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Combined neurothrombectomy or thrombolysis with adjunctive delivery of 3K3A-activated protein C in acute ischemic stroke.

Amar AP, Griffin JH, Zlokovic BV - Front Cell Neurosci (2015)

Bottom Line: In the treatment of acute ischemic stroke (AIS), vessel recanalization correlates with improved functional status and reduced mortality.Mechanical neurothrombectomy achieves a higher likelihood of revascularization than intravenous thrombolysis (IVT), but there remains significant discrepancy between rates of recanalization and rates of favorable outcome.Activated protein C (APC) exerts pleiotropic anti-inflammatory, anti-apoptotic, antithrombotic, cytoprotective, and neuroregenerative effects in stroke and appears a compelling candidate for this novel approach.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Keck School of Medicine of the University of Southern California, University of Southern California Los Angeles, CA, USA.

ABSTRACT
In the treatment of acute ischemic stroke (AIS), vessel recanalization correlates with improved functional status and reduced mortality. Mechanical neurothrombectomy achieves a higher likelihood of revascularization than intravenous thrombolysis (IVT), but there remains significant discrepancy between rates of recanalization and rates of favorable outcome. The poor neurological recovery among some stroke patients despite successful recanalization confirms the need for adjuvant therapy, such as pharmacological neuroprotection. Prior clinical trials of neuroprotectant drugs failed perhaps due to inability of the agent to reach the ischemic tissue beyond the occluded artery. A protocol that couples mechanical neurothrombectomy with concurrent delivery of a neuroprotectant overcomes this pitfall. Activated protein C (APC) exerts pleiotropic anti-inflammatory, anti-apoptotic, antithrombotic, cytoprotective, and neuroregenerative effects in stroke and appears a compelling candidate for this novel approach.

No MeSH data available.


Related in: MedlinePlus

Neuroprotective direct effects of APC on cells involves receptors endothelial protein C receptor (EPCR) and PAR-1. The cellular receptors EPCR and PAR1 are required for APC’s beneficial effects on many types of brain cells. These activities include APC-mediated anti-apoptotic activities, anti-inflammatory activities, protection of endothelial barrier functions, and alterations of gene expression profiles. One or more of these activities plus other yet to be defined signaling actions are required for APC’s multiple neuroprotective activities (Zlokovic and Griffin, 2011). This paradigm in which EPCR-bound APC activates PAR-1 to initiate biased signaling (Griffin et al., 2015) is supported by many in vitro and in vivo data (Zlokovic and Griffin, 2011; Griffin et al., 2015). Localization of APC signaling in the caveolin-1 rich microdomains (caveolae) may help differentiate mechanisms for cytoprotective APC signaling vs. proinflammatory thrombin signaling (Zlokovic and Griffin, 2011; Griffin et al., 2015). Additional mechanisms for APC effects on cells may also involve other receptors, such as PAR-3, sphingosine-1-phosphate receptor 1, apolipoprotein E Receptor 2, and/or Mac1 (CD11b/CD18). For example, the beneficial actions of APC or 3K3A-APC on middle cerebral artery occlusion (MCAO) injury required PAR-1, EPCR, and PAR-3 (Cheng et al., 2003, 2006; Guo et al., 2004, 2013; Thiyagarajan et al., 2008; Gorbacheva et al., 2010; Petraglia et al., 2010; Zlokovic and Griffin, 2011) and stimulation of development of neurons within human neuroprogenitor cell populations required PAR-1, PAR-3, and sphingosine-1-phosphate receptor 1 (Guo et al., 2013).
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Figure 1: Neuroprotective direct effects of APC on cells involves receptors endothelial protein C receptor (EPCR) and PAR-1. The cellular receptors EPCR and PAR1 are required for APC’s beneficial effects on many types of brain cells. These activities include APC-mediated anti-apoptotic activities, anti-inflammatory activities, protection of endothelial barrier functions, and alterations of gene expression profiles. One or more of these activities plus other yet to be defined signaling actions are required for APC’s multiple neuroprotective activities (Zlokovic and Griffin, 2011). This paradigm in which EPCR-bound APC activates PAR-1 to initiate biased signaling (Griffin et al., 2015) is supported by many in vitro and in vivo data (Zlokovic and Griffin, 2011; Griffin et al., 2015). Localization of APC signaling in the caveolin-1 rich microdomains (caveolae) may help differentiate mechanisms for cytoprotective APC signaling vs. proinflammatory thrombin signaling (Zlokovic and Griffin, 2011; Griffin et al., 2015). Additional mechanisms for APC effects on cells may also involve other receptors, such as PAR-3, sphingosine-1-phosphate receptor 1, apolipoprotein E Receptor 2, and/or Mac1 (CD11b/CD18). For example, the beneficial actions of APC or 3K3A-APC on middle cerebral artery occlusion (MCAO) injury required PAR-1, EPCR, and PAR-3 (Cheng et al., 2003, 2006; Guo et al., 2004, 2013; Thiyagarajan et al., 2008; Gorbacheva et al., 2010; Petraglia et al., 2010; Zlokovic and Griffin, 2011) and stimulation of development of neurons within human neuroprogenitor cell populations required PAR-1, PAR-3, and sphingosine-1-phosphate receptor 1 (Guo et al., 2013).

