The effects of an RNA synthesis inhibitor on the survival and regeneration of rat motoneurones injured at birth.

This preliminary study aimed to test the proposal that neuronal death is triggered by expression of specific genes. In rat pups, the sciatic nerve was injured unilaterally on the first day after birth and actinomycin D, an RNA synthesis inhibitor, was administered 3 days later in a lower and higher dose to rat pups just prior to onset of motoneurone death induced by the lesion. Four weeks later, sciatic motoneurones from operated and contralateral pools were counted and their size measured. Significantly fewer motoneurones (16.7% +/- 2.9 SD) survived when the animals were treated with a lower dose of the inhibitor compared to saline treated controls (36.6% +/- 12.7 SD). Experiments recording tension generated in soleus muscle in response to sciatic nerve stimulation, at different ages following nerve crush, suggested that the treatment with the RNA synthesis inhibitor may have delayed regeneration of motor axons back to the muscle. However, survival of motoneurones after treatment with the higher dose did not differ significantly from controls (27.5% +/- 1.3 SD). Nevertheless, the higher dose significantly reduced growth of motoneurones after 4 weeks. Therefore, the higher dose, although impeding normal development of motoneurones, is less neurotoxic than a lower dose. This suggests that a balancing of conflicting effects may have occurred. The neurodegenerative effects of delayed reinnervation induced by RNA synthesis inhibition may be balanced by some neuroprotective effects at a higher dose. More extensive studies are required to validate these pilot findings.