Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Mikko T. Huuskonen ◽  
Yaoming Wang ◽  
Angeliki Maria Nikolakopoulou ◽  
Axel Montagne ◽  
Zhonghua Dai ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Corpus Callosum ◽  
Functional Outcomes ◽  
Protein C ◽  
Activated Protein C ◽  
Clinical Importance ◽  
Subcortical White Matter ◽  
Stroke Patients ◽  
Protease Activated Receptor 1

Subcortical white matter (WM) stroke accounts for 25% of all strokes and is the second leading cause of dementia. Despite such clinical importance, we still do not have an effective treatment for ischemic WM stroke, and the mechanisms of WM postischemic neuroprotection remain elusive. 3K3A-activated protein C (APC) is a signaling-selective analogue of endogenous blood protease APC that is currently in development as a neuroprotectant for ischemic stroke patients. Here, we show that 3K3A-APC protects WM tracts and oligodendrocytes from ischemic injury in the corpus callosum in middle-aged mice by activating protease-activated receptor 1 (PAR1) and PAR3. We show that PAR1 and PAR3 were also required for 3K3A-APC’s suppression of post–WM stroke microglia and astrocyte responses and overall improvement in neuropathologic and functional outcomes. Our data provide new insights into the neuroprotective APC pathway in the WM and illustrate 3K3A-APC’s potential for treating WM stroke in humans, possibly including multiple WM strokes that result in vascular dementia.

scholarly journals Activated protein C, protease activated receptor 1, and neuroprotection

Blood ◽  
2018 ◽  
Vol 132 (2) ◽  
pp. 159-169 ◽  
Author(s):  
John H. Griffin ◽  
Berislav V. Zlokovic ◽  
Laurent O. Mosnier
Keyword(s):  
Ischemic Stroke ◽  
Cell Signaling ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Single Agent ◽  
Active Form ◽  
Activated Protein C ◽  
Stroke Patients ◽  
Protease Activated Receptor 1

Abstract Protein C is a plasma serine protease zymogen whose active form, activated protein C (APC), exerts potent anticoagulant activity. In addition to its antithrombotic role as a plasma protease, pharmacologic APC is a pleiotropic protease that activates diverse homeostatic cell signaling pathways via multiple receptors on many cells. Engineering of APC by site-directed mutagenesis provided a signaling selective APC mutant with 3 Lys residues replaced by 3 Ala residues, 3K3A-APC, that lacks >90% anticoagulant activity but retains normal cell signaling activities. This 3K3A-APC mutant exerts multiple potent neuroprotective activities, which require the G-protein–coupled receptor, protease activated receptor 1. Potent neuroprotection in murine ischemic stroke models is linked to 3K3A-APC–induced signaling that arises due to APC’s cleavage in protease activated receptor 1 at a noncanonical Arg46 site. This cleavage causes biased signaling that provides a major explanation for APC’s in vivo mechanism of action for neuroprotective activities. 3K3A-APC appeared to be safe in ischemic stroke patients and reduced bleeding in the brain after tissue plasminogen activator therapy in a recent phase 2 clinical trial. Hence, it merits further clinical testing for its efficacy in ischemic stroke patients. Recent studies using human fetal neural stem and progenitor cells show that 3K3A-APC promotes neurogenesis in vitro as well as in vivo in the murine middle cerebral artery occlusion stroke model. These recent advances should encourage translational research centered on signaling selective APC’s for both single-agent therapies and multiagent combination therapies for ischemic stroke and other neuropathologies.

Abstract 102: Reduced Hemorrhagic Transformation and Neurological Worsening with Neuroprotection (3K3A-APC) During Thrombolysis and Thrombectomy

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Kyle Ogami ◽  
Shlee Song ◽  
Patrick Lyden ◽  
Ariana Anderson ◽  
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Hemorrhagic Transformation ◽  
Significant Variable ◽  
Gradient Echo ◽  
Stroke Patients ◽  
Hemorrhagic Infarction ◽  
The Central Nervous System ◽  
Protease Activated Receptor 1

