The role of endogenous versus exogenous tPA on edema formation in murine ICH

Thiex, Ruth; Mayfrank, L.; Rohde, Veit; Gilsbach, Joachim M.; Tsirka, Styliani-Anna E.

doi:10.1016/j.expneurol.2004.05.021

Cited by 37 publications

(26 citation statements)

References 23 publications

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“…plasminogen activator appears to be associated with microglial activation subsequent to the induction of ICH, eventually culminating in BBB breakdown and brain edema (Thiex et al, 2004). Thus, this cascade of reactions, which involves glutamate, NMDAR, and tPA, constitutes a vicious cycle which culminates in catastrophic neurotoxicity (Liu et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Memantine Reduces Hematoma Expansion in Experimental Intracerebral Hemorrhage, Resulting in Functional Improvement

Lee

Chu

Jung

et al. 2006

J Cereb Blood Flow Metab

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Glutamate is accumulated in abundance during the early period of experimental hematoma, and the activation of N-methyl-D-aspartate (NMDA) receptors by glutamate can result in an influx of calcium and neuronal death in cases of intracerebral hemorrhage (ICH). Memantine, which is known to be a moderate-affinity, uncompetitive, NMDA receptor antagonist, was investigated with regard to its ability to block the glutamate overstimulation and tissue plasminogen activator (tPA)/urokinase plasminogen activator (uPA)/matrix metalloproteinase (MMP)-9 modulation in experimental ICH. Intracerebral hemorrhage was induced via the infusion of collagenase into the left basal ganglia of adult rats. Either memantine (20 mg/kg/day) or PBS was intraperitoneally administered 30 min after the induction of ICH, and, at daily intervals afterwards, for either 3 or 14 days. Hemorrhage volume decreased by 47% in the memantine group, as compared with the ICH-only group. In the memantine group, the numbers of TUNEL + , myeloperoxidase (MPO) + , and OX42 + cells decreased in the periphery of the hematoma. Memantine resulted in an upregulation of bcl-2 expression and an inhibition of caspase-3 activation. Memantine also exerted a profound inhibitory effect on the upregulation of tPA/uPA mRNA, and finally decreased the MMP-9 level in the hemorrhagic brain. In modified limb-placing test, the memantine-treated rats exhibited lower scores initially, and recovered more quickly and thoroughly throughout the 35 days of the study. Here, we show that memantine causes a reduction of hematoma expansion, coupled with an inhibitory effect on the tPA/ uPA and MMP-9 level. Subsequently, memantine was found to reduce inflammatory infiltration and apoptosis, and was also determined to induce functional recovery after ICH.

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Section: Discussionmentioning

confidence: 99%

Memantine Reduces Hematoma Expansion in Experimental Intracerebral Hemorrhage, Resulting in Functional Improvement

Lee

Chu

Jung

et al. 2006

J Cereb Blood Flow Metab

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“…For instance, the clinical significance of cerebral edema remains controversial. Rodent studies have suggested an association between reduced edema volume and improved functional outcome [55,116,117]. However, significant functional recovery can be achieved in the absence of edema reduction, suggesting that absolute edema volume does not independently predict outcome [118].…”

Section: Discussionmentioning

confidence: 99%

Advances in Neuroprotective Strategies: Potential Therapies for Intracerebral Hemorrhage

et al. 2010

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Intracerebral hemorrhage (ICH) is associated with higher mortality and morbidity than any other form of stroke. However, there currently are no treatments proven to improve outcomes after ICH, and therefore, new effective therapies are urgently needed. Growing insight into ICH pathophysiology has led to the development of neuroprotective strategies that aim to improve the outcome through reduction of secondary pathologic processes. Many neuroprotectants target molecules or pathways involved in hematoma degradation, inflammation or apoptosis, and have demonstrated potential clinical benefits in experimental settings. We extensively reviewed the current understanding of ICH pathophysiology as well as promising experimental neuroprotective agents with particular focus on their mechanisms of action. Continued advances in ICH knowledge, increased understanding of neuroprotective mechanisms, and improvement in the ability to modulate molecular and pathologic events with multitargeting agents will lead to successful clinical trials and bench-to-bedside translation of neuroprotective strategies.

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“…Microglia have been implicated as important mediators of cell death in kainate excitotoxicity [130] and, interestingly, tPA functions in a non-proteolytic fashion to activate microglia in the same model [131,132] and to cause monocytes to adhere to sites of inflammation [136]. Administration of tPA directly into sites of intracerebral hemorrhage to aid in the breakdown of the hematoma is accompanied by significant infiltration by inflammatory cells [137] in addition to exacerbating the edema, as mentioned before [116,117]. This could be a result of microglial activation (mediated by tPA) and microglial chemotaxis (mediated by plasmin) followed by inflammatory cell recruitment from the bloodstream or a direct chemotactic effect of plasmin and/or adhesion effect of tPA on circulating monocytes.…”

Section: The Neurotoxicity Of Tpamentioning

confidence: 99%

“…tPA was also found to exacerbate brain edema thus leading to worsening of neurological outcomes in two types of brain injury unrelated to ischemia: brain trauma [115] and intracerebral hemorrhage [116,117]. A potential mechanism to explain the exacerbation of brain edema comes from stroke models and involves the action of tPA on the Blood Brain Barrier (BBB): it was shown that tPA can disrupt the BBB via LRP-mediated signaling to brain vascular endothelial cells.…”

Section: The Neurotoxicity Of Tpamentioning

confidence: 99%

Tissue-type plasminogen activator as a therapeutic target in stroke

Gravanis

Tsirka

2008

Expert Opinion on Therapeutic Targets

119

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Background-Ischemic stroke is a leading cause of morbidity and mortality worldwide and recombinant human tissue-type Plasminogen Activator (tPA) is the prominent among very few therapeutics used in its treatment. Due to complications attributed to the drug, most notably transformation of ischemia to hemorrhage, tPA is used only in a small number of ischemic stroke cases, albeit significantly more often in specialized stroke centers.

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The role of endogenous versus exogenous tPA on edema formation in murine ICH

Cited by 37 publications

References 23 publications

Memantine Reduces Hematoma Expansion in Experimental Intracerebral Hemorrhage, Resulting in Functional Improvement

Memantine Reduces Hematoma Expansion in Experimental Intracerebral Hemorrhage, Resulting in Functional Improvement

Advances in Neuroprotective Strategies: Potential Therapies for Intracerebral Hemorrhage

Tissue-type plasminogen activator as a therapeutic target in stroke

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