High dose infusion of activated protein C (rhAPC) fails to improve neuronal damage and cognitive deficit after global cerebral ischemia in rats

Brückner, Melanie; Lasarzik, Irina; Jahn‐Eimermacher, Antje; Peetz, D.; Werner, Christian; Engelhard, Kristin; Thal, Serge C.

doi:10.1016/j.neulet.2013.06.055

Cited by 4 publications

(1 citation statement)

References 32 publications

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“…Many successful in vivo preclinical studies for APC therapy for ischaemic stroke employed bolus dosing. Interestingly, one study using continuous infusion failed to demonstrate beneficial effects (87). Bolus dosing also limits APC-mediated, ongoing systemic proteolysis of FV and FVIII that may promote bleeding due to consumption of these clotting factors (88).…”

Section: K3a-apc: Preclinical and Clinical Developmentmentioning

confidence: 99%

Cytoprotective-selective activated protein C therapy for ischaemic stroke

Mosnier¹,

Zloković²,

Griffin³

2014

Thromb Haemost

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SummaryDespite years of research and efforts to translate stroke research to clinical therapy, ischemic stroke remains a major cause of death, disability, and diminished quality of life. Primary and secondary preventive measures combined with improved quality of care have made significant progress. However, no novel drug for ischemic stroke therapy has been approved in the past decade. Numerous studies have shown beneficial effects of activated protein C (APC) in rodent stroke models. In addition to its natural anticoagulant functions, APC conveys multiple direct cytoprotective effects on many different cell types that involve multiple receptors including protease activated receptor (PAR) 1, PAR3, and the endothelial protein C receptor (EPCR). Application of molecular engineered APC variants with altered selectivity profiles to rodent stroke models demonstrated that the beneficial effects of APC primarily require its cytoprotective activities but not its anticoagulant activities. Extensive basic, preclinical, and clinical research provided a compelling rationale based on strong evidence for translation of APC therapy that has led to the clinical development of the cytoprotective-selective APC variant, 3K3A-APC, for ischemic stroke. Recent identification of non-canonical PAR1 and PAR3 activation by APC that give rise to novel tethered-ligands capable of inducing biased cytoprotective signaling as opposed to the canonical signaling provides a mechanistic explanation for how APC-mediated PAR activation can selectively induce cytoprotective signaling pathways. Collectively, these paradigmshifting discoveries provide detailed insights into the receptor targets and the molecular mechanisms for neuroprotection by cytoprotective-selective 3K3A-APC, which is currently a biologic drug in clinical trials for ischemic stroke.

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Section: K3a-apc: Preclinical and Clinical Developmentmentioning

confidence: 99%

Cytoprotective-selective activated protein C therapy for ischaemic stroke

Mosnier¹,

Zloković²,

Griffin³

2014

Thromb Haemost

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

Yamato

Nakajo

Yamamoto-Imoto

et al. 2020

neuopn

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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.

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A new concept of action of hemostatic proteases on inflammation, neurotoxicity, and tissue regeneration

Горбачева

Савинкова

et al. 2017

Biochemistry Moscow

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Key hemostatic serine proteases such as thrombin and activated protein C (APC) are signaling molecules controlling blood coagulation and inflammation, tissue regeneration, neurodegeneration, and some other processes. By interacting with protease-activated receptors (PARs), these enzymes cleave a receptor exodomain and liberate new amino acid sequence known as a tethered ligand, which then activates the initial receptor and induces multiple signaling pathways and cell responses. Among four PAR family members, APC and thrombin mainly act via PAR1, and they trigger divergent effects. APC is an anticoagulant with antiinflammatory and cytoprotective activity, whereas thrombin is a protease with procoagulant and proinflammatory effects. Hallmark features of APC-induced effects result from acting via different pathways: limited proteolysis of PAR1 localized in membrane caveolae with coreceptor (endothelial protein C receptor) as well as its targeted proteolytic action at a receptor exodomain site differing from the canonical thrombin cleavage site. Hence, a new noncanonical tethered PAR1 agonist peptide (PAR1-AP) is formed, whose effects are poorly investigated in inflammation, tissue regeneration, and neurotoxicity. In this review, a concept about a role of biased agonism in effects exerted by APC and PAR1-AP via PAR1 on cells involved in inflammation and related processes is developed. New evidence showing a role for a biased agonism in activating PAR1 both by APC and PAR1-AP as well as induction of antiinflammatory and cytoprotective cellular responses in experimental inflammation, wound healing, and excitotoxicity is presented. It seems that synthetic PAR1 peptide-agonists may compete with APC in controlling some inflammatory and neurodegenerative diseases.

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High dose infusion of activated protein C (rhAPC) fails to improve neuronal damage and cognitive deficit after global cerebral ischemia in rats

Cited by 4 publications

References 32 publications

Cytoprotective-selective activated protein C therapy for ischaemic stroke

Cytoprotective-selective activated protein C therapy for ischaemic stroke

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

A new concept of action of hemostatic proteases on inflammation, neurotoxicity, and tissue regeneration

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