Nerve Growth Factor mimetics with neuroprotective activity in ischemic brain damage

Neurotrophins are a family of cytokines that regulate growth, development, and survival of neural cells. Many studies on neurotrophins and their receptors are focused on neurodegenerative disorders, such as Alzheimer Disease, Parkinson Disease, and Amyotrophic Lateral Sclerosis. Unfortunately, neurotrophins present unfavourable pharmacologic properties and cannot be used as drugs, because of their sensitivity to proteolysis, restricted penetration to the central nervous system, and expensive production. Small molecules able to interact with neurotrophin receptors, either as agonists or antagonists, are of great interest for many therapeutic applications and could represent the suitable solution for the above concerns. These small molecules could be potentially used for the treatment of acute brain ischemia, for cutaneous pressure ulcers and for corneal neurotrophic ulcers. Aim of our study is to evaluate the neuroprotective properties of a class of low-MW, non-peptidic compounds, recently developed at the University of Florence. These compounds are able to bind TrkA receptor and to elicit its signal transduction pathways, mimicking NGF properties. The neuroprotective effect of MT2, a representative NGF-mimetic compound (1) was tested in an in vitro model of rat organotypic hippocampal slices subjected to 30 min of oxygen and glucose deprivation (OGD) and in in vivo model of global ischemia in gerbils. In both assays MT2 was able to prevent the activation of neuronal apoptosis. To investigate the molecular mechanisms of MT-2-induced neuroprotection we studied the modulation of selective kinases (JNK, p38MAPK, Akt) differently involved in the ischemia/repurfusion-induced apoptotic process.