Background: Agonism of protease-activated receptor 1 (PAR1) potently protects neurons and vasculature in the central nervous system during stroke. We evaluated the effects of 3K3A-APC, a recombinant variant of activated protein C active at PAR1, in acute ischemic stroke patients during conventional recanalization with thrombolysis or thrombectomy or both. We hypothesized that 3K3A-APC would reduce post-treatment hemorrhage and symptomatic neurologic deterioration. Methods: Using the NeuroNEXT trial NN104 (RHAPSODY) database, susceptibility weighted and gradient echo images were graded for intracerebral hemorrhage size according to radiographic criteria described in ECASS (Hemorrhagic infarction type 1 and 2 and parenchymal hematoma type 1 and 2) at four time points (0, 7, 30, and 90 days after treatment). Of 110 participants enrolled, 101 had appropriate imaging for analysis. Images were evaluated and graded by two blinded, independent raters with an expert providing consensus reads. Utilizing NIHSS following drug treatment, neurological worsening was defined as an increase in NIHSS ≥ 4 points. We compared placebo versus drug administration using multi-variate regression. Results: Of 101 participants evaluated, those receiving placebo (n=41) were significantly more likely to have hemorrhage at any time compared with those receiving any amount of drug (n=60) (p = 0.04; CI: 1.080 - 7.544; OR = 2.73). Age was found to be the only significant variable leading independently to increased neurological worsening (p = 0.038; CI: 1.015-1.193; OR = 1.086). Conclusion: The neuroprotectant 3K3A-APC showed significant reduction in hemorrhagic transformation when co-administered with conventional recanalization therapy. Further studies are underway for determining the effect of 3K3A-APC on functional outcome.

Prestroke statin use enhances collateralization in acute ischemic stroke patients

2020 ◽  
Vol 38 (4) ◽  
pp. 311-321
Author(s):  
Jiaying Zhu ◽  
Mengmeng Ma ◽  
Jinghuan Fang ◽  
Jiajia Bao ◽  
Shuju Dong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Acute Ischemic Stroke ◽  
Statin Therapy ◽  
Cerebral Artery ◽  
Functional Outcomes ◽  
Collateral Circulation ◽  
Stroke Severity ◽  
Stroke Patients ◽  
Statin Use

Background: Statin therapy has been shown to be effective in the prevention of ischemic stroke. In addition, recent studies have suggested that prior statin therapy could lower the initial stroke severity and improve stroke functional outcomes in the event of stroke. It was speculated that prestroke statin use may enhance collateral circulation and result in favorable functional outcomes. Objective: The aim of the study was to investigate the association of prestroke statin use with leptomeningeal collaterals and to determine the association of prestroke statin use with stroke severity and functional outcome in acute ischemic stroke patients. Methods: We prospectively and consecutively enrolled 239 acute ischemic stroke patients with acute infarction due to occlusion of the middle cerebral artery within 24 h in the neurology department of West China Hospital from May 2011 to April 2017. Computed tomographic angiography (CTA) imaging was performed for all patients to detect middle cerebral artery thrombus; regional leptomeningeal collateral score (rLMCS) was used to assess the degree of collateral circulation; the National Institutes of Health Stroke Scale (NIHSS) was used to measure stroke severity at admission; the modified Rankin scale (mRS) was used to measure outcome at 90 days; and premorbid medications were recorded. Univariate and multivariate analyses were performed. Results: Overall, 239 patients met the inclusion criteria. Fifty-four patients used statins, and 185 did not use statins before stroke onset. Prestroke statin use was independently associated with good collateral circulation (rLMCS > 10) (odds ratio [OR], 4.786; 95% confidence interval [CI], 1.195–19.171; P = 0.027). Prestroke statin use was not independently associated with lower stroke severity (NIHSS score≤14) (OR, 1.955; 95% CI, 0.657–5.816; p = 0.228), but prestroke statin use was independently associated with favorable outcome (mRS score≤2) (OR, 3.868; 95% CI, 1.325–11.289; P = 0.013). Conclusions: Our findings suggest that prestroke statin use was associated with good leptomeningeal collaterals and clinical outcomes in acute ischemic stroke (AIS) patients presenting with occlusion of the middle cerebral artery. However, clinical studies should be conducted to verify this claim.

scholarly journals Association of Ambulatory Blood Pressure and Heart Rate With Advanced White Matter Lesions in Ischemic Stroke Patients

