17beta-estradiol rescues spinal motoneurons from AMPA-induced toxicity: a role for glial cells.

The ability of astrocytes to mediate 17beta-estradiol neuroprotection of spinal motoneurons challenged with AMPA has been evaluated in a co-culture system in which pure motoneurons were pulsed with 20 microM AMPA and then transferred onto an astrocyte layer pretreated for 24 h with 10 nM 17beta-estradiol. Under these conditions, AMPA toxicity was reverted, an effect that was likely related to increased production and release of GDNF, as shown by RT-PCR, Western blot analysis and ELISA assay. In addition, treatment with GDNF during the 24 h that followed the AMPA pulse produced a similar neuroprotective effect, whereas addition of a neutralizing anti-GDNF antibody prevented neuroprotection. These data suggest a role for astrocytes in the neuroprotective effect of 17beta-estradiol against spinal motoneuron death and find strong support in the marked up-regulation of estrogen receptor alpha found in spinal astrocytes of amyotrophic lateral sclerosis patients.