Stroke Protection: a Thrombin Inhibitor Steps Forward


A stroke is the result of loss of adequate blood supply to the brain and is a major cause of disability worldwide, and the second leading cause of death after 60 years of age. Each year roughly 15 million people suffer a stroke and 6 million die from it. Ischemic stroke (versus hemorrhagic) accounts for about 80% of incidents.

The endogenous serine protease thrombin paradoxically can both stimulate and prevent blood clotting, and is involved in both types of stroke. Thrombin appears to function in multiple activities in brain tissue including inflammation and vascular disruption and operates through a complex network of feedback loops mediating both neuroprotective and degenerative effects.

In order to devise safe and effective clinical treatment strategies aimed at targets in thrombin pathways, a greater understanding of the molecular mechanisms of thrombin signaling networks in stroke is essential.

In the latest issue of IJMS, Mirante and coworkers demonstrate that the potent endogenous inhibitor of thrombin, protease nexin-1 (PN-1), is protective against cerebral ischemia. Using PN-1 knockout and PN-1/lacZ reporter mutant mouse strains, the researchers report the exciting finding that PN-1 is involved in protecting against neuronal cell injury caused by oxygen and glucose deprivation, and that it plays a key role in mediating the well-known neuroprotective phenomenon of thrombin preconditioning (TPC).

Mirante, O.; Price, M.; Puentes, W.; Castillo, X.; Benakis, C.; Thevenet, J.; Monard, D.; Hirt, L. Endogenous Protease Nexin-1 Protects against Cerebral Ischemia. Int. J. Mol. Sci. 201314, 16719-16731.