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[P2.02]: Repeated carbenoxolone injection during late pregnancy decreased SPAR but increased Snk expression in the hippocampus of rat pups
Author(s) -
Jutapakdeegul N.,
Surakul P.,
Vanichviriyakit R.,
Weerachatyanukul W.
Publication year - 2010
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2010.07.132
Subject(s) - carbenoxolone , hippocampus , medicine , library science , chemistry , computer science , gap junction , biochemistry , intracellular
Homeostasis of circulating cortisol is maintained by two enzymes of 11 -hydroxysteroid dehydrogenase, 11 -HSD1 and 11 -HSD2. 11 -HSD2 is NAD-dependent dehydrogenase that inactivates cortisol into cortisone. In addition, 11 -HSD2 is abundantly expressed in the placenta where it protects the fetus from active maternal glucocorticoids. Administration of carbenoxolone (CBX), a powerful 11 -HSD2 inhibitor, leads to an increased of fetal cortisol level and decreased plasma cortisone levels. Previous data showed that intrauterine environment plays crucial roles in determining hippocampal structure and function in later life. Exposure to high level of corticosteroid during pregnancy lead to a low birth weight offspring, increased risk of aged related memory and cognitive deficits, however, mechanism still unclear. We proposed that repeated CBX injections during late pregnancy may alter scaffolding proteins of NMDA receptor in the hippocampus of rat pups. Here we show that pregnant rats receiving CBX injections (30 mg/kg) during GD14-21 lead to a significant decreased of SPAR (spine Associated Rap Guanylate kinase activating protein) (p < 0.01) but significant increased of Snk (Serum inducible kinase) (p < 0.01) in the pup’s hippocampus at P40 and P60, while the level of PSD-95 remain unchanged. NMDA receptor function has been shown to be influenced by turnover of the scaffolding proteins via ubiquitin proteasome system (UPS). Normally, Snk is induced by neuronal activity and plays an important role in phosphorylate SPAR. The phosphorylated SPAR was then recognized and degraded by ubiquitin-proteasome system, causing the depletion of SPAR and PSD-95 from the spines and leading to spine shrinkage and loss. The results suggest that fetal exposure with excessive corticosteroids may activate Snk/SPAR pathway and lead to the depletion of SPAR. Since, corticosteroid drugs are commonly used in various obstetric and paediatric conditions, it is important to consider the risk–benefit of prenatal GC exposure to prevent the neurodevelopment delay in the offspring.