This Article Full Text Full Text (PDF) All Versions of this Article: 149/7/3713    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Lamirand, A. Articles by Courtin, F. PubMed PubMed Citation Articles by Lamirand, A. Articles by Courtin, F.

Oxidative Stress Regulates Type 3 Deiodinase and Type 2 Deiodinase in Cultured Rat Astrocytes

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 854 (A.L., M.R., M.P., F.C.) and INSERM Unité 488 (S.P.-M.), Le Kremlin-Bicêtre 94276, France; and Université Paris-Sud (A.L., S.P-M., M.R., M.P., F.C.), Orsay F-91405, France

Address all correspondence and requests for reprints to: Françoise Courtin, Unité Mixte de Recherche 854 Institut National de la Santé et de la Recherche Médicale, 80 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre, France. E-mail: francoise.courtin{at}inserm.fr.

Type 2 deiodinase (D2) and type 3 deiodinase (D3) locally achieve the determination of the concentration of T₃, which binds to the thyroid hormone receptor with high affinity. D2 converts T₄ into T₃, and D3 degrades T₄ and T₃. Neurons take up T₃ released by astrocytes, the main cerebral site for the D2 expression. Because oxidative stress is believed to be involved in several neurological disorders, we explored the effects of oxidative stress on D3 and D2 in primary culture of rat astrocytes. H₂O₂ (250 µM) increased D3 activity with maximal effects around 8 h. Stimulation of D3 activity by H₂O₂ was synergistic with T₄, phorbol ester, and also cAMP. H₂O₂ (250 µM) did not affect basal D2 activity but inhibited the stimulation of D2 activity by cAMP and factors implicating cAMP-independent pathways in astrocytes, TSH, and phorbol ester. N-Acetyl cysteine and selenium repletion, which respectively increase intracellular glutathione and glutathione peroxidase, inhibited D2 and D3 regulation by H₂O₂, whereas L-buthionine sulfoximine, which decreases intracellular glutathione, mimicked H₂O₂ effects. Oxidative stress up-regulated D3 and inhibited cAMP-stimulated D2 by transcriptional mechanisms. A decrease in cAMP by oxidative stress could contribute to the inhibition of cAMP-stimulated D2. Using specific inhibitors of signaling pathways, we show that the ERK pathway was required in D2 and D3 regulation by oxidative stress and that the p38 MAPK pathway was implicated in H₂O₂-induced D3. We suggest that the expected decrease in T₃ might modulate the cellular injury of oxidative stress in some pathological brain conditions.