression, and BBB permeability were evaluated. The expression of endogenous MSP and p-RON was decreased after ICH. Exogenous rhMSP administration reduced brain edema, neurological deficits, BBB permeability, and increased the expression of tight junction proteins in ICH mice. rhMSP administration increased the expression of p-RON, p-GAB1, p-Src, nuclear ß-catenin, and tight junction proteins after ICH. These effects were reversed with RON and GAB1 siRNA. We conclude that MSP activation of RON preserved BBB integrity via GAB-1/Src/ß-catenin pathway, thereby reducing brain edema and neurological deficits after ICH in mice.

Protective effects of urinary trypsin inhibitor on vascular permeability following subarachnoid hemorrhage in a rat model.

AIMS: Inflammation and apoptosis play important roles in increasing vascular permeability following subarachnoid hemorrhage (SAH). The objective of this study was to evaluate whether urinary trypsin inhibitor (UTI), a serine protease inhibitor, attenuates vascular permeability by its antiinflammatory and antiapoptotic effects after experimental SAH. METHODS: Subarachnoid hemorrhage models were established in adult male Sprague-Dawley rats by endovascular perforation. UTI was administered by intraperitoneal injection immediately following SAH. Brain edema was assessed by magnetic resonance imaging (MRI) at 24 h after SAH. Neurological deficits, brain water content, vascular permeability, malondialdehyde (MDA) concentration, and myeloperoxidase (MPO) activity were evaluated. Immunohistochemical staining and Western blot were used to explore the underlying protective mechanism of UTI. RESULTS: Urinary trypsin inhibitor 50,000 U/kg significantly attenuated brain edema and neurological deficits and reduced vascular permeability at 24 h after SAH. MDA concentration and MPO activity in hippocampus were significantly decreased with UTI treatment. Furthermore, the levels of phosphorylated JNK, NF-κB (p65), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and proapoptotic protein p53, caspase-3 were elevated in the microvascular endothelial cells of the hippocampus after SAH, which were alleviated with UTI treatment. CONCLUSION: Urinary trypsin inhibitor reduced vascular permeability after SAH through its antiinflammatory and antiapptotic effects via blocking the activity of JNK, NF-κB, and p53.