Mentions: EPCR-bound APC activates a family of G-protein coupled protease-activated receptors (PARs), including PAR1 (Domotor et al., 2003). The latter can also be activated by thrombin, but each ligand triggers divergent intracellular signaling cascades (biased agonism; Griffin et al., 2015). Whereas thrombin-mediated activation of PAR 1 leads to disruption of the BBB, vascular leakage, neurotoxicity, apoptosis, and neuroinflammation, APC-mediated activation of PAR1 produces the opposite effects. APC-induced biased signaling following PAR-1 activation is required for neuroprotective actions of APC (see Figure 1). These multiple downstream effects of APC have been reviewed elsewhere (Griffin et al., 2002, 2015; Zlokovic and Griffin, 2011) and are summarized below.


Combined neurothrombectomy or thrombolysis with adjunctive delivery of 3K3A-activated protein C in acute ischemic stroke.

Amar AP, Griffin JH, Zlokovic BV - Front Cell Neurosci (2015)

Neuroprotective direct effects of APC on cells involves receptors endothelial protein C receptor (EPCR) and PAR-1. The cellular receptors EPCR and PAR1 are required for APC’s beneficial effects on many types of brain cells. These activities include APC-mediated anti-apoptotic activities, anti-inflammatory activities, protection of endothelial barrier functions, and alterations of gene expression profiles. One or more of these activities plus other yet to be defined signaling actions are required for APC’s multiple neuroprotective activities (Zlokovic and Griffin, 2011). This paradigm in which EPCR-bound APC activates PAR-1 to initiate biased signaling (Griffin et al., 2015) is supported by many in vitro and in vivo data (Zlokovic and Griffin, 2011; Griffin et al., 2015). Localization of APC signaling in the caveolin-1 rich microdomains (caveolae) may help differentiate mechanisms for cytoprotective APC signaling vs. proinflammatory thrombin signaling (Zlokovic and Griffin, 2011; Griffin et al., 2015). Additional mechanisms for APC effects on cells may also involve other receptors, such as PAR-3, sphingosine-1-phosphate receptor 1, apolipoprotein E Receptor 2, and/or Mac1 (CD11b/CD18). For example, the beneficial actions of APC or 3K3A-APC on middle cerebral artery occlusion (MCAO) injury required PAR-1, EPCR, and PAR-3 (Cheng et al., 2003, 2006; Guo et al., 2004, 2013; Thiyagarajan et al., 2008; Gorbacheva et al., 2010; Petraglia et al., 2010; Zlokovic and Griffin, 2011) and stimulation of development of neurons within human neuroprogenitor cell populations required PAR-1, PAR-3, and sphingosine-1-phosphate receptor 1 (Guo et al., 2013).
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Related In: Results  -  Collection

