Neuroprotective Effects of Estradiol on Motoneurons in a Model of Rat Spinal Cord Embryonic Explants

Amyotrophic lateral sclerosis (ALS) is an adult-onset degenerative disorder characterized by motoneuron death. Clinical and experimental studies in animal models of ALS have found gender differences in the incidence and onset of disease, suggesting that female hormones may play a beneficial role. Cumulative evidence indicates that 17 beta-estradiol (17 beta E2) has a neuroprotective role in the central nervous system. We have previously developed a new culture system by using rat spinal cord embryonic explants in which motoneurons have the singularity of migrating outside the spinal cord, growing as a monolayer in the presence of glial cells. In this study, we have validated this new culture system as a useful model for studying neuroprotection by estrogens on spinal cord motoneurons. We show for the first time that spinal cord motoneurons express classical estrogen receptors and that 17 beta E2 activates, specifically in these cells, the Akt anti-apoptotic signaling pathway and two of their downstream effectors: GSK-3 beta and Bcl-2. To further validate our system, we demonstrated neuroprotective effects of 17 beta E2 on spinal cord motoneurons when exposed to the proinflammatory cytokines TNF-alpha and IFN-gamma. These effects of 17 beta E2 were fully reverted in the presence of the estrogen receptor antagonist ICI 182,780. Our new culture model and the results presented here may provide the basis for further studies on the effects of estrogens, and selective estrogen receptor modulators, on spinal cord motoneurons in the context of ALS or other motoneuron diseases.