Therapeutic Strategies to Attenuate Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment for Acute Ischemic Stroke - PubMed (original) (raw)

Review

. 2017 Mar 1;24(3):240-253.

doi: 10.5551/jat.RV16006. Epub 2016 Dec 13.

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Review

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

Masato Kanazawa et al. J Atheroscler Thromb. 2017.

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.

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Conflict of interest statement

TS is an academic adviser of the ShimoJani LLC biotech company.

Figures

Fig. 1.

Fig. 1.

Mechanisms of intracerebral hemorrhagic transformation after tPA treatment and therapeutic targets BBB, blood-brain barrier; MMP, matrix metalloproteinase; ROS, reactive oxygen species; tPA, tissue plasminogen activator

Fig. 2.

Fig. 2.

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

Fig. 3.

Fig. 3.

The schema of protease-mediated BBB disruption BBB, blood-brain barrier; ECM, extracellular matrix; MMP, matrix metalloproteinase; tPA, tissue plasminogen activator

Fig. 4.

Fig. 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).

Fig. 5.

Fig. 5.

VEGF signaling cascade and anti-VEGF therapy (quoted from reference 57) After cerebral ischemia, vascular endothelial growth factor (VEGF) is expressed in the microvascular wall, and receptors that are conjugated to VEGF as a ligand are phosphorylated and activated. The subsequent activation of matrix metalloproteinase-9 (MMP-9) and degradation of protein components of the basal lamina cause intracerebral hemorrhage. The VEGF signaling cascade is inhibited by the anti-VEGF antibody that neutralizes VEGF and VEGF receptor inhibitors that inhibit VEGF receptors from being phosphorylated. BBB, blood-brain barrier.

Fig. 6.

Fig. 6.

The pleiotropic effects of the brain protective target progranulin (PGRN) The growth factor PGRN could protect against acute focal cerebral ischemia through a variety of mechanisms, which we call brain protection. The nuclear protein TAR DNA binding protein-43 (TDP-43) is localized in the nucleus. However, cytoplasmic redistribution of TDP-43 occurs after ischemia. Intravenously administered recombinant PGRN significantly reduced the cerebral infarct and edema volumes, suppressed hemorrhagic transformation, and improved motor outcome in thromboembolic rats with delayed tissue plasminogen activator (tPA) treatment because of neuroprotection that occurred in part through the inhibition of the cytoplasmic redistribution of TDP-43, suppression of neuroinflammation through anti-inflammatory interleukin-10 (IL-10) in microglia, and attenuation of BBB disruption through the vascular endothelial growth factor (VEGF). PGRN might be a novel therapeutic target that provides brain protection through processes, such as vascular protection, anti-neuroinflammation, and neuroprotection.

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