scholarly journals Low-Dose Activated Protein C Suppresses the Development of Cerebral Infarction and Neurological Deficits in Mice

2020 ◽  
Vol 1 (4) ◽  
Author(s):  
Keiko Yamato ◽  
Yukako Nakajo ◽  
Hitomi Yamamoto-Imoto ◽  
Koichi Kokame ◽  
Toshiyuki Miyata ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Protein C ◽  
Low Dose ◽  
Activated Protein C ◽  
Chronic Phase ◽  
Hemorrhagic Transformation ◽  
Neurological Deficits ◽  
High Dose ◽  
Vessel Occlusion ◽  
Significant Attenuation

Abstract BACKGROUND A large prospective study previously reported that a higher plasma level of protein C (PC) was associated with a lower incidence of ischemic stroke. OBJECTIVE To investigate the neuroprotective properties of activated PC (APC) against acute ischemic stroke using the 3-vessel occlusion model. METHODS Male C57BL/6J mice received APC (human APC) at 0.25, 0.5, or 1.0 (low dose) or 2.0, 4.0, or 8.0 mg/kg (high dose). Edaravone (Eda) (1.0, 3.0, or 10 mg/kg, a neuroprotectant approved for use in Japan), albumin (2.0 mg/kg), heparin (100 or 600 U/kg), or saline was used as the control. The drug or control was administered intravenously twice in the initial 24 h or 5 times in 3 d, starting 5 min after the induction of ischemia. RESULTS Low-dose APC significantly reduced lesion volumes, not affecting the depth of ischemia. High-dose APC did not significantly reduce lesion volumes, causing hemorrhagic transformation in some cases. In the chronic phase, lesion volumes were significantly suppressed in the APC or Eda group, and only the APC group showed a significant attenuation of neurological deficits. The protease-activated receptor (PAR)-1 antagonist SCH79797, administered during preischemia, completely abolished APC-induced neuroprotection. The overshoot-like abrupt recovery in regional cerebral blood flow observed in the control in the initial reperfusion phase was significantly suppressed by the APC treatment, indicating that the cerebral autoregulation system, consisting of endothelial cells and blood-brain barrier functions, was preserved. CONCLUSION Low-dose APC, potentially via the PAR-1-dependent anti-inflammatory cascade, protects the brain against ischemic stroke without increasing the risk of hemorrhagic transformation or death.

Activated Protein C, Sepsis, and the Innate Immune Response to Infection

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-43-SCI-43
Author(s):  
Hartmut Weiler ◽  
John H. Griffin
Keyword(s):  
Bone Marrow ◽  
Severe Sepsis ◽  
Protein C ◽  
Second Generation ◽  
Low Dose ◽  
Activated Protein C ◽  
Innate Immune ◽  
Great Promise ◽  
High Dose ◽  
Increased Risk

