Neuroscience
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Estrogen receptor-related receptor-α (ERRα) is an orphan member of the nuclear receptor superfamily that interacts with peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) to stimulate vascular endothelial growth factor (VEGF) expression and angiogenesis in a hypoxia-inducible factor-1α-independent pathway. Although it is not regulated by any natural ligand, the action of ERRα can be blocked by the synthetic molecule XCT790. In the present study, Sprague-Dawley rats were randomly allocated to a sham group, injury-saline group or injury-XCT90 group. ⋯ Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) analyses also indicated that XCT790 dramatically repressed the expression of ERRα, thus reducing the expression of VEGF and angiopoietin-2 (Ang-2) throughout the duration of the experiment, but the expression of PGC-1α was not affected. Immunofluorescence analyses indicated that vascular density and endothelial cell proliferation were decreased in the injury-XCT90 group compared with the injury-saline group. These results suggest that ERRα is involved in mediating angiogenesis after SCI in the rat traumatic SCI model.
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This study aimed to clarify whether ischemia-induced early growth response 1 (EGR1) influenced the outcomes of experimental stroke by regulating brain-derived neurotrophic factor (BDNF) expression. ⋯ Ischemia-induced EGR1 expression may exaggerate brain injury by reducing BDNF expression. Inhibiting EGR1 may become a potential treatment for improving outcomes of ischemic stroke.
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During the past decade, one of the most striking discoveries in the treatment of major depression was the clinical finding that a single infusion of a sub-anesthetic dose of the N-methyl-d-aspartate receptor antagonist ketamine produces a rapid (i.e. within a few hours) and long-lasting (i.e. up to two weeks) antidepressant effect in both treatment-resistant depressed patients and in animal models of depression. Notably, converging clinical and preclinical evidence support that responsiveness to antidepressant drugs is sex-differentiated. Strikingly, research regarding the antidepressant-like effects of ketamine has focused almost exclusively on the male sex. ⋯ Most importantly, a single injection of ketamine (10mg/kg) induced sex-dependent behavioral effects in mice subjected to the chronic mild stress (CMS) model of depression. Intriguingly, female mice were more reactive to the earlier effects of ketamine, as assessed in the open field and the FST (at 30 min and 24h post-treatment, respectively) but the antidepressant potential of the drug proved to be longer lasting in males, as assessed in the splash test and the FST (days 5 and 7 post-treatment, respectively). Taken together, present data revealed that ketamine treatment induces sex-dependent rapid and sustained neurochemical and behavioral antidepressant-like effects in stress-naïve and CMS-exposed C57BL/6J mice.
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Intestinal inflammation causes initial axonal degeneration and neuronal death, as well as the proliferation of intestinal smooth muscle cells (ISMC), but subsequent axonal outgrowth leads to re-innervation. We recently showed that expression of glial cell-derived neurotrophic factor (GDNF), the critical neurotrophin for the post-natal enteric nervous system (ENS) is upregulated in ISMC by inflammatory cytokines, leading us to explore the relationship between ISMC growth and GDNF expression. In co-cultures of myenteric neurons and ISMC, GDNF or fetal calf serum (FCS) was equally effective in supporting neuronal survival, with neurons forming extensive axonal networks among the ISMC. ⋯ We conclude that in the inflamed intestine, smooth muscle proliferation supports the ENS, and thus its own re-innervation, by expression of GDNF. In chronic inflammation, a compromised smooth muscle phenotype may lead to progressive neural damage. Intestinal stricture formation in human disease, such as inflammatory bowel disease (IBD), may be an endpoint of failure of this homeostatic mechanism.
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Modulation of dopamine (DA) released by serotonin-2 (5-HT2) receptors has been implicated in the mechanism of action of antipsychotic drugs. The mesocortical DA system has been implicated particularly in the cognitive deficits observed in schizophrenia. Agonism at 5-HT2A receptors in the prefrontal cortex (PFC) is associated with increases in cortical DA release. ⋯ The present study does so by measuring 5-HT2 agonist-induced DA release in the cortex after infusions of glutamate antagonists into the VTA of the rat. Infusions of a combination of a N-methyl-d-aspartic acid (NMDA) (AP-5: 2-amino-5-phosphopentanoic acid) and an AMPA/kainate (CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione) receptor antagonist into the VTA blocked the increases in cortical DA produced by administration of the 5-HT2 agonist DOI [(±)-2,5-dimethoxy-4-iodoamphetamine] (2.5mg/kg s.c.). These results demonstrate that stimulation of glutamate receptors in the VTA is necessary for 5-HT2 agonist-induced increases in cortical DA.