Can adjunctive therapies augment the efficacy of endovascular thrombolysis? A potential role for activated protein C. (15th May 2018)

• Record Type: Journal Article
• Authors: Amar, Arun Paul; Sagare, Abhay P.; Zhao, Zhen; Wang, Yaoming; Nelson, Amy R.; Griffin, John H.; Zlokovic, Berislav V.
• Is Part Of: Neuropharmacology. Volume 134:Part B(2018)
• Page Start: 293
• Page End: 301
• Publication Date: 2018-05-15
• Subjects: Activated protein C (APC) -- Endovascular restorative neurosurgery -- Mechanical neurothrombectomy -- Neuroprotection -- Neurorestoration -- Stroke -- Thrombolysis; (AIS) acute ischemic stroke -- (Akt) protein kinase B -- (APC) activated protein C -- (BBB) blood-brain barrier -- (CNS) central nervous system -- (EPCR) endothelial protein C receptor -- (ERK1/2) extracellular signal-regulated kinase 1/2 -- (FDA) food and drug administration -- (GA) general anesthesia -- (IV tPA) intravenous tissue plasminogen activator -- (LVO) large vessel occlusion -- (MMP9) matrix metalloproteinase-9 -- (NFkB) nuclear factor kappa-light-chain-enhancer of activated B cells -- (NMDA) N-methyl-d-aspartate -- (NPCs) neural progenitor cells -- (NSC) neural stem cell -- (NVU) neurovascular unit -- (PC) protein C -- (PAR1) protease activated receptor 1 -- (PAR3) protease activated receptor 3 -- (Rac1) Ras-related C3 botulinum toxin substrate 1 -- (RhoA) Ras homolog gene family, member A -- (Serpins) serine protease inhibitors -- (STAIR) stroke therapy academic industry roundtable -- (SVZ) subventricular zone -- (IIa) thrombin -- (TM) thrombomodulin -- (tPA) tissue plasminogen activator -- (TRAP) thrombin receptor-activating peptides -- (wt) wild-type; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.09.021
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: In the management of acute ischemic stroke, vessel recanalization correlates with functional status, mortality, cost, and other outcome measures. Thrombolysis with intravenous tissue plasminogen activator has many limitations that restrict its applicability, but recent advances in the development of mechanical thrombectomy devices as well as improved systems of stroke care have resulted in greater likelihood of vessel revascularization. Nonetheless, there remains substantial 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 pharmacological therapy for neuroprotection and/or neurorestoration. Prior clinical trials of such drugs may have failed due to the inability of the agent to access the ischemic tissue beyond the occluded artery. A protocol that couples revascularization with concurrent delivery of a neuroprotectant drug offers the potential to enhance the benefit of thrombolysis. Analogs of activated protein C (APC) exert pleiotropic anti-inflammatory, anti-apoptotic, antithrombotic, cytoprotective, and neuroregenerative effects in ischemic stroke and thus appear to be promising candidates for this novel approach. A multicenter, prospective, double-blinded, dose-escalation Phase 2 randomized clinical trial has enrolled 110 patients to assess the safety, pharmacokinetics, and efficacy of human recombinant 3K3A-APC following endovascular thrombolysis. This article is part of the Special Issue entitled 'Cerebral Ischemia'. Graphical abstract: Highlights: Stroke is a leading cause of death and disability. Current ischemic stroke interventions have limited success rates. 3K3A-APC is a potent cytoprotective, anti-inflammatory and neuroregenerative agent. 3K3A-APC is a promising candidate for adjunctive therapy for ischemic stroke.