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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.

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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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Figure 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.

Mentions: As described above, we have demonstrated that the inhibition of the VEGF signaling pathway and the administration of Ang1 attenuates HT after tPA treatment of ischemic stroke. Although this treatment can enable vascular protection, it cannot reduce the cerebral infarct volume52, 54) because it does not have neuroprotective or anti-inflammatory effects. We suggest that brain protection, which includes vascular protection, neuroprotection, and anti-inflammation, is an ideal therapeutic strategy for ischemic stroke. We identified a target molecule, progranulin (PGRN) (Fig. 6)65). In the central nervous system, PGRN is a growth factor that is thought to play crucial roles in maintaining physiological functions66) because mutations of the PGRN gene cause the familial dementia, TAR DNA binding protein-43 (TDP-43)-positive frontotemporal lobar degeneration67–69). We have reported nuclear the TDP-43 might be involved in neuronal cell death prior to cell death after cerebral ischemia65, 70). We have demonstrated dynamic changes in PGRN expression, including increased levels of PGRN expression in microglia within the ischemic core and in surviving neurons, as well as the induction of PGRN expression in endothelial cells within the ischemic penumbra, in ischemic rats. We have observed that PGRN protects against acute focal cerebral ischemia through brain protection, including neuroprotection that occurs in part by the inhibition of the cytoplasmic redistribution of nuclear TDP-43, suppression of neuroinflammation through anti-inflammatory interleukin-10 in microglia, and attenuation of BBB disruption through the inhibition of VEGF. Finally, intravenously administered recombinant PGRN significantly reduces the volumes of cerebral infarcts and edema, suppresses HT, and improves motor outcomes in thromboembolic rats with delayed tPA treatment65). Several other researchers have also shown the pleiotropic protective effects of PGRN71–73). PGRN might be a novel therapeutic target that provides brain protection.


Therapeutic Strategies to Attenuate Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment for Acute Ischemic Stroke
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.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 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.
Mentions: As described above, we have demonstrated that the inhibition of the VEGF signaling pathway and the administration of Ang1 attenuates HT after tPA treatment of ischemic stroke. Although this treatment can enable vascular protection, it cannot reduce the cerebral infarct volume52, 54) because it does not have neuroprotective or anti-inflammatory effects. We suggest that brain protection, which includes vascular protection, neuroprotection, and anti-inflammation, is an ideal therapeutic strategy for ischemic stroke. We identified a target molecule, progranulin (PGRN) (Fig. 6)65). In the central nervous system, PGRN is a growth factor that is thought to play crucial roles in maintaining physiological functions66) because mutations of the PGRN gene cause the familial dementia, TAR DNA binding protein-43 (TDP-43)-positive frontotemporal lobar degeneration67–69). We have reported nuclear the TDP-43 might be involved in neuronal cell death prior to cell death after cerebral ischemia65, 70). We have demonstrated dynamic changes in PGRN expression, including increased levels of PGRN expression in microglia within the ischemic core and in surviving neurons, as well as the induction of PGRN expression in endothelial cells within the ischemic penumbra, in ischemic rats. We have observed that PGRN protects against acute focal cerebral ischemia through brain protection, including neuroprotection that occurs in part by the inhibition of the cytoplasmic redistribution of nuclear TDP-43, suppression of neuroinflammation through anti-inflammatory interleukin-10 in microglia, and attenuation of BBB disruption through the inhibition of VEGF. Finally, intravenously administered recombinant PGRN significantly reduces the volumes of cerebral infarcts and edema, suppresses HT, and improves motor outcomes in thromboembolic rats with delayed tPA treatment65). Several other researchers have also shown the pleiotropic protective effects of PGRN71–73). PGRN might be a novel therapeutic target that provides brain protection.

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.


Related in: MedlinePlus