Involvement of mineralocorticoid receptor in trimethyltin-induced neuronal cell damage in the dentate gyrus of mouse brain

M SHUTO; CHIE SUGIYAMA; GB ACOSTA; N KURAMOTO; K OGITA

Kyoto, Japón. 13-14 November, 2009

Congreso; The 1st Meeting of the Asian College of Neuropsychopharmacology (AsCNP); 2009

Asian College of Neuropsychopharmacology

Involvement of mineralocorticoid receptor in trimethyltin-induced neuronal cell damage in the dentate gyrus of mause brain Makoto Shuto, Chie Sugiyama, Gabriela Acosta, Nobuyuki Kuramoto, and Kiyokazu Ogita Makoto Shuto, Chie Sugiyama, Gabriela Acosta, Nobuyuki Kuramoto, and Kiyokazu Ogita Department of Medical Pharmacy, Setsunan University, Hirakata, Osaka, Japan, Department of Pharmacology, Setsunan University, Hirakata, Osaka, Japan, Research Associate, Institute of Pharmacological Research (CONICET), Buenos Aires, Argentina The systemic administration of trimethyltin (TMT) is known to induce granule cell death in the dentate gyrus of mice.  We have previously shown that the neuronal damage induced by TMT at the dose of 2.0 mg/kg was enhanced by adrenalectomy (ADX), with glucocorticoid receptor (GR) agonist dexamethasone being capable of abolishing enhancement by ADX.  However, little has been known about the role of mineralocorticoid receptor (MR) in the TMT-induced neuronal death.  In this study, we examined the effects of MR agonist and antagonist on TMT-induced damage in the dentate granule neurons.  Male mice at age of 4-5 weeks were anesthetized and then the dorsal skin was cut and fascia opened to reveal the kidney.  The adrenal gland were removed and sutured.  ADX and sham-operated animals were given TMT on day 7 after surgery.  TMT-induced neuronal damage was assessed by the immunohistochemical analysis of single-stranded DNA.  ADX and sham-operated animals were given MR agonist aldosterone (0.1 mg/kg, s.c.) every 12 h for 2 day (4 time) after TMT injection.  Aldosterone exacerbated neuronal damage induced by TMT in the dentate gyrus of both ADX and sham-operated animals.  GR antagonist mifepristone had the ability to enhance TMT-induced neuronal damage, whereas MR antagonist spironolactone was effective in protecting against the neuronal damage.  These results suggest that the activation of MR promotes TMT-induced neuronal damage in the dentate gyrus. The systemic administration of trimethyltin (TMT) is known to induce granule cell death in the dentate gyrus of mice.  We have previously shown that the neuronal damage induced by TMT at the dose of 2.0 mg/kg was enhanced by adrenalectomy (ADX), with glucocorticoid receptor (GR) agonist dexamethasone being capable of abolishing enhancement by ADX.  However, little has been known about the role of mineralocorticoid receptor (MR) in the TMT-induced neuronal death.  In this study, we examined the effects of MR agonist and antagonist on TMT-induced damage in the dentate granule neurons.  Male mice at age of 4-5 weeks were anesthetized and then the dorsal skin was cut and fascia opened to reveal the kidney.  The adrenal gland were removed and sutured.  ADX and sham-operated animals were given TMT on day 7 after surgery.  TMT-induced neuronal damage was assessed by the immunohistochemical analysis of single-stranded DNA.  ADX and sham-operated animals were given MR agonist aldosterone (0.1 mg/kg, s.c.) every 12 h for 2 day (4 time) after TMT injection.  Aldosterone exacerbated neuronal damage induced by TMT in the dentate gyrus of both ADX and sham-operated animals.  GR antagonist mifepristone had the ability to enhance TMT-induced neuronal damage, whereas MR antagonist spironolactone was effective in protecting against the neuronal damage.  These results suggest that the activation of MR promotes TMT-induced neuronal damage in the dentate gyrus.