Neuroscience
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Microglia, the resident immune cells of the central nervous system (CNS), are activated at the beginning of the inflammatory response and induce detrimental neuroinflammation by producing excessive pro-inflammatory cytokines. Nuclear factor kappa B (NF-κB) signaling facilitates the onset of microglia activation. However, the molecular mechanisms underlying the negative regulation of NF-κB remain to be fully elucidated. ⋯ Co-immunoprecipitation experiments further revealed an interaction between H4R and tumor necrosis factor receptor-associated factor 6 (TRAF6) in microglia, which was verified both in vivo and in vitro. Our experimental results support our hypothesis that H4R interacts with TRAF6 to inhibit the release of inflammatory cytokines in LPS-induced microglia cells by decreasing TRAF6-mediated ubiquitination of K63. These findings provide theoretical and experimental evidence regarding the role of H4R in the microglia inflammatory response, which may aid in the development of novel treatments for inflammation.
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Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. Sensory-processing deficits are common in humans with FXS and an animal model, the Fmr1 knockout (KO) mouse, manifesting in the auditory system as debilitating hypersensitivity and abnormal electroencephalographic (EEG) and event-related potential (ERP) phenotypes. FXS is a neurodevelopmental disorder, but how EEG/ERP phenotypes change during development is unclear. ⋯ Genotype differences in stimulus-evoked gamma power were present in both cortical regions, but the direction and strength of the changes were age-dependent. These findings suggest that cortical deficits are present during early development and may contribute to sensory-processing deficits in FXS, which in turn may lead to anxiety and delayed language. Developmental changes in EEG measures indicate that observations at a single time-point during development are not reflective of FXS disease progression and highlight the need to identify developmental trajectories and optimal windows for treatment.
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Prolonged occupational exposure to hand-held vibrating tools leads to pain and reductions in tactile sensitivity, grip strength and manual dexterity. The goal of the current study was to use a rat-tail vibration model to determine how vibration frequency influences factors related to nerve injury and dysfunction. Rats were exposed to restraint, or restraint plus tail vibration at 62.5 Hz or 250 Hz. ⋯ There was an increase in glutathione, but no changes in other measures of oxidative activity in the peripheral nerve. However, measures of oxidative stress were increased in the dorsal root ganglia (DRG). These changes in pro-inflammatory factors and markers of oxidative stress in the peripheral nerve and DRG were associated with inflammation, and reductions in myelin basic protein and post-synaptic density protein (PSD)-95 gene expression, suggesting that vibration-induced changes in sensory function may be the result of changes at the exposed nerve, the DRG and/or the spinal cord.
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Our previous study showed that acid-sensing ion channel 3 (ASIC3) in the trigeminal nucleus caudalis (TNC) is involved in the pathogenesis of recurrent migraine. ASIC3 is regulated by nerve growth factor (NGF), which induces hyperalgesia in various pain disorders. Neutralization of NGF is considered an effective treatment method. ⋯ An intracerebroventricular injection of an anti-NGF-neutralizing antibody relieved the cutaneous hyperalgesia of CM rats and decreased protein kinase C (PKC), ASIC3, calcitonin gene-related peptide (CGRP) and c-Fos expression in the TNC. Moreover, intracerebroventricular injection with the PKC blocker chelerythrine chloride alleviated IS infusion-induced hyperalgesia and reduced ASIC3, CGRP and c-Fos levels in the TNC. These results indicate that NGF might regulate ASIC3 expression via PKC activity in the TNC following repeated IS dural stimulation, and this signaling pathway might participate in IS-induced hyperalgesia.
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Peripheral diabetic neuropathy (PDN) manifests in 50-60% of type I and II diabetic patients and is the major cause of limb amputation. Adequate therapy for PDN is a current challenge. There are evidences that the activation of the P2X4 receptor (P2X4R) expressed on microglial cells of the central nervous system takes part in the development of neuropathic pain. ⋯ Finally, our study showed a functional expression of P2X4R in SGCs of the rat's DRG, because the P2X4R agonist BzATP elicits an increase in intracellular calcium concentration in SGCs, which was reduced by PSB-15417. These findings indicate that P2X4R activation in DRG is essential to diabetes-induced neuropathic mechanical hyperalgesia. Therefore, this purinergic receptor in DRG could be an interesting therapeutic target for quaternary P2X4R antagonists that do not cross the hematoencephalic barrier, for the control of neuropathic pain, preserving central nervous system functions.