Choline exposure reduces potentiation of N-methyl-D-aspartate toxicity by corticosterone in the developing hippocampus.
Exposure to high levels of glucocorticoids (GCs) may adversely affect neuronal viability, particularly in the developing hippocampus, via increased function or sensitivity of N-methyl-D-aspartate (NMDA)-type glutamate receptors. Conversely, choline supplementation in the developing brain may reduce the severity of subsequent insult. The present studies aimed to examine the extent to which short-term exposure to high concentrations of corticosterone would produce neuronal injury mediated by NMDA receptor activity. These studies also assessed the ability of choline to prevent this form of injury via interactions with nicotinic acetylcholine receptors (nAChRs) expressing the alpha7 subunit. Organotypic hippocampal slice cultures derived from neonatal rat were pre-treated for 72 h with corticosterone (100 nM) alone or with choline (0.1-10 mM), prior to a brief (1 h) NMDA exposure (5 microM). NMDA exposure produced significant cellular damage, reflected as increased fluorescence of the non-vital marker propidium iodide, in the CA1 region. While exposure to corticosterone alone did not produce damage, pre-treatment of cultures with corticosterone markedly exacerbated NMDA-induced toxicity. Pre-treatment with choline (> or =1 mM) alone or in combination with corticosterone markedly reduced subsequent NMDA toxicity, effects blocked by co-exposure to methyllycaconitine (100 nM), an antagonist active at nAChRs expressing the alpha7 subunit. These data suggest that even short-term exposure to high concentrations of GCs may adversely affect neuronal viability and that choline supplementation protects the brain from NMDA receptor-mediated damage, including that associated with hypercortisolemia.
Mulholland
Patrick J
PJ
Department of Psychology, University of Kentucky, 115 Kastle Hall, Lexington, KY 40506-0044, USA.
Self
Rachel L
RL
Harris
Barton R
BR
Littleton
John M
JM
Prendergast
Mark A
MA
D000818:Animals; D002794:Choline / Q000494:pharmacology*; D004396:Coloring Agents; D003345:Corticosterone / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004357:Drug Synergism; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D008297:Male; D008856:Microscopy, Fluorescence; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009924:Organ Culture Techniques; D011419:Propidium; D051381:Rats; D017207:Rats, Sprague-Dawley
D004396:Coloring Agents; D018690:Excitatory Amino Acid Agonists; D011419:Propidium; D016202:N-Methylaspartate; D002794:Choline; D003345:Corticosterone