Cytoprotective protein C pathways and implications for stroke and neurological disorders

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.