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Therapeutic Strategies to Attenuate Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment for Acute Ischemic Stroke

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ABSTRACT

This review focuses on the mechanisms and emerging concepts of stroke and therapeutic strategies for attenuating hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment for acute ischemic stroke (AIS). The therapeutic time window for tPA treatment has been extended. However, the patients who are eligible for tPA treatment are still <5% of all patients with AIS. The risk of serious or fatal symptomatic hemorrhage increases with delayed initiation of treatment. HT is thought to be caused by 1) ischemia/reperfusion injury; 2) the toxicity of tPA itself; 3) inflammation; and/or 4) remodeling factor-mediated effects. Modulation of these pathophysiologies is the basis of direct therapeutic strategies to attenuate HT after tPA treatment. Several studies have revealed that matrix metalloproteinases and free radicals are potential therapeutic targets. In addition, we have demonstrated that the inhibition of the vascular endothelial growth factor-signaling pathway and supplemental treatment with a recombinant angiopoietin-1 protein might be a promising therapeutic strategy for attenuating HT after tPA treatment through vascular protection. Moreover, single-target therapies could be insufficient for attenuating HT after tPA treatment and improving the therapeutic outcome of patients with AIS. We recently identified progranulin, which is a growth factor and a novel target molecule with multiple therapeutic effects. Progranulin might be a therapeutic target that protects the brain through suppression of vascular remodeling (vascular protection), neuroinflammation, and/or neuronal death (neuroprotection). Clinical trials which evaluate the effects of anti-VEGF drugs or PGRN-based treatment with tPA will be might worthwhile.

No MeSH data available.


The cascade of tPA-induced adverse effectsAPC, activated protein C; LRP, Low-density lipoprotein receptor-related protein; MMP, matrix metalloproteinase; NMDA, N-methyl-D-aspartate; tPA, tissue plasminogen activator
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Figure 2: The cascade of tPA-induced adverse effectsAPC, activated protein C; LRP, Low-density lipoprotein receptor-related protein; MMP, matrix metalloproteinase; NMDA, N-methyl-D-aspartate; tPA, tissue plasminogen activator

Mentions: tPA is thought to cause neuronal damage and be directly involved in BBB disruption (Fig. 2). The results of animal studies have indicated that tPA increases neuronal damage after focal cerebral ischemia that is mediated by glutamatergic receptors by modifying the properties of the N-methyl-D-aspartate (NMDA) receptor20). In addition, tPA potentiates apoptosis in ischemic endothelium by shifting the apoptotic pathways from caspase-9 to caspase-8, which directly activates caspase-321). Activated protein C, which is a serine protease with anticoagulant activity, inhibits tPA-induced caspase-8 induction and caspase-3 activation in endothelium and hemorrhage21, 22). tPA cleaves the low-density lipoprotein receptor-related protein (LRP) in the plasma membrane of astrocytes, which are located around blood vessels, and the cleaved extracellular fragments induce MMP-9 through nuclear factor-κB pathway activation23). In addition, tPA promotes neutrophil degranulation and MMP-9 release24). The administration of tPA results in the degradation of the protein components of the basal lamina and extracellular matrixes by plasmin and MMP-925–27) (Fig. 3). MMP-9 might directly degrade tight junction proteins27, 28). Several mechanisms of tPA-induced BBB disruption have been described. However, no evidence currently exists for direct injury effects of tPA in the degradation of tight junction proteins of the BBB in the acute time frame of the use of tPA because the administration of tPA within a few hours after onset is not clinical evidence of the induction of HT27).


Therapeutic Strategies to Attenuate Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment for Acute Ischemic Stroke
The cascade of tPA-induced adverse effectsAPC, activated protein C; LRP, Low-density lipoprotein receptor-related protein; MMP, matrix metalloproteinase; NMDA, N-methyl-D-aspartate; tPA, tissue plasminogen activator
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383539&req=5

Figure 2: The cascade of tPA-induced adverse effectsAPC, activated protein C; LRP, Low-density lipoprotein receptor-related protein; MMP, matrix metalloproteinase; NMDA, N-methyl-D-aspartate; tPA, tissue plasminogen activator
Mentions: tPA is thought to cause neuronal damage and be directly involved in BBB disruption (Fig. 2). The results of animal studies have indicated that tPA increases neuronal damage after focal cerebral ischemia that is mediated by glutamatergic receptors by modifying the properties of the N-methyl-D-aspartate (NMDA) receptor20). In addition, tPA potentiates apoptosis in ischemic endothelium by shifting the apoptotic pathways from caspase-9 to caspase-8, which directly activates caspase-321). Activated protein C, which is a serine protease with anticoagulant activity, inhibits tPA-induced caspase-8 induction and caspase-3 activation in endothelium and hemorrhage21, 22). tPA cleaves the low-density lipoprotein receptor-related protein (LRP) in the plasma membrane of astrocytes, which are located around blood vessels, and the cleaved extracellular fragments induce MMP-9 through nuclear factor-κB pathway activation23). In addition, tPA promotes neutrophil degranulation and MMP-9 release24). The administration of tPA results in the degradation of the protein components of the basal lamina and extracellular matrixes by plasmin and MMP-925–27) (Fig. 3). MMP-9 might directly degrade tight junction proteins27, 28). Several mechanisms of tPA-induced BBB disruption have been described. However, no evidence currently exists for direct injury effects of tPA in the degradation of tight junction proteins of the BBB in the acute time frame of the use of tPA because the administration of tPA within a few hours after onset is not clinical evidence of the induction of HT27).

View Article: PubMed Central - PubMed

ABSTRACT

This review focuses on the mechanisms and emerging concepts of stroke and therapeutic strategies for attenuating hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment for acute ischemic stroke (AIS). The therapeutic time window for tPA treatment has been extended. However, the patients who are eligible for tPA treatment are still <5% of all patients with AIS. The risk of serious or fatal symptomatic hemorrhage increases with delayed initiation of treatment. HT is thought to be caused by 1) ischemia/reperfusion injury; 2) the toxicity of tPA itself; 3) inflammation; and/or 4) remodeling factor-mediated effects. Modulation of these pathophysiologies is the basis of direct therapeutic strategies to attenuate HT after tPA treatment. Several studies have revealed that matrix metalloproteinases and free radicals are potential therapeutic targets. In addition, we have demonstrated that the inhibition of the vascular endothelial growth factor-signaling pathway and supplemental treatment with a recombinant angiopoietin-1 protein might be a promising therapeutic strategy for attenuating HT after tPA treatment through vascular protection. Moreover, single-target therapies could be insufficient for attenuating HT after tPA treatment and improving the therapeutic outcome of patients with AIS. We recently identified progranulin, which is a growth factor and a novel target molecule with multiple therapeutic effects. Progranulin might be a therapeutic target that protects the brain through suppression of vascular remodeling (vascular protection), neuroinflammation, and/or neuronal death (neuroprotection). Clinical trials which evaluate the effects of anti-VEGF drugs or PGRN-based treatment with tPA will be might worthwhile.

No MeSH data available.