Mast Cell Blocking Reduces Brain Edema and Hematoma Volume and Improves Outcome after Experimental Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is associated with high mortality and disability, and there is no widely approved clinical therapy. Poor outcome after ICH results mostly from a mass effect owing to enlargement of the hematoma and brain swelling, leading to displacement and disruption of brain structures. Cerebral mast cells (MC) are resident inflammatory cells that are located perivascularly and contain potent vasoactive, proteolytic, and fibrinolytic substances. We previously found pharmacological MC stabilization and genetic MC deficiency to be associated with up to 50% reduction of postischemic brain swelling in rats. Here, we studied the role of MC and MC stabilization in ICH using in vivo magnetic resonance imaging and ex vivo digital imaging for calculating brain edema and hematoma volume. In a rat ICH model of autologous blood injection into the basal ganglia, four groups of Wistar rats received either saline or sodium cromoglycate (MC stabilizer, two groups) or compound 48/80 (MC degranulator). Evaluated 24 h later, MC stabilization had resulted in highly significantly better neurologic scores (P<0.001), decrease mortality (P=0.002), less brain swelling (P<0.001), and smaller hematoma volume growth (P<0.001) compared with saline and compound 48/80. Moreover, to support our hypothesis, we induced ICH in MC-deficient rats and their wild-type littermates (WT). MC-deficient rats responded with significantly better neurologic scores (P<0.001), decrease mortality (0% versus 25%), less brain swelling (P<0.05), and smaller hematoma growth (P<0.05) than WT. The role of MC deserves a close evaluation as a potential target in the development of novel forms of ICH therapy.

Mast Cell Stabilization Reduces Hemorrhage Formation and Mortality After Administration of Thrombolytics in Experimental Ischemic Stroke

“…13 These findings, together with the characteristic perivascular location of MCs, the ability of their proteases to degrade the basement membrane proteins such as fibronectin, 14 -16 and our observation of colocalization of MCs and HF, led us to hypothesize that MCs might be involved in hazardous tPA-mediated cerebral bleedings after stroke. tPA led to robust MC degranulation in vitro.…”

“…This agrees with our recent findings that MCs regulate ischemic brain swelling 12 and intracerebral hemorrhage-related edema. 13 tPA did not reduce the lesion size, as we focused on the untoward postreperfusion effects of tPA rather than therapeutic recanalization. This led us to use a nylon thread model with controlled reperfusion and not a blood clot model, which requires further examination of the efficacy of the present drug combination.…”

Mast cells inhibit intramacrophageFrancisella tularensisreplication via contact and secreted products including IL-4

“…To evaluate the role of contact-dependent mechanisms versus secreted mast cell products, we treated LVS-challenged WT mice with disodium cromoglycate (DSCG; 10 g/g body weight) to stabilize mast cell membranes (30)(31)(32). DSCG-treated mice demonstrated a significantly greater loss of body weight compared with mock (PBS)-treated mice early after pulmonary LVS challenge (3,000 cfu), but progressed to regain the initial body weight by day 14 (Fig.…”

MRI of the Perihemorrhagic Zone in a Rat ICH Model: Effect of Hematoma Evacuation

“…Therapeutic interventions other than hematoma evacuation may influence outcome in ICH. Different experiments showed that thrombin, NMDA-receptor antagonists, G-CSF and mast cells may play key roles for the functional and morphological recovery and thereby are interesting substrates for further study [24,[29][30][31].…”