Neuroscience
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Blast-induced tinnitus, along with associated auditory impairment and traumatic brain injury, is a primary concern facing military service members. To search for treatment, we investigated the therapeutic effects of sildenafil, a phosphodiesterase-5 inhibitor, given its vasodilatory effects and evidence suggesting its beneficial effects on noise-induced hearing loss. Rats were subjected to three consecutive blast exposures at 22 psi and were monitored for tinnitus using a gap-detection acoustic startle reflex paradigm. ⋯ Complex results were observed in the startle force data, where sildenafil-treated rats displayed significantly reduced startle force compared to the untreated blasted group, suggesting possible mitigation of traumatic brain injury and suppression of hyperacusis-like percepts. Taken together, sildenafil showed a therapeutic effect on blast-induced tinnitus and audiological impairment in a time-dependent manner. Other regimens such as higher dosage prior to blast exposure and combination with other treatments deserve further investigation to optimize the therapeutic effects.
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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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The interaction between excitatory and inhibitory inputs is critical to neuronal signal processing. However, little is known about this fundamental property, largely due to the inability to clearly isolate the respective inputs. Here we took advantage of the characteristic stereotypical architecture of synaptic connections in the main olfactory bulb, which enabled us to entirely separate excitatory and inhibitory inputs. ⋯ Unexpectedly, these forms of plasticity depend on activity of somatic (mainly non-synaptic) NMDA receptors (NMDARs). In contrast, the same repetitive stimulation induced the LTP of excitatory inputs in strongly activated MCs (MC2) that require activity of synaptic NMDARs. These distinct forms of plasticity in the developing olfactory circuit may represent a novel rule of modification in convergent inputs that leads to decorrelation of inputs and facilitates odor discrimination.
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Increased reactive oxygen species generation and mitochondrial dysfunction occur during ethanol hangover. The aim of this work was to study the effect of melatonin pretreatment on motor performance and mitochondrial function during ethanol hangover. Male mice received melatonin solution or its vehicle in drinking water during 7 days and i.p. injection with EtOH (3.8 g/kg BW) or saline at the eighth day. ⋯ No differences were observed in nNOS protein expression, while iNOS expression was increased in the melatonin group. Increased NO production by melatonin could be involved in the decrease of succinate-dependent oxygen consumption and the inhibition of complex IV observed in our study. Melatonin seems to act as an antioxidant agent in the ethanol hangover condition but also exhibited some dual effects related to NO metabolism.
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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.