Nerve growth factor (NGF) mimetics modulate ischemic brain damage

Nerve Growth Factor (NGF) and the other neurotrophins are endowed with differentiation-inducing, tropic, and trophic properties. The inherent biochemical pathways involve the family of MAP kinases, as well as proteins of the Bcl-2 family, that are implicated in the development of apoptotic death occurring in ischemia. On this basis, we hypothesized that NGF biologic signal might be useful for modulating the ischemic brain damage. We therefore used a class of low-MW, non-peptidic compounds, recently developed at the University of Firenze, able to bind TrkA receptor and to elicit its signal transduction, thus mimicking NGF properties, in in vitro and in vivo models of ischemia. To test the neuroprotective properties of our molecules we used a rat organotypic hippocampal slice model subjected to 30 min of oxygen and glucose deprivation (OGD) in an anaerobic chamber, that leads to a selective damage in CA1 region 24h after OGD. Exposing the slices immediately after OGD and in the subsequent 24h to NGF mimetics, we observed a significant and dose-dependent reduction in CA1 damage. To comprehend the mechanisms of neuroprotection, we carried out western blot analysis using antibodies against ERK1/2, Jnk, p38 and Akt phosphorylation levels. We observed that NGF mimetics are able to modulate the phosphorylation levels of JNK and ERK ½ 1h after 30 min OGD. These compounds also attenuated CA1 pyramidal cell death in in vivo model of ischemia in gerbils. Biochemical experiments reveal again a modulation of MAP-kinase pathways observed 1h after ischemia in gerbil hippocampus. In conclusion, we propose to consider NGF compounds for exploiting pharmacologically the intense trophic properties of the neurotrophin – which cannot be vehiculated into the brain because of its proteic nature – for treatment of brain ischemia.