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

1 Neurotrophic factors have been used for the treatment of several neurodeg enerative diseases. However, their use is limited by their inability to cro ss the blood-brain barrier, their short half life and their side effects. S R 57746A is a new orally active compound that exhibits in vivo and in vitro neurotrophic effects in several experimental models. 2 We show here that SR 57746A (1 mu M) 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 an d number of their neurites. It acts in a dose-dependent manner up to 1 mu M which is the optimal concentration. Above this concentration, its neurotro phic effect decreases. 3 Genistein (10 mu M), a protein tyrosine kinase inhibitor, also increases the phenotypic survival and differentiation of mouse motoneurons. It does n ot act in a synergistic or additive manner with SR 57746A. However, at conc entrations equal or superior to 25 mu M, it decreases the survival of moton eurons. This suggests that the neurotrophic effect of genistein is due to a favourable alteration of equilibrium between phosphorylated and dephosphor ylated states of proteins involved in survival and differentiation of moton eurons. 4 Like genistein, SR 57746A should be used at a critical concentration (1 m u M) to exert its optimal effects. Since SR 57746A does not act synergistic ally with genistein, it is likely that its mechanism of action involves a p athway similar to that affected by this tyrosine kinase inhibitor. 5 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. Tt sho uld thus be considered as a good candidate for the treatment of motoneuron diseases.