Opposing roles of glucocorticoid receptor and mineralocorticoid receptor in trimethyltin-induced cytotoxicity in the mouse hippocampus.
The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the murine brain. Earlier studies indicate that TMT-induced neuronal degeneration is enhanced by adrenalectomy and prevented by exogenous glucocorticoid. The aim of this study was to investigate the regulation of TMT neuroxicity by corticosterone receptors including type I (mineralocorticoid receptor, MR) and type II (glucocorticoid receptor, GR) in adult mice. The systemic injection of TMT at the dose of 2.0 or 2.8 mg/kg produced a marked elevation in the level of plasma corticosterone that was both dose and time dependent. The MR agonist aldosterone had the ability to exacerbate TMT cytotoxicity in the dentate granule cell layer, whereas its antagonist spironolactone protected neurons from TMT cytotoxicity there. In contrast, the GR antagonist mifepristone exacerbated the TMT cytotoxicity. Taken together, our data suggest TMT cytotoxicity is oppositely regulated by GR and MR signals, being exacerbated by MR activation in adult mice.
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka 573-0101, Japan. ogita@pharm.setsunan.ac.jp
Kiyokazu
K
Ogita
Chie
C
Sugiyama
Gabriela Beatriz
GB
Acosta
Nobuyuki
N
Kuramoto
Makoto
M
Shuto
Masanori
M
Yoneyama
Yukary
Y
Nakamura
Tatsuo
T
Shiba
Taro
T
Yamaguchi
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D003345:Corticosterone / Q000097:blood; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism* / Q000502:physiology; D018161:Receptors, Mineralocorticoid / Q000819:agonists / Q000378:metabolism* / Q000502:physiology; D013148:Spironolactone / Q000494:pharmacology; D014298:Trimethyltin Compounds / Q000633:toxicity*
D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D014298:Trimethyltin Compounds; C046488:trimethyltin; D013148:Spironolactone; D000450:Aldosterone; D003345:Corticosterone