Warfarin Pretreatment Reduces Cell Death and MMP-9 Activity in Experimental Intracerebral Hemorrhage

Abstract

Little is known about the pathophysiology of oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH). We compared hematoma volume, number of terminal deoxynucleotidyl dUTP nick-end labeling (TUNEL)-positive cells (indicating cell death), MMP-9 levels, and perilesional edema formation between warfarin-treated mice and controls. Intracerebral hemorrhage was induced by an injection of collagenase into the right striatum. Twenty-four hours later, hematoma volume was measured using a photometric hemoglobin assay. Cell death was quantified using TUNEL staining. MMP-9 levels were determined by zymography, and edema formation was assessed via the wet-dry method. Warfarin increased hematoma volume by 2.6-fold. The absolute number of TUNEL-positive cells in the perihematomal zone was lower in warfarin-treated animals (300.5 ± 39.8 cells/mm2) than in controls (430.5 ± 38.9 cells/mm2; p = 0.034), despite the larger bleeding volume. MMP-9 levels were reduced in anticoagulated mice as compared to controls (p = 0.018). Perilesional edema formation was absent in warfarin mice and modestly present in controls. Our results suggest differences in the pathophysiology of OAC-ICH compared to intracerebral hemorrhage occurring under normal coagulation. A likely explanation is that thrombin, a strong inductor of apoptotic cell death and blood-brain barrier disruption, is produced to a lesser extent in OAC-ICH. In humans, however, we assume that the detrimental effects of a larger hematoma volume in OAC-ICH by far outweigh potential protective effects of thrombin deficiency.

Neuroprotective effect of hyperbaric oxygen therapy in a juvenile rat model of repetitive mild traumatic brain injury

“…These findings are consistent to the previous study of ours and the others in adult rats (Huang et al, 2013;Yang et al, 2015). Among a collection of therapeutic strategies against neurological diseases (Dock et al, 2015;Li et al, 2015;Lioutas et al, 2015;Merali et al, 2015;Ploughman et al, 2015;Qi et al, 2015;Reuter et al, 2015;Schlunk et al, 2015;Soliman et al, 2015;Zhu et al, 2015), medical gas regimens have been extensively explored with the advantage of administration feasibility (Harch, 2015;Herrera et al, 2015;Hu et al, 2015;Ichihara et al, 2015;Langston and Toombs, 2015;Miller et al, 2015;Parra et al, 2015;Stoller, 2015;Weaver and Liu, 2015;Yan et al, 2015). Emerging evidence has shown HBO induces neuroprotection against a variety of neurological disorders including severe TBI (Huang and Obenaus, 2011).…”

Dimethyl fumarate confers neuroprotection by casein kinase 2 phosphorylation of Nrf2 in murine intracerebral hemorrhage

“…Hematoma volume can be an independent predictor of outcome, and as such, can greatly affect other consequences of ICH, including blood brain barrier integrity and brain water content. 38,39 To test whether Dimethyl fumarate was improving other indices after ICH by reducing hematoma volume, we measured hemorrhage volumes in Dimethyl fumarate and vehicle treated groups using the hemoglobin assay. We found no significant difference in hemorrhage volumes between the two groups.…”

Intracerebral Hemorrhage: Perihemorrhagic Edema and Secondary Hematoma Expansion: From Bench Work to Ongoing Controversies

“…OAC-related hematoma enlargement occurred in the first 3 h of ICH onset (132). Interestingly, warfarin also reduced the cell death and MMP-9 levels; however, HE was out of proportion than this positive effect (133). Warfarin-related HE has been confirmed in several human studies (134–137).…”