title: Allopregnanolone prevents dieldrin-induced NMDA receptor internalization and neurotoxicity by preserving GABA(A) receptor function.
abstract: Dieldrin is an endocrine disruptor that accumulates in mammalian adipose tissue and brain. It induces convulsions due to its antagonism of the γ-aminobutyric acid A receptor (GABA(A)R). We have previously reported that long-term exposure to dieldrin causes the internalization of the N-methyl-D-aspartate receptor (NMDAR) as a result of persistent GABA(A)R inhibition. Because the neurosteroids 17β-estradiol (E2) and allopregnanolone are known to modulate the function and trafficking of GABA(A)R and NMDAR, we examined the effects of E2 and allopregnanolone on dieldrin-induced GABA(A)R inhibition, NMDAR internalization, and neuronal death in cortical neurons. We found that 1 nM E2 increased the membrane expression of NR1/NR2B receptors and postsynaptic density 95 but did not induce their physical association. In contrast, 10 nM E2 had no effect on these proteins but reduced NR2A membrane expression. We also found that exposure to 60 nM dieldrin for 6 d in vitro caused the internalization of NR1 and NR2B but not NR2A. Treatment with either 1 nM E2 or 10 μM allopregnanolone prevented the dieldrin-induced reduction in membrane levels of the NR1/NR2B receptors. Furthermore, prolonged exposure to 200 nM dieldrin down-regulated the expression of NR2A; this was inhibited only by allopregnanolone. Although both hormones restored NMDAR function, as measured by the NMDA-induced rise in intracellular calcium, allopregnanolone (but not E2) reversed the inhibition of GABA(A)R and neuronal death caused by prolonged exposure to dieldrin. Our results indicate that allopregnanolone protects cortical neurons against the neurotoxicity caused by long-term exposure to dieldrin by maintaining GABA(A)R and NMDAR functionality.
authors.affiliation: Department of Neurochemistry and Neuropharmacology, Consejo Superior de Investigaciones Científicas-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IIBB-CSIC-IDIBAPS), Centro de Investigación Biomédica en Red Epidemiology and Public Health (CIBERESP), E-08036, Barcelona, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Briz
authors.forename: Jyoti
authors.initials: J
authors.lastname: Parkash
authors.forename: Sara
authors.initials: S
authors.lastname: Sánchez-Redondo
authors.forename: Vincent
authors.initials: V
authors.lastname: Prevot
authors.forename: Cristina
authors.initials: C
authors.lastname: Suñol
mesh_terms: D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane; D002540:Cerebral Cortex / Q000166:cytology; D004026:Dieldrin / Q000009:adverse effects*; D000076122:Disks Large Homolog 4 Protein; D004622:Embryo, Mammalian / Q000166:cytology; D052244:Endocrine Disruptors / Q000009:adverse effects; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011280:Pregnanolone / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D000777:Anesthetics; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D052244:Endocrine Disruptors; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D004958:Estradiol; D011280:Pregnanolone; C491075:Dlgh3 protein, mouse; D051528:Guanylate Kinases; D004026:Dieldrin