PT  - JOURNAL ARTICLE
AU  - Simona F Spampinato
AU  - Gemma Molinaro
AU  - Sara Merlo
AU  - Luisa Iacovelli
AU  - Filippo Caraci
AU  - Giuseppe Battaglia
AU  - Ferdinando Nicoletti
AU  - Valeria Bruno
AU  - Maria Angela Sortino
TI  - Estrogen Receptors and Type-1 Metabotropic Glutamate Receptors are Interdependent in Protecting Cortical Neurons against β-amyloid Toxicity
AID  - 10.1124/mol.111.074021
DP  - 2011 Oct 07
TA  - Molecular Pharmacology
PG  - mol.111.074021
4099  - http://molpharm.aspetjournals.org/content/early/2011/10/07/mol.111.074021.short
4100  - http://molpharm.aspetjournals.org/content/early/2011/10/07/mol.111.074021.full
AB  - We examined the interaction between estrogen receptors (ERs) and type-1 metabotropic glutamate receptors (mGlu1 receptors) in mechanisms of neurodegeneration/neuroprotection using mixed cultures of cortical cells challenged with β-amyloid peptide. Both receptors were present in neurons, whereas only ERα, but not mGlu1a receptors, were found in astrocytes. Addition of 17-β-estradiol (17βE2) protected cultured neurons against amyloid toxicity, and its action was mimicked by the selective ERα agonist, 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) as well as by a cell-impermeable BSA conjugate of 17βE2. The selective ERβ agonist, diarylpropionitrile (DPN), was only slightly neuroprotective. The mGlu1/5 receptor agonist, 3,5,-dihydroxyphenylglycine (DHPG), was also neuroprotective against amyloid toxicity, and its action was abolished by the mGlu1 receptor antagonist, JNJ16259685. Neuroprotection by 17βE2 or PPT (but not DPN) and DHPG was less than additive, suggesting that ERα and mGlu1 receptors activate the same pathway of cell survival. More important, neuroprotection by 17βE2 was abolished not only by the ER antagonist, ICI182,780, but also by JNJ16259685, and neuroprotection by DHPG was abolished by ICI182,780. ERα and mGlu1 receptors were also interdependent in activating the phosphatidylinositol-3-kinase pathway, and pharmacological blockade of this pathway abolished neuroprotection by 17βE2, DHPG, or their combination. These data provide the first evidence that ERα and mGlu1 receptors critically interact in promoting neuroprotection, an information that should be taken into account when examining the impact of estrogen on neurodegeneration associated with CNS disorders.