title: Dexamethasone-induced acute excitotoxic cell death in the developing brain.
abstract: There is substantial evidence that the use of glucocorticoids in neonates is associated with an increased risk of neurodevelopmental disorders. However, it remains unclear how treatment with low doses of dexamethasone (DEX) may result in behavioral abnormalities without evident signs of immediate neurotoxicity in the neonatal brain. It is possible that cells vulnerable to the pro-apoptotic effects of low doses of DEX escaped detection due to their small number in the developing brain. In agreement with this suggestion, low-dose DEX treatment (0.2mg/kg) failed to induce apoptosis in the cortex or hippocampus proper of neonatal rats. However, this treatment was capable of inducing apoptosis specifically in the dorsal subiculum via a two-step mechanism that involves glutamate excitotoxicity. Application of DEX leads to increased activity of CA1/CA3 hippocampal MAP2-positive neurons, as determined by c-Fos expression at 0.5-1h after DEX injection. Five hours later, the apoptotic markers (fragmented nuclei, active caspase-3 and TUNEL labeling) increased in the dorsal subiculum, which receives massive glutamatergic input from CA1 neurons. Pretreatment with memantine, an antagonist of glutamate NMDA receptors, dose dependently blocked the DEX-induced expression of apoptotic markers in the subicular neurons and astrocytes. These findings provide new insights into the mechanisms of DEX-induced neurotoxicity as well as on the mechanism of therapeutic action of antagonists of NMDA receptors against neurobehavioral disorders caused by neonatal exposure to glucocorticoids.
authors.affiliation: Functional Neurogenomics Laboratory, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian Federation. Electronic address: dmitriylanshakov@gmail.com.
authors.forename: Dmitriy A
authors.initials: DA
authors.lastname: Lanshakov
authors.affiliation: Functional Neurogenomics Laboratory, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian Federation. Electronic address: evsukhareva@mail.ru.
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Sukhareva
authors.affiliation: Functional Neurogenomics Laboratory, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian Federation; Novosibirsk State University, Novosibirsk, Russian Federation. Electronic address: kalin@bionet.nsc.ru.
authors.forename: Tatjana S
authors.initials: TS
authors.lastname: Kalinina
authors.affiliation: Functional Neurogenomics Laboratory, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian Federation; Novosibirsk State University, Novosibirsk, Russian Federation. Electronic address: dygalo@bionet.nsc.ru.
authors.forename: Nikolay N
authors.initials: NN
authors.lastname: Dygalo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000254:growth & development*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000378:metabolism; D017208:Rats, Wistar
chemical_list: D005938:Glucocorticoids; D003907:Dexamethasone; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: Apoptosis; Caspase-3; DNA fragmentation; Dexamethasone; Excitotoxicity; Hippocampus; Memantine; Neonatal; Subiculum; c-Fos