Abstract Abstract SCI-43 The phase 3 PROWESS clinical trial in 2001 resulted in approval of recombinant human activated protein C (APC) using low-dose, 96 hour infusion therapy to reduce mortality for adult severe sepsis linked to bacterial infection (1). In that trial, APC reduced mortality from 30.8% to 24.7%, an absolute mortality reduction of 6.1% (19.4% relative risk reduction), but this therapy carried a risk of serious bleeding (4.0 vs. 1.5%, p=0.06). Trials of APC therapy for less than severe adult or pediatric sepsis failed to show benefit but confirmed increased risk for serious bleeding. Subsequently, 10 years after the PROWESS trial, the similarly designed large trial (PROWESS SHOCK) (2) failed to document therapeutic efficacy in adult severe sepsis, reporting mortalities of 26.4% vs. 24.2% and, curiously, no increased risk of serious bleeding (1.2 vs. 1.0%, p=0.81). Recombinant APC was thus withdrawn from the market in late 2011. A simple comparison of PROWESS to PROWESS-SHOCK is confounded by significant improvements in ICU standard of care for severe sepsis over a decade. These two trials were notable in being limited to therapy using low-dose APC infusion for four days. The success of PROWESS stimulated major research advances in 2002–2012 for understanding APC's in vitro and in vivo mechanisms of action. In preclinical work, APC is highly effective for sepsis, non-infectious inflammatory disease, ischemic stroke and neurodegenerative disorders. This presentation will review current knowledge about mechanisms for APC's antithrombotic and cellular cytoprotection, about new insights that might help explain the absence of efficacy in PROWESS-SHOCK, and about possible avenues towards translating the benefits of APC seen in preclinical studies to patients. This presentation will discuss the rationale for use of second generation APC variants that may reduce the risk of bleeding while retaining beneficial anti-inflammatory and cytoprotective functions. Recent preclinical animal studies indicate that such second-generation APC variants might widen the time-window of opportunity for successful therapies, including for lethal infections. Remarkably, APC reduces mortality caused by high-dose total body radiation in mice by preserving bone marrow cells (3). This presentation will review cellular and molecular mechanisms by which APC affects the response of bone marrow-derived innate immune cells to stress induced by infection or radiation. This presentation will provide evidence for the existence of a previously unrecognized role of coagulation Factor V as a modifier of the response to sepsis therapy with APC. Based on APC's direct cellular effects, one would speculate that the use of second generation APC variants given in high-dose bolus regimens holds great promise for multiple maladies. Disclosures: Weiler: BloodCenter of Wisconsin: Patents & Royalties.

Abstract WMP81: Low Dose tPA Worsens The Short Term Outcomes After Thromboembolic Stroke In Both Male And Female Diabetic Animals

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
John Paul Valenzuela ◽  
Guangkuo Dong ◽  
Rebecca Ward ◽  
Susan C Fagan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Infarct Size ◽  
Functional Outcome ◽  
Low Dose ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Diabetic Rats ◽  
Embolic Stroke ◽  
Neurological Deficits ◽  
Male And Female

Diabetes worsens stroke outcome and increases the risk of hemorrhagic transformation (HT) after ischemic stroke, especially with tPA treatment. We previously showed that low dose tPA decreased infarct size and improved functional outcome in both male and female control rats with embolic stroke. In the current study, we hypothesized that low dose tPA will also improve the functional recovery after the embolic stroke in both male and female animals with diabetes. Diabetes was induced in age matched male and female Wistar rats with high fat diet and low dose streptozotocin (30 mg/kg, i.p.). Embolic stroke was induced with middle cerebral artery occlusion. The animals were treated with or without tPA (1 mg/kg, i.v.) at 90 min after surgery. Neurological deficits (composite score and adhesive removal test-ART), infarct size, edema ratio, and HT index were assessed 3 days after surgery. The blood flow has increased in the tPA treated animals in the first 1 to 1.5 hr after treatment. The infarct size and edema was not significantly different in untreated animals, but HT was greater in female diabetic rats. The tPA treatment worsened HT in both genders with no change in infarct size. Decline in ART was worsened with tPA treatment in both sexes. Our data suggest that the low dose tPA after ischemic stroke has detrimental effects on the cerebrovascular recovery and functional outcome in both male and female animals with diabetes.

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.

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.

Abstract WMP17: Computerized Tomography Perfusion to Characterize Lack of Clinical Improvement After Recanalization in Acute Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Alvaro Garcia-Tornel ◽  
Marta Olive-Gadea ◽  
Marc Ribo ◽  
David Rodriguez-Luna ◽  
Jorge Pagola ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Infarct Volume ◽  
Significant Proportion ◽  
Hemorrhagic Transformation ◽  
Vessel Occlusion ◽  
Clinical Recovery ◽  
Good Functional Outcome ◽  
Significant Difference

