Neuroscience
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The present study aims to identify transcription factors (TFs) contributing to angiogenesis, a mechanism involved in giving plasticity to the brain, as potential therapeutic targets after cerebral ischemia. The promoter sequences from candidate genes involved in angiogenesis were submitted to a comparative analysis by bioinformatics software. High-mobility group I-Y protein (HMGIY) TF characterization in a rat permanent focal cerebral ischemia model was performed by quantitative real time polymerase chain reaction and Western blot for the TF expression profile study. ⋯ The interaction array analysis revealed that ischemia promotes the interaction of HMGIY with TFs involved in different cerebral plasticity processes. In vitro knockdown studies showed that angiopoietin 1 and vascular endothelial growth factor expression is controlled by HMGIY and that this TF is involved in cell survival in brain endothelial cells. These findings suggest that HMGIY is a potential therapeutic target that could promote brain repair functions after stroke.
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This study investigated a possible role for a toll-like receptor 4 (TLR4)-mediated PTEN/PI3K/AKT/NF-κB signaling pathway in neuroinflammation in rat hippocampal neurons. Cultured neurons were treated with lipopolysaccharide (LPS), a TLR4 ligand, or pre-treated with TLR4 antibodies to block TLR4 signaling. Neurons were also treated with dipotassium bisperoxo (pyridine-2-carboxyl) oxovanadate [bpV(pic)] and pyrrolidine dithiocarbamate (PDTC), selective inhibitors of PTEN and NF-κB, respectively, in the presence of LPS. ⋯ Blocking TLR4 increased the levels of pPTEN and decreased the levels of pAKT, while pre-treatment with bpV(pic) led to a reduction in levels of pPTEN and pAKT. Furthermore, treatment with TLR4 antibody, bpV(pic), and PDTC decreased LPS-induced nuclear translocation of NF-κB, and resulted in a downregulation of TNF-α and IL-1β expression. Taken together, these results provide evidence for a TLR4-mediated PTEN/PI3K/AKT/NF-κB signaling pathway in rat hippocampal neurons, which is associated with the activation of a neuroinflammatory response.
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Chronic exposure to n-hexane induces peripheral-central axonopathy, mediated by its metabolite 2,5-hexanedione (2,5-HD), in occupational workers and experimental animals, but the underlying mechanism is still unclear. In the current study, we investigated the effects of 2,5-HD on middle-molecular-weight neurofilament (NF-M) axonal transport using live-cell imaging technique in cultured rat dorsal root ganglia (DRG) cells. PA-GFP-NF-M plasmid was transfected into DRG neurons and live-cell imaging was performed to observe the slow axonal transport of NF-M. ⋯ The results showed that 2,5-HD administration resulted in a decrease of NF-M axonal transport and a reduction of three neurofilament subunits levels in DRG cells. Furthermore, 2,5-HD exposure significantly decreased ATP contents and the protein levels of kinesin heavy chain (KHC). These findings indicated that 2,5-HD reduced slow axonal transport, neurofilaments cargoes, motor proteins and ATP energy in rat DRG cells, which may contribute to 2,5-HD-induced neurotoxicity.
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Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase are transiently phosphorylated (activated) in the spinal cord and trigeminal nucleus by acute noxious stimuli. Acute stimulation of dental pulp induces short-lived ERK activation in trigeminal subnucleus caudalis (Vc), and p38 inhibition attenuates short-term sensitization in Vc induced by acute pulpal stimulation. We have developed a model to study central changes following chronic inflammation of dental pulp that induces long-term sensitization. Here, we examine the effects of chronic inflammation and acute stimulation on the expression of phosphorylated ERK (pERK), phosphorylated p38 (pp38) and Fos in Vc. ⋯ This study provides the first demonstration that chronic inflammation of tooth pulp induces persistent bilateral activation of ERK and p38 within Vc, and that this activation is further increased by acute stimulation. This altered activity in intracellular signaling is likely to be linked to the sensitization that is seen in our animal model and in patients with pulpitis. Our data indicate that pERK and pp38 are more accurate markers of central change than Fos expression. In our model, localization of pERK and pp38 within specific cell types differs from that seen following acute stimulation. This may indicate specific roles for different cell types in the induction and maintenance of pulpitic and other types of pain.
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During chronic pain states, peripheral nociceptive stimulation can induce long-term potentiation (LTP) in the spinal dorsal horn, but it is not clear how quickly spinal LTP develops after peripheral noxious stimulation. Furthermore, transient receptor potential vanilloid type 1 (TRPV1) receptors are abundant in spinal cord dorsal horn, especially in the superficial layers, and are thought to be involved in synaptic plasticity. In this study, we investigated the time frame of LTP induction after inflammatory insult and electrical stimulation and the involvement of TRPV1 receptors. ⋯ Topical application of the TRPV1 receptor antagonist capsazepine onto the spinal cord inhibited the induction of spinal LTP by CFA or formalin. Furthermore, capsazepine and another TRPV1 antagonist, (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide, partially or completely blocked the LTP induced by conditioning stimulation with high- and low-frequency electrical stimulation. These results suggest that acute peripheral inflammatory stimulation by CFA or 5% formalin can induce spinal LTP very early after stimulation onset and that TRPV1 receptors in the spinal dorsal horn might contribute to this LTP induction.