Neuroscience
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Cell surface glycoconjugates are thought to mediate cell-cell recognition and play roles in neuronal development and functions. We demonstrated here that exposure of neuronal cells to nanomolar levels of gangliosides Neu5Acalpha 8Neu5Acalpha 3Galbeta 4GlcCer, Galbeta 3GalNAcbeta 4(Neu5Acalpha 8Neu5Acalpha 3)Galbeta 4GlcCer (GD1b), Neu5Acalpha 3Galbeta 3GalNAcbeta 4(Neu5Acalpha 8Neu5Acalpha 3)Galbeta 4GlcCer (GT1b) or its oligosaccharide portion induced a rapid and transient activation of Ca2+/calmodulin-dependent protein kinase II (CaM-KII) in the subplasmalemma. Galbeta 3GalNAcbeta 4(Neu5Acalpha 3)Galbeta 4GlcCer (GM1), GalNAcbeta 4(Neu5Acalpha 3)Galbeta 4GlcCer, Neu5Acalpha 3Galbeta 4GlcCer, Neu5Acalpha 3Galbeta 3GalNAcbeta 4(Neu5Acalpha 3)Galbeta 4GlcCer (GD1a), and Neu5Acalpha 8Neu5Acalpha 3Galbeta 3GalNAcbeta 4(Neu5Acalpha 8Neu5Acalpha 3)-Galbeta 4GlcCer were ineffective. ⋯ The filopodia formation induced by the gangliosides may have a physiological relevance because long-term exposure of hippocampal neurons to GT1b oligosaccharide induced advanced dendritogenesis. Furthermore, exposure of cerebellar neurons to GT1b oligosaccharide facilitated CaM-KII-dependent dendritic outgrowth and branch formation of cerebellar Purkinje neurons, in which actin isoforms were localized to motile structures in dendrites. Thus, the ganglioside/CaM-KII signal plays a role in modulating dendritic morphogenesis by inducing cdc42-mediated actin reorganization.
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Comparative Study
[3H]-nociceptin ligand-binding and nociceptin opioid receptor mrna expression in the human brain.
Following the cloning of the novel nociceptin opioid receptor (NOP(1)) and the identification of its endogenous ligand orphanin FQ/nociceptin the distribution and functional role of the NOP(1) receptor system have been studied mainly in the rodent CNS. In the present study the regional distribution and splice variant expression of the NOP(1) receptor was investigated in the adult human brain using [(3)H]-nociceptin autoradiography, NOP(1) reverse transcriptase PCR and mRNA in situ hybridization. Ligand binding revealed strong expression of functional NOP(1) receptors in the cerebral cortex and moderate signals in hippocampus and cerebellum. ⋯ A considerable expression of N-terminal NOP(1) splice variant mRNAs was not detectable in the human brain by means of in situ hybridization. This suggests that functional NOP(1) receptors in the human brain are encoded by N-terminal full length NOP(1) transcripts. The present data on the anatomical distribution of nociceptin binding sites and NOP(1) receptor mRNA contribute to the knowledge about opioid receptor systems in the human brain and may promote the understanding of function and pharmacology of the orphanin FQ/nociceptin receptor system in the human CNS.
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Comparative Study
Androgens modulate neuronal vulnerability to kainate lesion.
Testosterone has been shown to have multiple beneficial effects on neuronal viability in developing and adult animals. Most often, testosterone promotes neural health indirectly via enzymatic conversion to estradiol by aromatase. Unclear is whether androgens can directly modulate vulnerability to neuronal insults in adult animals. ⋯ The depletion of endogenous androgens by GDX significantly augmented lesion severity, consistent with the hypothesis that androgens are involved in maintaining cell viability. Importantly, DHT hormone replacement in GDX rats significantly attenuated kainate-induced neuron loss in CA2/3, suggesting direct androgen neuroprotection. These results demonstrate that androgens act as endogenous modulators of neuron viability, a function that may be compromised in aging men as a consequence of normal, age-related androgen depletion.
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To identify possible intracellular mediators of hair cell (HC) death due to ototoxins, we treated basal-turn, neonatal, rat HCs in vitro with several intracellular signaling inhibitors, prior to and during gentamicin exposure. The general guanine nucleotide-binding protein (G-protein) inhibitor, GDP-betaS (1 mM), provided potent HC protection, suggesting involvement of G-proteins in the intracellular pathway linking gentamicin exposure to HC death. ⋯ Spectroscopic analysis of peptide fragments from this band matched its sequence with H-Ras. The Ras inhibitors B581 (50 microM) and FTI-277 (10 microM) provided potent protection against damage and reduced c-Jun activation in HC nuclei, suggesting that activation of Ras is functionally involved in damage to these cells due to gentamicin.
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Comparative Study
Local sensory ganglion ischemia induced by endothelin vasoconstriction: vulnerability of diabetic neurons and microvessels.
In some disorders of the peripheral nervous system, it is relevant to understand how sensory neurons respond to selective ganglion ischemia. Sensory dorsal root ganglia may be susceptible to ischemic damage and irretrievable neuron loss because of their metabolic requirements. In diabetes, heightened sensitivity to ischemia associated with elevated endothelin levels might render ganglia particularly vulnerable. ⋯ Both intraganglionic axons and downstream sural sensory axons developed evidence of axonal degeneration. Local endothelin-induced vasoconstriction of microvessels supplying dorsal root ganglia provides a selective model of ischemia. Diabetic vessels and neurons, exposed to a greater depth and duration of ischemia from endothelin, are especially vulnerable.