A significant proportion of patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy (EVT) present poor functional outcome despite recanalization. We aim to investigate computed tomography perfusion (CTP) patterns after EVT and their association with outcome Methods: Prospective study of anterior large vessel occlusion AIS patients who achieved complete recanalization (defined as modified Thrombolysis in Cerebral Ischemia (TICI) 2b - 3) after EVT. CTP was performed within 30 minutes post-EVT recanalization (POST-CTP): hypoperfusion was defined as volume of time to maximal arrival of contrast (Tmax) delay ≥6 seconds in the affected territory. Hyperperfusion was defined as visual increase in cerebral blood flow (CBF) and volume (CBV) with advanced Tmax compared with the unaffected hemisphere. Dramatic clinical recovery (DCR) was defined as a decrease of ≥8 points in NIHSS score at 24h or NIHSS≤2 and good functional outcome by mRS ≤2 at 3 months. Results: One-hundred and forty-one patients were included. 49 (34.7%) patients did not have any perfusion abnormality on POST-CTP, 60 (42.5%) showed hypoperfusion (median volume Tmax≥6s 17.5cc, IQR 6-45cc) and 32 (22.8%) hyperperfusion. DCR appeared in 56% of patients and good functional outcome in 55.3%. Post-EVT hypoperfusion was related with worse final TICI, and associated worse early clinical evolution, larger final infarct volume (p<0.01 for all) and was an independent predictor of functional outcome (OR 0.98, CI 0.97-0.99, p=0.01). Furthermore, POST-CTP identified patients with delayed improvement: in patients without DCR (n=62, 44%), there was a significant difference in post-EVT hypoperfusion volume according to functional outcome (hypoperfusion volume of 2cc in good outcome vs 11cc in poor outcome, OR 0.97 CI 0.93-0.99, p=0.04), adjusted by confounding factors. Hyperperfusion was not associated with worse outcome (p=0.45) nor symptomatic hemorrhagic transformation (p=0.55). Conclusion: Hypoperfusion volume after EVT is an accurate predictor of functional outcome. In patients without dramatic clinical recovery, hypoperfusion predicts good functional outcome and defines a “stunned-brain” pattern. POST-CTP may help to select EVT patients for additional therapies.

Abstract T P26: Combining Clinical and Imaging Data to Develop a Highly Predictive Model of Outcomes in the MR RESCUE Trial

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Chelsea S Kidwell ◽  
Reza Jahan ◽  
Jeffrey Gornbein ◽  
Jeffry R Alger ◽  
Val Nenov ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Infarct Volume ◽  
Patient Characteristics ◽  
Hemorrhagic Transformation ◽  
Imaging Data ◽  
Vascular Events ◽  
Vessel Occlusion ◽  
Intermediate Variables ◽  
Core Volume

Background: Identifying patient characteristics that predict outcomes in acute ischemic stroke may assist in triaging those who are candidates for endovascular therapies. We sought to identify predictors of outcome in the overall Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) cohort and compare results to the previously validated Totaled Health Risks in Vascular Events (THRIVE) score. Methods: MR RESCUE randomized 118 acute ischemic stroke patients with multimodal imaging to embolectomy or standard care within 8 hours of onset. For this analysis, we investigated 17 baseline variables (e.g. age, predicted core volume, time to enrollment) and 8 intermediate variables (e.g. hemorrhagic transformation, day 7 recanalization, final infarct volume) with the potential to impact outcomes (day 90 mRS). The baseline variables were analyzed employing bivariate and multivariate methods (random forest and logistic regression). Two models were developed, one including only significant baseline variables, and the second also incorporating significant intermediate variables. Results: A multivariate model (Table) employing only baseline covariates achieved an overall accuracy (C statistic) of 85% in predicting poor outcome (day 90 mRS 3-6) compared to 80.5% for the THRIVE score. A second model (Table) adding significant intermediate variables achieved 89% accuracy in predicting day 90 mRS. Conclusions: In the MR RESCUE trial, advanced imaging variables, including predicted core volume and site of vessel occlusion, contributed to a highly accurate multivariable model of outcome. In the development phase, this model achieved higher accuracy than the THRIVE score. Future studies are needed to validate this model in an independent cohort.

