Neuroscience
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Our previous studies have shown that intracerebral administration of endotoxin, lipopolysaccharide (LPS), induces selective white matter injury and hypomyelination in the neonatal rat brain and that the LPS-induced brain injury is associated with activation of microglia. To test the hypothesis that inhibition of microglial activation may protect against LPS-induced white matter injury, we examined roles of minocycline, a putative suppressor of microglial activation, on LPS-induced brain injury in the neonatal rat. A stereotactic intracerebral injection of LPS (1 mg/kg) was performed in postnatal day 5 Sprague-Dawley rats and control rats were injected with sterile saline. ⋯ The protective effect of minocycline was associated with suppressed microglial activation as indicated by the decreased number of activated microglial cells following LPS stimulation and with consequently decreased elevation of interleukin 1beta and tumor necrosis factor-alpha concentrations induced by LPS and a reduced number of inducible nitric oxide synthase expressing cells. Protection of minocycline was also linked with the reduction in LPS-induced oxidative stress, as indicated by 4-hydroxynonenal positive OLs. The overall results suggest that reduction in microglial activation may protect the neonatal brain from LPS-induced white matter injury and inhibition of microglial activation might be an effective approach for the therapeutic treatment of infection-induced white matter injury.
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The corticospinal tract is widely used to study regeneration and is essential for voluntary movements in humans. In young rats, corticospinal axons on the uninjured side sprout and grow into the denervated side. Neurotrophin-3 (NT-3) induces such crossed collateral sprouting in adults. ⋯ NT-3 caused sprouting of local calcitonin gene-related peptide-positive fibers. These results suggest that NT-3 reduces collateral sprouting of spared corticospinal axons from within the denervated regions, possibly because of the injury environment or by increasing sprouting of local afferents. They identify an unexpected context-dependent outgrowth inhibitory effect of NT-3.
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Recent data suggest that anesthetic drugs may cause widespread and dose-dependent apoptotic neurodegeneration during development. The window of vulnerability to this neurotoxic effect, particularly with N-methyl-D-aspartate (NMDA) antagonists such as ketamine, is restricted to the period of synaptogenesis. The purposes of this study are to determine whether treatment of forebrain cultures with ketamine results in a dose-related increase in neurotoxicity and whether upregulation of NMDA receptor subunit NR1 promotes ketamine-induced apoptosis. ⋯ Western analysis showed that neurotoxic concentrations of ketamine increased Bax and NR1 protein levels. NR1 antisense prevented this increase caused by ketamine, suggesting that ketamine-induced cell death is associated with a compensatory upregulation of the NMDA receptor. These data suggest that NR1 antisense offers neuroprotection from apoptosis in vitro, and that upregulation of the NR1 following ketamine administration is, at least, partially responsible for the observed apoptosis.
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We have previously found that tissue type and urokinase type plasminogen activators (tPA and uPA) are induced in dorsal root ganglia (DRG) neurons after peripheral axotomy and that tPA plays crucial roles in generating neuropathic pain. Here we examined whether the plasminogen activator inhibitor-1 and -2 (PAI-1 and PAI-2) mRNA, endogenous inhibitors of tPA and uPA, are induced in the DRG following sciatic nerve transection. L4 and L5 DRG sections were examined using in situ hybridization histochemistry. ⋯ The precise expression patterns of PAI-1 and PAI-2 mRNA at 3 days after axotomy revealed that PAI-1 mRNA was observed in predominantly small neurons, while much of the PAI-2 mRNA was expressed in large neurons. Double-labeling analysis of these mRNAs with activated transcription factor 3, known as an injury marker, revealed that most PAI-1 and PAI-2 mRNAs was induced in injured neurons. Co-expression of PAI-1, 2 with tPA and uPA in DRG neurons suggests that these inhibitors may act in an autocrine manner to modulate extracellular proteolytic activity after nerve injury.
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CNS activity is generally coupled to the vigilance state, being primarily active during wakefulness and primarily inactive during deep sleep. During periods of high neuronal activity, a significant volume of oxygen is used to maintain neuronal membrane potentials, which subsequently produces cytotoxic reactive oxygen species (ROS). Glutathione, a major endogenous antioxidant, is an important factor protecting against ROS-mediated neuronal degeneration. ⋯ Indeed, Ca2+ release from mitochondria and delayed-onset Ca2+ influx via N-methyl-D-aspartate receptors was visualized during peroxide exposure using Ca2+ indicator proteins (YC-2.1 and mitochondrial-targeted Pericam) expressed in organotypic cultures of the POAH. In the in vitro models, t-butyl-hydroperoxide (50 microM) causes dendritic swelling followed by the intracellular Ca2+ mobilization, and D-AP5 (100 microM) or glutathione (500 microM) inhibited t-butyl-hydroperoxide-induced intracellular Ca2+ mobilization and protected POAH neurons from oxidative stress. These data suggest that low-level subcortical oxidation under the control of an antioxidant system may trigger sleep via the Ca(2+)-dependent release of sleep-inducing neuromodulators in the POAH, and thus we propose that a moderate increase of ROS during wakefulness in the neuronal circuits regulating sleep may be an initial trigger in sleep induction.