The effects of insulin-regulated aminopeptidase inhibition with HA08 on recognition memory acquisition and spatial working memory under reversed circadian conditions in male rats.

In 1995, a new M1 aminopeptidase member was discovered in fat and muscle cells, the insulin regulated aminopeptidase (IRAP; oxytocinase; placental leucine aminopeptidase). IRAP can be found in glucose transporter type 4 (GLUT4) vesicles and is believed to regulate cellular glucose uptake by mediating trafficking of GLUT4 to the plasma membrane. It is expressed in various tissues, including areas of the brain associated with cognition, and it cleaves multiple endogenous substrates like oxytocin, vasopressin, somatostatin and cholecystokinin-8. In the beginning of the century, IRAP was identified as the receptor of hexapeptide angiotensin IV (AngIV). AngIV and similar ligands binds to the active site of the peptidase, causing inhibition of its enzymatic activity, which is suggested to increase neuropeptide levels and modulate cellular glucose uptake. This mechanism is suggested to improve cognitive functions, and in 1988 the first evidence of Ang IV's memory enhancing effects was reported. Since then, several animal behaviour models have demonstrated the positive effects of AngIV on memory. One of the most potent synthetic IRAP inhibitors known today is the macrocyclic compound HA08, that we have previously demonstrated to increase dendritic spine density and restore cell viability. To further evaluate the potential of IRAP inhibitor HA08 as a cognitive enhancer, we have examined this macrocycle compound