Neuroscience
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A local elevation of H+-ion concentrations often occurs in inflammation and usually evokes pain by excitation of primary nociceptive neurons. Expression patterns and functional properties of the capsaicin receptor and acid-sensing ion channels suggest that they may be the main molecular substrates underlying this proton sensitivity. Here, we asked how the capsaicin receptor TRPV1 and acid-sensing ion channels (ASICS) contribute to the proton response in subpopulations of nociceptive neurons from adult rats and mice (wildtype C57/Bl6, Balb/C and TRPV1-null). ⋯ Together these findings indicate that there are significant differences between rat and mouse in the contribution of TRPV1 and ASIC subunits to proton sensitivity of sensory neurons. In both species ASIC subunits are more prevalent in the isolectin B4-negative neurons, some of which may represent thin myelinated nociceptors. However, the main acid-sensor in isolectin B4-positive and isolectin B4-negative unmyelinated nociceptors in mice is TRPV1.
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Insulin peptide, acting through tyrosine kinase receptor pathways, contributes to nerve development or repair. In this work, we examined the direction, impact and repertoire of insulin signaling in vivo during peripheral nerve regeneration in rats. First, we demonstrated that insulin receptor is expressed on lumbar dorsal root ganglia neuronal perikarya using immunohistochemistry. ⋯ Intrathecal insulin delivery was associated with greater recovery of thermal sensation and longer distances to stimulus response with the pinch test following sural nerve crush. Insulin signaling at neuron perikarya can drive distal sensory axon regrowth, rescue retrograde alterations of axons and alter axon peptide expression. Moreover, such actions are associated with upregulation of its own receptor.
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Comparative Study
Neuroprotection against ischemic brain injury by a small peptide inhibitor of c-Jun N-terminal kinase (JNK) via nuclear and non-nuclear pathways.
Our previous studies and the others have strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in ischemic brain injury. Here we reported that Tat-JNK binding domain (JBD) of JNK-interacting protein-1 (JIP-1), a smaller 11-mer peptide corresponding to residues 153-163 of murine JIP-1 conjugated to Tat peptide, perturbed the assembly of JIP-1-JNK3 complexes, thus inhibiting the activation of JNK3 induced by ischemia/reperfusion in the vulnerable hippocampal CA1 subregion. As a result, Tat-JBD diminished the increased phosphorylation of c-Jun (a nuclear substrate of JNK) and the increased expression of Fas ligand induced by ischemia/reperfusion in the vulnerable hippocampal CA1 subregion. ⋯ Importantly, Tat-JBD showed neuroprotective effects on ischemic brain damage in vivo, and administration of the peptide after ischemia also achieved the same effects as preinfusion of the peptide did. Thus, our findings imply that Tat-JBD induced neuroprotection against ischemia/reperfusion in rat hippocampal CA1 region via inhibiting nuclear and non-nuclear pathways of JNK signaling. Taken together, these results indicate that Tat-JBD peptide provides a promising therapeutic approach for ischemic brain injury.
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Comparative Study
Hypoxia/ischemia expands the regenerative capacity of progenitors in the perinatal subventricular zone.
Neurons and oligodendrocyte progenitors are highly sensitive to perinatal hypoxic-ischemic injury. As accumulating evidence suggests that many insults to the human infant occur in utero, and preventing brain damage to infants in utero will prove difficult, there is strong rationale to pursue regenerative strategies to reduce the morbidity associated with developmental brain injuries. The purpose of this study was to determine whether a hypoxic-ischemic insult stimulates the neural stem/progenitor cells in the subventricular zone to generate new neurons and oligodendrocytes. ⋯ Hypoxia-ischemia also increases neurogenesis in vivo. Doublecortin positive cells with migratory profiles were observed streaming from the ipsilateral subventricular zone to the striatum and neocortex, whereas, few doublecortin positive cells were found in the contralateral hemisphere after hypoxia-ischemia. These observations provide evidence that the somatic neural progenitors of the subventricular zone participate in the production of new brain cells lost after hypoxia-ischemia.
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Comparative Study
Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase.
PDE10A is a recently identified phosphodiesterase that is highly expressed by the GABAergic medium spiny projection neurons of the mammalian striatum. Inhibition of PDE10A results in striatal activation and behavioral suppression, suggesting that PDE10A inhibitors represent a novel class of antipsychotic agents. In the present studies we further elucidate the localization of this enzyme in striatum of rat and cynomolgus monkey. ⋯ Immuno-electron microscopy of striatum confirms that PDE10A is most often associated with membranes in dendrites and spines. Immuno-gold particles are observed on the edge of the postsynaptic density but not within this structure. Our studies indicate that PDE10A is associated with post-synaptic membranes of the medium spiny neurons, suggesting that the specialized compartmentation of PDE10A enables the regulation of intracellular signaling from glutamatergic and dopaminergic inputs to these neurons.