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

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.


Ischemic penumbra (modified by reference 8)The new definition of ischemic penumbra is the transition region from injury to repair (A) and with time course after injury (B).
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Figure 4: Ischemic penumbra (modified by reference 8)The new definition of ischemic penumbra is the transition region from injury to repair (A) and with time course after injury (B).

Mentions: Another new definition of an ischemic penumbra is the region of transition from an injury to repair by various mediators8) (Fig. 4). Interestingly, the factors that are associated with cell death and tissue damage during the acute period might also play roles in tissue recovery in the chronic period. In other words, these mediators have biphasic roles as a harmful and beneficial target in stroke pathophysiology. During the acute phase, most of these targets mediate injury. In contrast, during the recovery phase, the same mediators induce vascular remodeling/angiogenesis and neurogenesis after stroke. New vessels would not be fully matured. Therefore, during this vascular remodeling, vessels are leakier and prone to HT because of vascular unsteadiness46). The modulation of remodeling factors after stroke with tPA treatment might be one of the ideal therapeutic strategies to attenuate HT.


Therapeutic Strategies to Attenuate Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment for Acute Ischemic Stroke
Ischemic penumbra (modified by reference 8)The new definition of ischemic penumbra is the transition region from injury to repair (A) and with time course after injury (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Ischemic penumbra (modified by reference 8)The new definition of ischemic penumbra is the transition region from injury to repair (A) and with time course after injury (B).
Mentions: Another new definition of an ischemic penumbra is the region of transition from an injury to repair by various mediators8) (Fig. 4). Interestingly, the factors that are associated with cell death and tissue damage during the acute period might also play roles in tissue recovery in the chronic period. In other words, these mediators have biphasic roles as a harmful and beneficial target in stroke pathophysiology. During the acute phase, most of these targets mediate injury. In contrast, during the recovery phase, the same mediators induce vascular remodeling/angiogenesis and neurogenesis after stroke. New vessels would not be fully matured. Therefore, during this vascular remodeling, vessels are leakier and prone to HT because of vascular unsteadiness46). The modulation of remodeling factors after stroke with tPA treatment might be one of the ideal therapeutic strategies to attenuate HT.

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.