Brain research
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In this study, we investigated the role of GPR30 in 17β-estradiol- (E2) mediated neuroprotection after an ischemic injury in an organotypic hippocampal slice culture (OHSC) model. We report that after oxygen-glucose deprivation (OGD), a physiological concentration of 100 pM E2 provided the greatest significant reduction in cell death while supra-physiological levels were less effective. ⋯ Only supra-physiological levels of E2 led to significantly increased phosphorylation of Akt and Erk which are well known downstream effects of GPR30 activation. We conclude that GPR30 activation may facilitate acute E2 mediated neuroprotection after OGD, but is neither necessary nor sufficient.
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The complex symptoms of schizophrenia have recently been linked to disrupted neural circuits and corresponding malfunction of two higher-order intrinsic brain networks: The default mode network (DMN) and the fronto-parietal network (FPN). These networks are both functionally heterogeneous and consist of multiple subsystems. However, the extent to which these subsystems make differential contributions to disorder symptoms and to what degree such abnormalities occur in unaffected siblings have yet to be clarified. ⋯ In terms of inter-connectivity, all groups exhibited positive connections between FPN and DMN subsystems, with patients having even stronger interaction between rFPN and aDMN than the controls, a feature that may underlie their psychotic symptoms. Our results implicate that DMN subsystems exhibit different liabilities to the disease risk while FPN subsystems demonstrate distinct inter-connectivity alterations. These dissociating manners between network subsystems explicitly suggest their differentiating roles to the disease susceptibility and manifestation.
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The blood-brain barrier (BBB) is a functional structure which regulates and restricts the transfer of circulating molecules and immune cells into the central nervous system. The barrier is formed by the presence of tight junctions (TJ) between the specialized brain endothelial cells. The volatile anesthetic isoflurane may affect the permeability of the BBB. Previous studies have proven that isoflurane alters hypoxia-inducible factor-1α (HIF-1α) expression, which may affect the TJ proteins; however, the mechanism of how TJ proteins are affected by isoflurane is still unclear. Primary human brain vascular endothelial cells (HBVEC) were exposed to isoflurane at various concentrations (0-2.5%) and different time periods (0-6 h). The cell viability, occludin expression, paracellular permeability, VEGF expression, TGF-β3 expression and occludin protein endocytosis were quantified. Isoflurane treatment induced a time- and concentration-dependent decrease in occludin mRNA and protein levels in HBVEC. This effect was partially abrogated by silencing the HIF-1α expression. Isoflurane could activate HIF-1α, and the overexpression HIF-1α up-regulated the level of VEGF and TGF-β3, VEGF decreased the expression of occludin and TGF-β3 accelerated the endocytosis of occludin. RNA interference targeting HIF-1α reduced both VEGF and TGF-β3 expression after isoflurane treatment. ⋯ This study provides direct evidence in vitro that exposing isoflurane to HBVECs can trigger HIF-1α activation, leading to lower protein levels of occludin, and increased permeability of the BBB.
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It is generally believed that NMDA receptor antagonism accounts for most of the anesthetic and analgesic effects of ketamine, however, it interacts at multiple sites in the central nervous system, including NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic receptors, and adrenergic and opioid receptors. Interestingly, it was shown that at supraspinal sites, ketamine interacts with the μ-opioid system and causes supraspinal antinociception. In this study, we investigated the involvement of endogenous opioids in ketamine-induced central antinociception. ⋯ Additionally, the administration of the aminopeptidase inhibitor bestatin significantly enhanced low-dose ketamine-induced central antinociception. These data provide evidence for the involvement of endogenous opioids and μ- and δ-opioid receptors in ketamine-induced central antinociception. In contrast, κ-opioid receptors not appear to be involved in this effect.
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17β-Estradiol is a multi-active steroid that imparts neuroprotection via diverse mechanisms of action. However, its role as a neuroprotective agent after spinal cord injury (SCI), or the involvement of the estrogen receptor-alpha (ER-α) in locomotor recovery, is still a subject of much debate. In this study, we evaluated the effects of estradiol and of Tamoxifen (an estrogen receptor mixed agonist/antagonist) on locomotor recovery following SCI. ⋯ Rats treated with Tamoxifen recovered some locomotor activity at 21 and 28 DPI, which could be related to the antioxidant protection seen at these time points. These results show that estradiol improves functional outcome, and these protective effects are mediated by the ER-α dependent and independent-mechanisms. Tamoxifen׳s effects during late stages of SCI support the use of this drug as a long-term alternative treatment for this condition.