Myocardial infarction (MI) results from a biphasic ischemia/reperfusion (I/R) injury to the heart. The disease is linked to cardiomyocyte apoptosis and further along to inflammation-based tissue damage. Despite considerable effort, therapeutic interventions to disrupt this injury pattern are not optimal. Indeed, the inflammation’s multifactorial nature complicates attempts to limit the impact therapeutically.
This diversity makes blocking the disease at a receptor level unfeasible; however, inhibition at the subreceptor level is possible if a common signaling element is identified. Phosphoinositide 3-kinase (PI3K) could represent this gatekeeper, specifically the γ and δ isoforms as genetic deletion studies establish their roles in edema and inflammatory responses.
PI3K inhibitors are commonly associated with reduced inflammatory events in animal models but there is also considerable evidence supporting a prosurvival role for during ischemia and, in general PI3K pathways are considered beneficial events that should not be disrupted during I/R injuries. On the whole, it is quite controversial whether inhibition of PI3K signaling would prove beneficial, detrimental, or inconsequential to infarct development.
Researchers tried using a previously undescribed PI3Kγ/δ inhibitor (TG100-115) to interrupt the reperfusion phase of I/R injury. The molecule was confirmed as a potent inhibitor of edema and inflammation induced by both receptors linked to PI3K, but at the same time spared tissue repair processes.
In a mouse ischemia and porcine models, it reduced infarct development and improved myocardial function. Cardioprotection was seen upon delivery up to several hours after reperfusion, an important factor for human care. The data support the hypothesis that broadly blocking proinflammatory processes can limit I/R injury even well after the initiation of ischemic damage.
Based on the results of this study, the researchers believe that selective PI3K isoform inhibition holds promise for bridging that gap between preclinical efficacy and clinical utility.
Syncrosome, a scientific preclinical CRO based in France, also uses mouse ischemia models for Myocardial Ischemia for efficacy testing. They monitor Coronary artery ligation, reperfusion, blood pressure, heart rate, planimetry, histology and morphological and functional biomarkers. By combining all these parameters, they can most reliably test for appropriate reaction.
http://www.pnas.org/content/103/52/19866.full
Key words: preclinical CRO, preclinical study, animal model, animal research, myocardial, ischemia, infarction, reperfusion, heart, porcine model, mouse model, inflammation, inflammatory, proinflammatory, isoform.