PREVENTION OF APOPTOTIC MOTONEURON DEATH IN-VITRO BY NEUROTROPHINS AND MUSCLE EXTRACT

In this study, it is shown that rat motoneurons in culture are highly dependent on trophic support and die in the absence of such support vi a active cell death, or apoptosis. This apoptotic death occurs in thei r 'in vitro' life (within 24 h) and can be partially prevented by trea ting the cultures with neurotrophic substances. The most effective sup port comes from an extract prepared from embryonic chick muscle: witho ut muscle extract, no healthy, neurite-bearing motoneurons are present , but with 0.3 and 1.2% muscle extract, their numbers increase dose-de pendently. Neurotrophins, such as brain-derived neurotrophic factor (B DNF) and neurotrophin-4 (NT-4), cannot replace muscle extract and keep motoneurons alive on their own, but in the presence of muscle extract (0.3%) they have a significant effect on survival (increase up to fou r times, compared to 0.3% muscle extract). At the same time, they prev ent apoptotic cell death. Selective motoneuron death has been implicat ed in the neurodegenerative disease amyotrophic lateral sclerosis (ALS ). Despite strong evidence that motoneurons in ALS die via apoptosis, this has not been shown unequivocally in post mortem material. This st udy shows that motoneurons are very sensitive to conditions that initi ate apoptosis, and that cell death can be prevented to a large degree with relatively low concentrations of neurotrophic factors. In view of the fact that several patient trials with neurotrophic factors alread y are underway, studies with motoneurons in culture may prove importan t in understanding the mechanism of cell death and the efficacy of dru gs such as neurotrophic factors, but also other types of drug. (C) 199 7 Elsevier Science Ltd.