Journal of neuroscience research
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Neonatal hypoxia-ischemia (HI) induces immediate early gene (IEG) c-fos expression as well as neuron death. The precise role of IEGs in neonatal HI is unclear. We investigated the temporal and spatial patterns of c-Fos expression in postnatal day 7 mice after unilateral carotid ligation and exposure to 8% oxygen. mRNA levels of c-fos quantitated by real-time polymerase chain reaction (PCR) increased nearly 40-fold (log 1.2 +/- 0.4) in the ipsilateral hippocampus 3 hr following neonatal HI, then returned to basal levels within 12 hr, although no change was observed in c-jun mRNA. ⋯ Double-labeling experiments showed c-Fos and cleaved caspase-3 immunoreactivity localized in spatially distinct neuron subpopulations. Prominent c-Fos immunoreactivity was observed in surviving CA2-3 and external granular DG neurons, and robust cleaved caspase-3 immunoreactivity was observed in pyknotic CA1, CA2-3, and subgranular DG neurons. The differential expression of c-Fos in HI-resistant hippocampal subpopulations vs. cleaved caspase-3 in dying neurons suggests a neuroprotective role for c-Fos expression in neonatal HI.
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Nociceptin/orphanin FQ (N/OFQ) is an opioid-related peptide that is markedly up-regulated in sensory neurons in vivo following peripheral inflammation and plays a key role in pain physiology. To identify substances that up-regulate N/OFQ expression in sensory neurons, we carried out an in vitro screen using purified adult mouse dorsal root ganglion (DRG) neurons and identified the potent proinflammatory agent bacterial lipopolysaccharide (LPS) as a very effective inducer of N/OFQ. ⋯ Blocking antibodies against TLR4 and MD-1 prevented induction of N/OFQ by LPS, and, in immunoprecipitation experiments, MD-1 coprecipitated with TLR4. Our findings suggest that LPS regulates N/OFN expression in sensory neurons via a novel combination of LPS receptor components and demonstrate for the first time a direct action of a key initiator of innate immune responses on neurons.
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High-mobility group box-1 (HMGB1) was originally identified as a ubiquitously expressed, abundant nonhistone DNA-binding protein. Recently, it was found to act as a cytokine-like mediator of delayed endotoxin lethality and of acute lung injury. Previously, we reported that HMGB1 is massively released extracellularly and plays a cytokine-like function in the postischemic brain. ⋯ After 1 hr of MCAO, HMGB1 immediately translocated from the neuron nuclei to the cytoplasm and subsequently was depleted from neurons during the excitotoxicity-induced acute damaging process. Moreover, beginning 2 days after reperfusion, HMGB1 was notably induced in activated microglia, astrocytes, and in microvascular structures, and these delayed gradual inductions were sustained for several days. These findings suggest that HMGB1 functions as a cytokine-like mediator in a paracrine and autocrine manner in the postischemic brain.