The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · May 2002
Modulation of cellular expression of glucocorticoid receptor and glucocorticoid response element-DNA binding in rat brain during alcohol drinking and withdrawal.
To define the molecular mechanisms of abnormal hypothalamic pituitary adrenal (HPA) axis during ethanol dependence, we investigated the effect of chronic ethanol treatment (15 days) and its withdrawal (24 h) on the expression of glucocorticoid receptors (GRs) and glucocorticoid response element (GRE)-DNA binding in the rat brain. The effects of chronic mianserin [serotonin (5-HT)(2A/2C) antagonist] treatment on these parameters in various brain structures of control diet-fed and ethanol-fed rats were also investigated. It was found that ethanol treatment and withdrawal significantly decreased the GR protein levels in cortical (cingulate gyrus, frontal, parietal, and piriform cortex) and amygdaloid (central, medial, and basolateral) structures and paraventricular nucleus (PVN) of hypothalamus of rats. ⋯ Furthermore, ethanol treatment and its withdrawal or mianserin treatment had no effect on the neuron-specific nuclear protein levels in the various brain structures. Taken together, these results indicate that interaction of 5-HT(2A/2C) receptors with GRs in cortical, central amygdaloid, and PVN structures may play a role in neural mechanisms of alcohol dependence. It is possible that decreased GR expression in PVN may be responsible for the abnormal HPA axis during ethanol exposure and withdrawal.
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J. Pharmacol. Exp. Ther. · May 2002
The role of superoxide and nuclear factor-kappaB signaling in N-methyl-D-aspartate-induced necrosis and apoptosis.
N-Methyl-D-aspartate (NMDA) receptor-mediated cell death is complex, probably involving elements of necrosis and apoptosis. The mechanisms underlying this phenomenon are incompletely understood but have been suggested to involve reactive oxygen species such as nitric oxide and superoxide anion (O(2)) and nuclear factor-kappaB (NF-kappaB) signaling. In this study, we used a selective nonpeptidyl superoxide dismutase mimetic (M40403) and SN50, a peptide inhibitor of NF-kappaB translocation, to investigate the role of O(2) and the potential downstream signaling molecules in cell death induced by activation of the NMDA receptor. ⋯ SN50 was also able to block NMDA-induced cell death as well as the increased Bax/Bcl-X(L) ratio. Time course studies and experiments with SN50 and M40403 suggest that O(2) production and NF-kappaB translocation may be involved in necrosis and apoptosis, but the latter also requires an increased expression of Bax. The ability of M40403 to prevent NMDA-induced cell death relatively early in this cascade suggests its potential therapeutic utility in central nervous systems diseases such as stroke that are associated with increased NMDA receptor-mediated production of O(2).