Effect of the nonpeptide neurotrophic compound SR 57746A on the phenotypic survival of purified mouse motoneurons

Abstract

Neurotrophic factors have been used for the treatment of several neurodegenerative diseases. However, their use is limited by their inability to cross the blood-brain barrier, their short half life and their side effects. SR 57746A is a new orally active compound that exhibits in vivo and in vitro neurotrophic effects in several experimental models.We show here that SR 57746A (1 μM) increases the phenotypic survival of embryonic purified mouse motoneurons in vitro to the same extent as brain-derived neurotrophic factor (100 ng ml−1), and increases the outgrowth and number of their neurites. It acts in a dose-dependent manner up to 1 μM which is the optimal concentration. Above this concentration, its neurotrophic effect decreases.Genistein (10 μM), a protein tyrosine kinase inhibitor, also increases the phenotypic survival and differentiation of mouse motoneurons. It does not act in a synergistic or additive manner with SR 57746A. However, at concentrations equal or superior to 25 μM, it decreases the survival of motoneurons. This suggests that the neurotrophic effect of genistein is due to a favourable alteration of equilibrium between phosphorylated and dephosphorylated states of proteins involved in survival and differentiation of motoneurons.Like genistein, SR 57746A should be used at a critical concentration (1 μM) to exert its optimal effects. Since SR 57746A does not act synergistically with genistein, it is likely that its mechanism of action involves a pathway similar to that affected by this tyrosine kinase inhibitor.At the present time, SR 57746A is the only orally active compound and the only synthetic compound shown to be active on motoneurons in vitro. It should thus be considered as a good candidate for the treatment of motoneuron diseases.