title: Cytoprotective protein C pathways and implications for stroke and neurological disorders.
abstract: Recent studies indicate that single-action-single-target agents are unlikely to cure CNS disorders sharing a pathogenic triad consisting of vascular damage, neuronal injury/neurodegeneration and neuroinflammation. Here we focus on a recent example of a multiple-action-multiple-target approach for CNS disorders based on newly discovered biological properties of activated protein C (APC), an endogenous plasma protease with antithrombotic, cytoprotective and anti-inflammatory activities in the CNS. We propose that APC-mediated signaling through the protease activated receptor-1 (PAR1) can favorably regulate multiple pathways within the neurovascular unit in non-neuronal cells and neurons during acute or chronic CNS insults, leading to stabilization of the blood-brain barrier (BBB), neuroprotection and control of neuroinflammation. Although much remains to be understood regarding the biology of APC, preclinical studies suggest that APC has promising applications as disease-modifying therapy for ischemic stroke and other neuropathologies whose underlying pathology involves deficits in the vasculo-neuronal-inflammatory triad.
authors.affiliation: Center for Neurodegenerative and Vascular Brain Disorders, Department of Neurological Surgery, University of Rochester Medical Center, Rochester, New York, USA. berislav_zlokovic@urmc.rochester.edu
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002986:Clinical Trials as Topic; D019610:Cytoprotection; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D008958:Models, Molecular; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011486:Protein C / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D011487:Protein Conformation; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D011486:Protein C