Journal of neuroscience research
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Increasing evidence suggests a role for cyclooxygenase-2 (COX-2) in traumatic brain injury (TBI). In the present study, the role of COX-2 in TBI was investigated using COX-2 gene-disrupted (COX-2 null) mice and wild-type (WT) controls that were subjected to the controlled cortical impact (CCI) model of TBI. There was increased expression of COX-2 in ipsilateral hippocampus in WT mice subjected to CCI. ⋯ However, there was no difference in lesion volume 21 days after CCI in COX-2 null and WT mice. COX-2 gene disruption did not alter Morris water maze performance. Taken together, these results suggest only a minor role for COX-2 activity in determining outcome after TBI in mouse.
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Previously, we showed that in rat cortical neurons, chronic donepezil treatment (10 microM, 4 days) up-regulates nicotinic receptors (nAChR) and makes neurons more sensitive to the neuroprotective effect of donepezil. Here we examined the mechanism of donepezil-induced neuroprotection in neurons chronically treated with donepezil. The mechanism of neuroprotection was examined under different conditions of exposure to glutamate, acute and moderate, that induce cell death associated with necrotic and apoptotic cell death, respectively. ⋯ Neuroprotection was also inhibited by treatment with inhibitor of mitogen-activated protein kinase (MAPK) kinase. These results suggest that donepezil protects neurons against moderate glutamate neurotoxicity via nAChR-PI3K-Akt and MAPK signaling pathways. This study provides novel insight into the mechanism of donepezil-induced neuroprotection that involves nAChR up-regulation.
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Recent evidence has shown that the serotonergic mechanism of the lateral parabrachial nucleus (LPBN) participates in the regulation of renal and hormonal responses to isotonic blood volume expansion (BVE). We investigated the BVE-induced Fos activation along forebrain and hindbrain nuclei and particularly within the serotonergic clusters of the raphé system that directly project to the LPBN. We also examined whether there are changes in the concentration of serotonin (5HT) within the raphé nucleus in response to the same stimulus. ⋯ Our study also showed an increase in the number of serotonergic DRN neurons activated in response to isotonic BVE. We also observed decreased levels of 5HT and its metabolite 5-hydroxyindoleacetic acid (measured by high-pressure liquid chromatography) within the raphé nucleus 15 min after BVE. Given our previous evidence on the role of the serotonergic system in the LPBN after BVE, the present morphofunctional findings suggest the existence of a key pathway (DRN-LPBN) that may control BVE response through the modulation of 5HT release.
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Inflammatory pain, characterized by a decrease in the nociceptive threshold, arises through the actions of inflammatory mediators, and one of the key molecules is nerve growth factor (NGF). Here we report that the administration of neutralizing antibody to the neurotrophin receptor p75 (p75(NTR)) blocks hyperalgesia, which develops with complete Freund's adjuvant (CFA)-induced inflammation or with an intraplantar injection of NGF. Although CFA injection results in the up-regulation of calcitonin gene-related peptide (CGRP) levels in the primary sensory neurons, blocking p75(NTR) abolishes this effect. ⋯ In addition, an intraplantar injection of pro-NGF induces hyperalgesia. These data together suggest that pro-NGF, as well as mature NGF, binding to p75(NTR) plays an important role in inflammation-induced hyperalgesia. Interference in the binding may provide a therapeutic approach for the treatment of inflammatory pain.