Neuroscience
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Spiral ganglion neurons (SGNs), the target cells of the cochlear implant, undergo gradual degeneration following loss of the sensory epithelium in deafness. The preservation of a viable population of SGNs in deafness can be achieved in animal models with exogenous application of neurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3. For translation into clinical application, a suitable delivery strategy that provides ongoing neurotrophic support and promotes long-term SGN survival is required. ⋯ We found that fibroblasts that were nucleofected to express BDNF provided the most sustained neurotrophin expression, with ongoing BDNF expression for at least 30 weeks. In addition, the secreted neurotrophin was biologically active and elicited survival effects on SGNs in vitro. Nucleofected fibroblasts may therefore represent a method for safe, long-term delivery of neurotrophins to the deafened cochlea to support SGN survival in deafness.
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In a previous study, we have shown that the small organic compound tegaserod, a drug approved for clinical application in an unrelated condition, is a mimic of the regeneration-beneficial glycan polysialic acid (PSA) in a mouse model of femoral nerve injury. Several independent observations have shown positive effects of PSA and its mimetic peptides in different paradigms of injury of the central and peripheral mammalian nervous systems. Since small organic compounds generally have advantages over metabolically rapidly degraded glycans and the proteolytically vulnerable mimetic peptides, a screen for a small PSA mimetic compound was successfully carried out, and the identified molecule proved to be beneficial in neurite outgrowth in vitro, independent of its originally described function as a 5-HT4 receptor agonist. ⋯ Immunohistology of the spinal cord rostral and caudal to the lesion site showed increased numbers of neurons, and a reduced area and intensity of glial fibrillary acidic protein immunoreactivity. Quantification of regrowth/sprouting of axons immunoreactive for tyrosine hydroxylase and serotonin showed increased axonal density rostral and caudal to the injury site in the ventral horns of mice treated with tegaserod. The combined observations suggest that tegaserod has the potential for treatment of spinal cord injuries in higher vertebrates.
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Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein reported to have neuroprotective effects in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We investigated whether GPNMB is also neuroprotective against brain ischemia-reperfusion injury (IRI). Focal ischemia/reperfusion injury was induced via filament middle cerebral artery occlusion (MCAO) for 2h, followed by reperfusion upon withdrawal of the filament. ⋯ Furthermore, recombinant GPNMB also decreased infarction volume. These results indicate that GPNMB protected neurons against IRI, and phosphor-Akt and phosphor-ERK might be a part of the protective mechanisms, and that the neuroprotective effect of GPNMB was seemingly induced by the extracellular sequence of GPNMB. In conclusion, these findings indicate that GPNMB has neuroprotective effects against IRI, via phosphorylation of ERK1/2 and Akt, suggesting that GPNMB may be a therapeutic target for ischemia-reperfusion injuries.
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Stressful events promote a wide range of neurotransmitter and neuroendocrine changes, which likely serve in an adaptive capacity. However, with repeated stressor exposure, behavioral disturbances, such as anxiety and depression, may develop. Moreover, re-exposure to a stressor for some time following an initial aversive experience may instigate especially pronounced neurochemical variations that favor the emergence of depression and anxiety. ⋯ In the PFC an acute stressor treatment increased IL-1R expression, but otherwise had little effect. In a plus-maze test, stressed male mice displayed markedly reduced latencies to the open arms that was evident in a test 6 weeks later irrespective of whether mice were re-exposed to a stressor, whereas in females this outcome was less evident. These studies are consistent with the perspective that female mice are relatively resilient toward stressor-induced cytokine elevations even though in humans females are generally more prone to developing mood disturbances.
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P2X7 receptors play an important role in inflammatory hyperalgesia, but the mechanisms involved in their hyperalgesic role are not completely understood. In this study, we hypothesized that P2X7 receptor activation induces mechanical hyperalgesia via the inflammatory mediators bradykinin, sympathomimetic amines, prostaglandin E2 (PGE2), and pro-inflammatory cytokines and via neutrophil migration in rats. We found that 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate triethylammonium salt (BzATP), the most potent P2X7 receptor agonist available, induced a dose-dependent mechanical hyperalgesia that was blocked by the P2X7 receptor-selective antagonist A-438079 but unaffected by the P2X1,3,2/3 receptor antagonist TNP-ATP. ⋯ Co-administration of DALBK or bradyzide with BzATP significantly reduced BzATP-induced IL-1β and CINC-1 release. These results indicate that peripheral P2X7 receptor activation induces mechanical hyperalgesia via inflammatory mediators, especially bradykinin, which may contribute to pro-inflammatory cytokine release. These pro-inflammatory cytokines in turn may mediate the contributions of PGE2, sympathomimetic amines and neutrophil migration to the mechanical hyperalgesia induced by local P2X7 receptor activation.