2013 ◽  
Vol 27 (2) ◽  
pp. 177-183 ◽  
Author(s):  
Hyuk Sung Kwon ◽  
Young-Hyo Lim ◽  
Hyun Young Kim ◽  
Hee-Tae Kim ◽  
Hyung-Min Kwon ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Ischemic Stroke ◽  
White Matter ◽  
Ambulatory Blood Pressure ◽  
White Matter Lesions ◽  
Stroke Patients

Abstract MP16: Excessive White Matter Hyperintensity Burden and Functional Outcomes After Acute Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Sungmin Hong ◽  
Anne-katrin Giese ◽  
Markus D Schirmer ◽  
Adrian V Dalca ◽  
Anna Bonkhoff ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Functional Outcomes ◽  
Life Time ◽  
Stroke Recovery ◽  
White Matter Hyperintensity ◽  
Brain Health ◽  
Stroke Outcomes ◽  
The Brain

Objective: Ability of the brain to recover after an acute ischemic stroke (AIS) is linked to the pre-stroke burden of white matter hyperintensity (WMH), a radiographic marker of brain health. We sought to determine the excessive WMH burden in an AIS population and investigate its association with 3-month stroke outcomes. Data: We used 2,435 subjects from the MRI-GENIE study. Three-month functional outcomes of 872 subjects among those subjects were measured by 90-day modified Ranking Scale (mRS). Methods: We automatically quantified WMH volume (WMHv) on FLAIR images and adjusted for a brain volume. We modeled a trend using the factor analysis (FA) log-linear regression using age, sex, atrial fibrillation, diabetes, hypertension, coronary artery disease and smoking as input variables. We categorized three WMH burden groups based on the conditional probability given by the model (LOW: lower 33%, MED: middle 34%, and HIGH: upper 33%). The subgroups were compared with respect to mRS (median and dichotomized odds ratio (OR) (good/poor: mRS 0-2/3-6)). Results: Five FA components out of seven with significant relationship to WMHv (p<0.001) were used for the regression modeling (R 2 =0.359). The HIGH group showed higher median (median=2, IQR=2) mRS score than LOW (median=1, IQR=1) and MED (median=1, IQR=1). The odds (OR) of good AIS outcome for LOW and MED were 1.8 (p=0.0001) and 1.6 (p=0.006) times higher than HIGH, respectively. Conclusion: Once accounted for clinical covariates, the excessive WMHv was associated with worse 3-month stroke outcomes. These data suggest that a life-time of injury to the white matter reflected in WMH is an important factor for stroke recovery and an indicator of the brain health.

scholarly journals Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease-activated receptor-1 and endothelial cell protein C receptor

2003 ◽  
Vol 373 (1) ◽  
pp. 65-70 ◽  
Author(s):  
Laurent O. MOSNIER ◽  
John H. GRIFFIN
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Active Site ◽  
Protein C ◽  
Activated Protein C ◽  
Cell Protein ◽  
Protease Activated Receptor 1 ◽  
Induced Apoptosis ◽  
Apoptotic Effects ◽  
Dose Dependent

In a model of staurosporine-induced apoptosis using EAhy926 endothelial cells, inhibition of apoptosis by activated protein C was dose-dependent and required the enzyme's active site, implicating activated protein C-mediated proteolysis. Consistent with this implication, both protease-activated receptor-1 (PAR-1) and endothelial cell protein C receptor (EPCR) were required for the anti-apoptotic effects of activated protein C.

scholarly journals PAR1 biased signaling is required for activated protein C in vivo benefits in sepsis and stroke

Blood ◽  
2018 ◽  
Vol 131 (11) ◽  
pp. 1163-1171 ◽  
Author(s):  
Ranjeet K. Sinha ◽  
Yaoming Wang ◽  
Zhen Zhao ◽  
Xiao Xu ◽  
Laurent Burnier ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Mechanism Of Action ◽  
Protein C ◽  
Activated Protein C ◽  
Point Mutations ◽  
Key Points ◽  
Biased Signaling ◽  
Lethal Sepsis

Key Points R41Q and R46Q point mutations in PAR1 in mice enabled studies of APC’s in vivo mechanism of action in lethal sepsis and ischemic stroke. APC-biased, PAR1-dependent signaling due to cleavage at R46 in PAR1 is required for APC’s in vivo benefits in sepsis and ischemic stroke.

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