Dual effect of 17β-estradiol on NMDA-induced neuronal death: involvement of metabotropic glutamate receptor 1.
Pretreatment with 10 nm 17β-estradiol (17βE2) or 100 μm of the metabotropic glutamate 1 receptor (mGlu1R) agonist, dihydroxyphenylglycine (DHPG), protected neurons against N-methyl-d-aspartate (NMDA) toxicity. This effect was sensitive to blockade of both estrogen receptors and mGlu1R by their respective antagonists. In contrast, 17βE2 and/or DHPG, added after a low-concentration NMDA pulse (45 μm), produced an opposite effect, i.e. an exacerbation of NMDA toxicity. Again this effect was prevented by both receptor antagonists. In support of an interaction of estrogen receptors and mGlu1R in mediating a neurotoxic response, exacerbation of NMDA toxicity by 17βE2 disappeared when cultures were treated with DHPG prior to NMDA challenge, and conversely, potentiation of NMDA-induced cell death by DHPG was prevented by pretreatment with 17βE2. Addition of calpain III inhibitor (10 μm), 2 h before NMDA, prevented the increased damage induced by the two agonists, an affect that can be secondary to cleavage of mGlu1R by calpain. Accordingly, NMDA stimulation reduced expression of the full-length (140 kDa) mGluR1, an effect partially reversed by calpain inhibitor. Finally, in the presence of NMDA, the ability of 17βE2 to stimulate phosphorylation of AKT and ERK was impaired. Pretreatment with calpain inhibitor prevented the reduction of phosphorylated ERK but had no significant effect on phosphorylated AKT. Accordingly, the inhibition of ERK signaling by U0126 (1 μm) counteracted the effect of calpain inhibition on 17βE2-induced exacerbation of NMDA toxicity. The present data confirm the dual role of estrogens in neurotoxicity/neuroprotection and highlight the role of the timing of exposure to estrogens.
Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, 95125 Catania, Italy.
Simona Federica
SF
Spampinato
Sara
S
Merlo
Gemma
G
Molinaro
Giuseppe
G
Battaglia
Valeria
V
Bruno
Ferdinando
F
Nicoletti
Maria Angela
MA
Sortino
D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D002154:Calpain / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D002540:Cerebral Cortex / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011960:Receptors, Estrogen / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
D002070:Butadienes; D002396:Catechols; D004791:Enzyme Inhibitors; D009570:Nitriles; D011960:Receptors, Estrogen; D018094:Receptors, Metabotropic Glutamate; C113580:U 0126; C104077:metabotropic glutamate receptor type 1; C099561:3,4-dihydroxyphenylglycine; D004958:Estradiol; D016202:N-Methylaspartate; D048049:Extracellular Signal-Regulated MAP Kinases; D002154:Calpain; D005998:Glycine