Protection with estradiol in developmental models of apoptotic neurodegeneration.
Medical measures that bear no known danger for the adult brain may trigger active neuronal death in the developing brain. Pharmacological blockade of N-methyl-D-aspartate or activation of GABA(A) receptors, blockade of voltage-dependent sodium channels, and oxygen induce widespread apoptotic neurodegeneration during the period of rapid brain growth in rodents. Because such measures are often necessary in critically ill infants and toddlers, search for adjunctive neuroprotective strategies is warranted. We report that 17beta-estradiol ameliorates neurotoxicity of drugs that block N-methyl-D-aspartate receptors, activate GABA(A) receptors, or block voltage-gated sodium channels and reduces neurotoxicity of oxygen in the infant rat brain. This neuroprotective effect is reversed by tamoxifen and cannot be reproduced by 17alpha-estradiol. 17Beta-estradiol did not affect GABA(A) or N-methyl-D-aspartate currents in hippocampal neuronal cultures, indicating that direct modulation of neurotransmitter receptor/channel properties by this compound cannot explain neuroprotective effect. 17beta-Estradiol did, however, increase levels of phosphorylated extracellular signal-regulated kinase 1/2 and AKT, suggesting that activation of these prosurvival proteins may represent one mechanism for its neuroprotective action. 17Beta-estradiol and related compounds may be neuroprotective agents suitable for use in critically ill infants and toddlers. Its supplementation may particularly help to improve neurocognitive outcome in preterm infants who are prematurely deprived of maternal estrogen.
Asimiadou
Stiliani
S
Neuroscience Research Center, Charité, Humboldt University Berlin, Berlin, Germany.
Bittigau
Petra
P
Felderhoff-Mueser
Ursula
U
Manthey
Daniela
D
Sifringer
Marco
M
Pesditschek
Stefanie
S
Dzietko
Mark
M
Kaindl
Angela M
AM
Pytel
Maria
M
Studniarczyk
Dorota
D
Mozrzymas
Jerzy W
JW
Ikonomidou
Chrysanthy
C
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001640:Bicuculline / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D029742:Caenorhabditis elegans Proteins / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004958:Estradiol / Q000627:therapeutic use*; D004965:Estrogen Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology; D000860:Hypoxia / Q000150:complications; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D008564:Membrane Potentials / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018408:Patch-Clamp Techniques / Q000379:methods; D010634:Phenobarbital; D010672:Phenytoin; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A; D016622:Silver Staining / Q000379:methods; D013629:Tamoxifen / Q000494:pharmacology
D029742:Caenorhabditis elegans Proteins; D004965:Estrogen Antagonists; C469698:GAB-1 protein, C elegans; D018756:GABA Antagonists; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D011963:Receptors, GABA-A; D013629:Tamoxifen; D004958:Estradiol; D010672:Phenytoin; D016291:Dizocilpine Maleate; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D001640:Bicuculline; D010634:Phenobarbital