Journal of neuroscience research
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Neuroglobin (Ngb) is a recently discovered tissue globin with a high affinity for oxygen that is widely and specifically expressed in neurons of vertebrate central and peripheral nervous systems. Our laboratory and others have shown Ngb overexpression can protect neurons against hypoxic/ischemic insults, but the underlying mechanisms remain poorly understood. In this study, we examined the effects of Ngb overexpression on mitochondrial function, oxidative stress, and neurotoxicity in primary cortical neurons following hypoxia/reoxygenation (H/R). ⋯ Rates of decline in ATP levels, MTT reduction, and mitochondrial membrane potential were significantly ameliorated in Ngb-Tg neurons. Furthermore, Ngb overexpression reduced superoxide anion generation after H/R, whereas glutathione levels were significantly improved compared with WT controls. Taken together, these data suggest that Ngb is neuroprotective against hypoxia, in part by improving mitochondria function and decreasing oxidative stress.
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The effect of the potent soluble guanylyl cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) on neurite outgrowth and retraction was investigated in PC12 cells and SH-SY5Y human neuroblastoma cells. ODQ inhibited neurite outgrowth and triggered neurite retraction in the cells stimulated with nerve growth factor (NGF), staurosporine, or Y-27632. The nitric oxide (NO) scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO) had little effect on neurite outgrowth induced by Y-27632 or staurosporine. ⋯ The MEK inhibitor PD98059 did not inhibit neurite outgrowth, and Y-27632 and staurosporine did not induce ERK phosphorylation, suggesting that the inhibitory effect of ODQ on neurite outgrowth is independent of the ERK signaling pathway. In contrast, pretreatment with dithionite or a hemin-glutathione mixture reversed the inhibitory effect of ODQ on Y-27632- and staurosporine-induced neurite outgrowth, indicating that ODQ might act on an intracellular redox-sensitive molecule. We conclude that ODQ inhibits Y-27632- and staurosporine-induced neurite outgrowth and triggers neurite retraction in an sGC-independent manner in neuronal cells and suggest that oxidation of unidentified redox-sensitive protein could be responsible for these effects.
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The inward-rectifier K(+) channel Kir4.1 is responsible for maintaining cochlear homeostasis and restoring neural excitability. The large-conductance calcium-activated K(+) channel (BK(Ca)) plays a key role in phase locking signals in the mammalian inner ear. To evaluate the influence of mitochondrial dysfunction on the expression and subcellular localization of these channels, 3-nitropropionic acid (3-NP) was administered to rat round window membranes for 30 min. ⋯ Kir4.1 was detected in intermediate cells of the stria, Deiter's cells, and spiral ganglion satellite cells. Kir4.1 failed to reach the perineural cytoplasm of the satellite cells after 3-NP treatment. The results of this study suggest that mitochondrial dysfunction disrupts trafficking of Kir4.1 in spiral ganglion satellite cells.
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Cognitive deficits, including spatial memory impairment, are very common after ischemic stroke. Neurogenesis in the dentate gyrus (DG) contributes to forming spatial memory in the ischemic brain. Fluoxetine, a selective serotonin reuptake inhibitor, can enhance neurogenesis in the hippocampus in physiological situations and some neurological diseases. ⋯ Disrupting hippocampal neurogenesis blocked the beneficial effect of fluoxetine on ischemia-induced spatial cognitive impairment. These results suggest that chronic fluoxetine treatment benefits spatial cognitive function recovery following ischemic insult, and the improved cognitive function is associated with enhanced newborn cell survival in the hippocampus. Our results raise the possibility that fluoxetine can be used as a drug to treat poststroke spatial cognitive deficits.