Neuroscience
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In genetically-modified Lmx1b(f/f/p) mice, selective deletion of LMX1B in Pet-1 expressing cells leads to failure of embryonic development of serotonin (5-HT) neurons. As adults, these mice have a decreased hypercapnic ventilatory response and abnormal thermoregulation. This mouse model has been valuable in defining the normal role of 5-HT neurons, but it is possible that developmental compensation reduces the severity of observed deficits. ⋯ One week after DT treatment, mice were challenged by dropping TA from 37°C to 24°C, which caused TB to decrease more in males than in females (29.7±0.31°C vs. 33.0±1.3°C, p<0.01). We conclude that the 20% of 5-HT neurons that remain after DT treatment in Pet1/DTR mice are sufficient to maintain normal baseline breathing and a normal response to CO2, while those affected include some essential for thermoregulation, in males more than females. In comparison to models with deficient embryonic development of 5-HT neurons, acute deletion of 5-HT neurons in adults leads to a greater defect in thermoregulation, suggesting that significant developmental compensation can occur.
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Toll-like receptor-4 (TLR4) has been identified in primary sensory neurons, both in vivo and in vitro, but is reportedly absent from satellite glial cells (SGCs). Herein we reveal that, in rat dorsal root ganglia (DRG), SGCs do express TLR4 but this expression is inhibited by direct contact with neurons. Thus, TLR4 mRNA and protein is strongly up-regulated in isolated DRG glial cells in the absence of neurons. ⋯ In addition to LPS, conditioned medium from heat-shocked DRG neurons also increased COX-2 mRNA expression in DRG glial cells in a partially TLR4-dependent manner. We therefore hypothesize that neuronal suppression of glial TLR4 activity is a protective mechanism to prevent uncontrolled inflammation within the DRG. Under conditions where DRG neuronal viability is compromised, DRG glial cells become responsive to PAMPs (pathogen-associated molecular patterns) and DAMPs (danger-associated molecular patterns) and generate a range of classical inflammatory responses.
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CCAAT/enhancer binding protein-beta (C/EBP-beta) is a transcription factor that belongs to the C/EBP family. To understand the role of C/EBP-beta in the peripheral nervous system, we investigated the expression of C/EBP-beta in the dorsal root ganglion. C/EBP-beta was weakly detected in nuclei of naive dorsal root ganglion (DRG) neurons. ⋯ Treatment with anti-TNF-alpha prevented SNL-induced pain hypersensitivity and C/EBP-beta expression in the DRG. Injection of TNF-alpha into the sciatic nerve produced transient pain hypersensitivity and induction of C/EBP-beta expression in the DRG. These results demonstrate that C/EBP-beta is activated in the DRG neurons by a TNF-alpha-dependent manner and might be involved in the activation of primary afferent neurons after nerve injury.
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Retinoic acid (RA) is required for development and homeostasis of the normal mammalian brain and may play a role in the initiation and progression of malignant brain tumors, such as the glioblastoma multiforme (GBM) and the gliosarcoma (Gsarc). The subpopulation of stem-like glioma cells (SLGCs) was shown to resist standard glioma radio-/chemotherapy and to propagate tumor regrowth. We used phenotypically distinct, self-renewing SLGC lines from six human GBMs, two Gsarcs, and two subcloned SLGC derivatives in order to investigate their responsiveness to all-trans retinoic acid (atRA) and to identify the RA-receptor (RAR) isotypes involved. ⋯ Only one GBM-derived cell line (T1338) and a subpopulation of another (T1389) displayed neural differentiation in response to atRA. Differentiation of T1338 was induced by RARα and RARγ isotype-selective retinoids, associated with down-regulation of Sox2, and the failure to induce orthotopic tumors in the brains of SCID mice. The differential responsiveness of the SLGC lines appeared unrelated to the expression of RARβ, as (i) atRA augmented RAR isotype mRNA expression and particularly rarβ mRNA in all SLGC lines, (ii) rarβ promoter hypomethylation in the SLGC lines was not related to differentiation and (iii) the induction of T1338 differentiation was by RARα- and RARγ-selective ligands.
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β-Caryophyllene (BCP), a natural bicyclic sesquiterpene present in several essential oils, displays analgesic and anti-inflammatory properties in vitro and in vivo. Astrocytes are a major class of glial cells that regulate extracellular ion balance, repair and scarring processes in the CNS following neuroinflammatory conditions and traumatic injuries. This study sought to determine the protective effect of BCP against glutamate (Glu)-induced cytotoxicity in the C6 glioma cell line on neurochemical parameters as well as their biochemical mechanism. ⋯ Moreover, BCP per se induced the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) which was reflected by improvement in the cellular GSH antioxidant system. Taken together, our results suggest that cytoprotective effects of BCP were mediated by the amelioration of cellular antioxidant responses via Nrf2 activation, which is, in part, dependent on cannabinoid receptor type 2 (CB2R) activation. This functional nonpsychoactive CB2R ligand, could represent an important molecule for protection of glial cells against oxidative stress induced by glutamate.