Title : A potent inhibitor of aminopeptidase P2 greatly reduces reperfusion injury in models of myocardial infarction and stroke
Abstract:
Tissue that undergoes ischemia followed by reperfusion is subject to extensive damage. Reperfusion itself is responsible for at least 50% of the total tissue damage. There is currently no effective way to prevent this reperfusion injury. However, during ischemia and reperfusion, vascular endothelial cells produce the autocoid bradykinin, which is well known to protect against tissue damage. But at the same time, endothelial cells have enzymes on their surface that can cleave and destroy the bradykinin. One of these enzymes is aminopeptidase P2. By inhibiting this enzyme, the concentration of bradykinin in the vasculature should build up, leading to tissue protection. We designed a synthetic peptidomimetic drug called ST-115 that is a highly specific and potent (IC50 = 3.7 nM) inhibitor of aminopeptidase P2. In a mouse model of myocardial infarction, injection of ST-115 just before the start of reperfusion reduced the infarct size by 58% compared to a saline injection. In a rat model of stroke, injection of ST-115 just before the start of reperfusion reduced deficits in skilled walking by 60%, and brain edema by 51%, and infarct size by 48% compared to a saline injection. In a mouse model of acute kidney injury, ST-115 reduced blood urea nitrogen, a marker of kidney damage, by 56% compared to saline. Therefore ST-115 appears to have a broad ability to completely prevent reperfusion injury. In the case of a large vessel stroke, a combination of thrombectomy and ST-115 treatment should simultaneously reduce both ischemic and reperfusion injury. (Reference:: the above title in the Journal of Pharmacology and Experimental Therapeutics, 380-220-229, March.2022. (ST-115 is n now commercially available for follow-on experiments).