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Figure 1: Neuroprotective direct effects of APC on cells involves receptors endothelial protein C receptor (EPCR) and PAR-1. The cellular receptors EPCR and PAR1 are required for APC’s beneficial effects on many types of brain cells. These activities include APC-mediated anti-apoptotic activities, anti-inflammatory activities, protection of endothelial barrier functions, and alterations of gene expression profiles. One or more of these activities plus other yet to be defined signaling actions are required for APC’s multiple neuroprotective activities (Zlokovic and Griffin, 2011). This paradigm in which EPCR-bound APC activates PAR-1 to initiate biased signaling (Griffin et al., 2015) is supported by many in vitro and in vivo data (Zlokovic and Griffin, 2011; Griffin et al., 2015). Localization of APC signaling in the caveolin-1 rich microdomains (caveolae) may help differentiate mechanisms for cytoprotective APC signaling vs. proinflammatory thrombin signaling (Zlokovic and Griffin, 2011; Griffin et al., 2015). Additional mechanisms for APC effects on cells may also involve other receptors, such as PAR-3, sphingosine-1-phosphate receptor 1, apolipoprotein E Receptor 2, and/or Mac1 (CD11b/CD18). For example, the beneficial actions of APC or 3K3A-APC on middle cerebral artery occlusion (MCAO) injury required PAR-1, EPCR, and PAR-3 (Cheng et al., 2003, 2006; Guo et al., 2004, 2013; Thiyagarajan et al., 2008; Gorbacheva et al., 2010; Petraglia et al., 2010; Zlokovic and Griffin, 2011) and stimulation of development of neurons within human neuroprogenitor cell populations required PAR-1, PAR-3, and sphingosine-1-phosphate receptor 1 (Guo et al., 2013).
Mentions: EPCR-bound APC activates a family of G-protein coupled protease-activated receptors (PARs), including PAR1 (Domotor et al., 2003). The latter can also be activated by thrombin, but each ligand triggers divergent intracellular signaling cascades (biased agonism; Griffin et al., 2015). Whereas thrombin-mediated activation of PAR 1 leads to disruption of the BBB, vascular leakage, neurotoxicity, apoptosis, and neuroinflammation, APC-mediated activation of PAR1 produces the opposite effects. APC-induced biased signaling following PAR-1 activation is required for neuroprotective actions of APC (see Figure 1). These multiple downstream effects of APC have been reviewed elsewhere (Griffin et al., 2002, 2015; Zlokovic and Griffin, 2011) and are summarized below.

Bottom Line: In the treatment of acute ischemic stroke (AIS), vessel recanalization correlates with improved functional status and reduced mortality.Mechanical neurothrombectomy achieves a higher likelihood of revascularization than intravenous thrombolysis (IVT), but there remains significant discrepancy between rates of recanalization and rates of favorable outcome.Activated protein C (APC) exerts pleiotropic anti-inflammatory, anti-apoptotic, antithrombotic, cytoprotective, and neuroregenerative effects in stroke and appears a compelling candidate for this novel approach.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Keck School of Medicine of the University of Southern California, University of Southern California Los Angeles, CA, USA.

ABSTRACT
In the treatment of acute ischemic stroke (AIS), vessel recanalization correlates with improved functional status and reduced mortality. Mechanical neurothrombectomy achieves a higher likelihood of revascularization than intravenous thrombolysis (IVT), but there remains significant discrepancy between rates of recanalization and rates of favorable outcome. The poor neurological recovery among some stroke patients despite successful recanalization confirms the need for adjuvant therapy, such as pharmacological neuroprotection. Prior clinical trials of neuroprotectant drugs failed perhaps due to inability of the agent to reach the ischemic tissue beyond the occluded artery. A protocol that couples mechanical neurothrombectomy with concurrent delivery of a neuroprotectant overcomes this pitfall. Activated protein C (APC) exerts pleiotropic anti-inflammatory, anti-apoptotic, antithrombotic, cytoprotective, and neuroregenerative effects in stroke and appears a compelling candidate for this novel approach.

No MeSH data available.


Related in: MedlinePlus