Abstract WP291: Diabetes Impairs Long-term Functional Recovery in an Embolic Stroke Model in Sex Independent Manner

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
Sherif Hafez ◽  
John Paul Valenzuela ◽  
Rebecca Ward ◽  
Guangkuo Dong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Hemorrhagic Transformation ◽  
Cognitive Outcome ◽  
Embolic Stroke ◽  
Neurological Deficits ◽  
Independent Manner ◽  
Male And Female ◽  
The Impact

Ischemic stroke is a leading cause of death and disability. Diabetes not only increases the risk of stroke, it also worsens the outcomes, increases the risk of hemorrhagic transformation (HT) and impairs recovery after stroke. It is well established that young females are more protected and show better outcomes than males after stroke. However, the impact of diabetes on long term recovery after stroke in both sexes was not clear. Accordingly, this study tested the hypothesis that diabetes impairs long term functional recovery after ischemic stroke in a sex independent manner. Methods: Diabetes was induced in male and female Wistar rats using high fat diet and low dose streptozotocin (30 mg/Kg). After 8 weeks of diabetes, animals were subjected to embolic stroke. Male and female Wistar normoglycemic age matched rats were used as controls. Motor (composite score: 14 best outcome and adhesive removal-ART) and cognitive (novel object recognition, NOR) deficits were assessed at day1, 3, 7 and 14. Results: Female control animals had better outcomes compared to the males. Mortality was higher in diabetic animals, especially in males. The neurological deficits were greater in diabetic animals with no difference between males and females. Conclusion: Diabetes impaired functional and cognitive outcome and recovery after ischemic stroke in a sex independent manner.

Recombinant murine-activated protein C is neuroprotective in a murine ischemic stroke model

2003 ◽  
Vol 30 (3) ◽  
pp. 271-276 ◽  
Author(s):  
José A Fernández ◽  
Xiao Xu ◽  
Dong Liu ◽  
Berislav V Zlokovic ◽  
John H Griffin
Keyword(s):  
Ischemic Stroke ◽  
Protein C ◽  
Activated Protein C ◽  
Stroke Model

Differential impact of conventional and low-dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system

2007 ◽  
Vol 97 (06) ◽  
pp. 938-943 ◽  
Author(s):  
Sigurd Liestøl ◽  
Marie-Christine Mowinckel ◽  
H. Coen Hemker ◽  
Per-Morten Sandset ◽  
Anette Eilertsen
Keyword(s):  
Hormone Therapy ◽  
Protein C ◽  
Low Dose ◽  
Acquired Resistance ◽  
Activated Protein C ◽  
System Sensitivity ◽  
Conventional Dose ◽  
Apc Resistance ◽  
The Difference ◽  
Progestin Therapy

SummaryRecent studies have shown that hormone therapy (HT) is associated with an acquired resistance to activated protein C (APC). The aims of the present study were to evaluate a possible dose-response relationship and differential effects of different HT regimens on functionality of the APC system. Two hundred two healthy women were randomly assigned to receive treatment for 12 weeks with tablets containing either low-dose HT containing 1 mg 17β-oestradiol + 0.5 mg norethisterone acetate (NETA) (n=50), conventional-dose HT containing 2 mg 17β-oestradiol and 1 mg NETA (n=50), 2.5 mg tibolone (n=51), or 60 mg raloxifene (n=51). Normalized APC system sensitivity ratios (nAPCsr) were determined in plasma collected at baseline and after 12 weeks using a thrombin generation-based APC resistance test probed with either recombinant APC (rAPC) or thrombomodulin (rTM). NAPCsr increased in both the conventional- and low-dose HT groups, consistent with reduced sensitivity to APC. The increase was slightly more pronounced in the conventional-dose group, but the difference between the two HT groups was not statistically significant. The sensitivity to APC was only marginally altered in those allocated to tibolone. Consequently, tibolone showed a different phenotype as compared with the low-dose HT group. A small increase in nAPCsr with both rAPC and rTM was seen in the raloxifene-group, but the increase was less than in the low-dose HT group. Our findings indicate that oestrogen-progestin therapy induces an APC resistant phenotype, which may be related to dose, whereas tibolone and raloxifene only marginally alter the sensitivity to APC.

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