Nerve Growth Factor mimetics reduce infarct size and functional damage upon coronary artery ligation in mice

Nerve Growth factor (NGF) biologic activity is exerted via triggering of TrkA surface receptor expressed by target cells, that comprise both neural and non-neural cells. NGF signalling includes recruitment of MKP-1, a phosphatase specifically acting on p38 MAPK. The latter kinase becomes strongly activated upon ischemia/reperfusion damage and translocates onto mitochondria, whereby it binds, phosphorylates, ind inactivates Bcl-2, leading to apoptosis. Consistently, NGF proved useful in modulating the morphologic and functional damage in mice subjected to left anterior descending (LAD) coronary artery ligation. However, the pharmacokinetics of NGF is unfavorable, essentially due to its proteic nature. To overcome such problems, a chemical library of low-MW non-peptidic compounds was designed, based on the crystallographic data of TrkA chain, and screened for molecules with NGF mimetic activity. In vitro, these compounds cound to TrkA molecule, induced its autophosphorylation, and triggered several downstream biochemical events, including ERK-1/2 activation, MKP-1 recruitment, and p38 MAPK dephosphorylation. Thus, NGF mimetics were tested in the classical mouse model of acute myocardial ischemia.