Time course of upregulation of inflammatory mediators in the hemorrhagic brain in rats: Correlation with brain edema

Abstract

Intracerebral hemorrhage (ICH) can cause secondary brain damage through inflammation-related pathways. Thrombin and one of its receptors, protease activated receptor-1 (PAR-1); matrix metalloproteinase (MMP)-9; and aquaporin (AQP)-4 are stroke-related inflammatory mediators that have been implicated in ICH pathology. To further characterize the inflammatory response after ICH, we studied the temporal profile of the expression of these inflammatory mediators and assessed their potential correlation with brain edema formation after brain hemorrhage in rats. ICH was modeled by infusing autologous blood into the striatum. Then mRNA and protein expression was assessed over the course of 5 days. We found that the mRNA and/or protein expression of thrombin, PAR-1, AQP-4, and MMP-9 was upregulated between 2 h and 5 days after ICH. Each reached a maximal level at day 2, except for AQP-4 protein, which peaked at day 5. Brain water content after ICH presented a similar trend; it was increased at 2 h, peaked at day 2, and then decreased but remained elevated at day 5. Our data provide novel evidence that upregulation of these selected inflammatory mediators occurs very early and persists for several days after ICH, and that temporal patterns of expression of thrombin and AQP-4 are associated with brain edema formation. These findings have important implications for efforts to reduce secondary brain damage after ICH.

Association of Molecular Markers With Perihematomal Edema and Clinical Outcome in Intracerebral Hemorrhage

“…25 In ICH animal models, several studies showed that elevated levels of MMP-9 lead to BBB breakdown and brain edema. [12][13][14][15] It was recently demonstrated that MMP-9 and MMP-3 jointly contributed to blood-induced lesions and neuronal cell death. 16,17 In previous clinical studies, MMP-9 levels significantly correlated with PHE volume in the first 24 hours after symptom onset.…”

“…[4][5][6][7] Matrix metalloproteinase (MMP)-3 and MMP-9, [8][9][10] as well as growth factors (GFs) such as vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1), 11 are expressed in abnormally high concentrations in brain and peripheral blood in ICH patients. In ICH animal models, elevated MMP-9 and MMP-3 contribute to blood-brain barrier (BBB) disruption, 12,13 brain edema, 14,15 and neuronal cell death. 16,17 Other animal models of ICH and brain injury showed that alteration of VEGF and Ang-1 was related to increased BBB permeability and brain edema.…”

Hematology and Inflammatory Signaling of Intracerebral Hemorrhage

“…18 Thrombin and proteinase-activated receptor-1 are upregulated starting at 3 hours and peaking 2 days after ICH in animal models. 25 Therapeutically, it may be possible to separate the beneficial and adverse effects of thrombin because they occur in different compartments and during different time frames or have different mechanisms. The beneficial effects of thrombin occur relatively soon after hemorrhage and are mostly vascular.…”

Effects of thrombin on the secondary cerebral injury of perihematomal tissues of rats after intracerebral hemorrhage

“…Previous studies (Sharp et al, 2008;Wu et al, 2010) suggest that thrombin can cause a secondary injury by recruiting inflammatory cells to form an excessive inflammatory reaction. In the early inflammatory reaction, there are two major cellular components: the peripheral blood-derived exogenous neutrophilic granulocytes and neutrophils and the central nervous tissue-derived endogenous microglia.…”