Cytoprotective-selective activated protein C therapy for ischaemic stroke

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Ischemic stroke remains a leading cause of death and disability, with limited therapeutic options despite extensive research.
• While preventive measures have improved, no new drugs for acute ischemic stroke therapy have been approved in the last decade.
• Activated protein C (APC) has demonstrated neuroprotective effects in preclinical stroke models, acting through both anticoagulant and direct cytoprotective mechanisms.

Purpose of the Study:

• To investigate the specific mechanisms underlying APC's neuroprotective effects in ischemic stroke.
• To evaluate the therapeutic potential of a modified APC variant, 3K3A-APC, that selectively targets cytoprotective pathways.
• To elucidate the molecular interactions between APC, its receptors (PAR1, PAR3, EPCR), and downstream signaling in neuroprotection.

Main Methods:

• Utilized rodent stroke models to assess the efficacy of APC and its variants.
• Employed molecular engineering to create APC variants with altered selectivity profiles.
• Investigated receptor-ligand interactions and downstream signaling pathways, including canonical and non-canonical protease-activated receptor (PAR) activation.

Main Results:

• APC's beneficial effects in stroke models were primarily attributed to its cytoprotective activities, independent of its anticoagulant properties.
• The engineered variant 3K3A-APC, designed for selective cytoprotection, showed significant therapeutic potential.
• Identified non-canonical PAR1 and PAR3 activation by APC, leading to biased signaling pathways that favor cytoprotection over canonical responses.

Conclusions:

• The neuroprotective effects of APC in ischemic stroke are mediated by its cytoprotective actions, particularly through selective PAR activation.
• 3K3A-APC represents a promising therapeutic agent for ischemic stroke, leveraging these specific cytoprotective mechanisms.
• Understanding the detailed molecular mechanisms of APC-mediated neuroprotection provides a strong foundation for clinical translation and development of novel stroke therapies.