Experimental neurology
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Experimental neurology · Nov 2014
Comparative StudyA comparative morphological, electrophysiological and functional analysis of axon regeneration through peripheral nerve autografts genetically modified to overexpress BDNF, CNTF, GDNF, NGF, NT3 or VEGF.
The clinical outcome of microsurgical repair of an injured peripheral nerve with an autograft is suboptimal. A key question addressed here is: can axon regeneration through an autograft be further improved? In this article the impact of six neurotrophic factors (BDNF, CNTF, GDNF, NGF, NT3 or VEGF) on axon regeneration was compared after delivery to a 1cm long nerve autograft by gene therapy. To distinguish between early and late effects, regeneration was assessed at 2 and 20weeks post-surgery by histological, electrophysiological and functional analysis. ⋯ These three factors did not have detectable pro-regenerative effects. In conclusion, autograft-based repair combined with gene therapy for three of the six growth factors investigated (BDNF, GDNF, NGF) showed considerable promise since these factors enhanced modality specific axon outgrowth in autografts. The remarkable and selective effects of BDNF, GDNF and NGF on motor or sensory regeneration will be exploited in future experiments that aim to carefully regulate their temporal and spatial expression since this has the potential to overcome the adverse effects on long-distance regeneration observed after uncontrolled delivery.
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Experimental neurology · Nov 2014
Over-expression of P2X7 receptors in spinal glial cells contributes to the development of chronic postsurgical pain induced by skin/muscle incision and retraction (SMIR) in rats.
Many patients suffer from chronic postsurgical pain (CPSP) following surgery, and the underlying mechanisms are poorly understood. In the present work, with use of the skin/muscle incision and retraction (SMIR) model, the role of P2X7 receptors (P2X7Rs) in spinal glial cells in the development of CPSP was evaluated. Consistent with previous reports, we found that SMIR decreased the ipsilateral 50% paw withdrawal threshold (PWT), lasting for at least 2weeks. ⋯ Intrathecal delivery of specific P2X7R antagonist BBG (10μM in 10μl volume) or A438079 (10μM in 10μl volume), started 30min before the surgery and once daily thereafter for 7days, prevented the mechanical allodynia. Intrathecal injection of BBG inhibited the activation of microglia and astrocytes, and the up-regulation of TNF-α induced by SMIR. These data suggest that P2X7Rs in the spinal dorsal horn might mediate the development of CPSP via activation of glial cells and up-regulation of TNF-α.
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Experimental neurology · Nov 2014
Peripheral prostaglandin E2 prolongs the sensitization of nociceptive dorsal root ganglion neurons possibly by facilitating the synthesis and anterograde axonal trafficking of EP4 receptors.
Prostaglandin E2 (PGE2), a well-known pain mediator enriched in inflamed tissues, plays a pivotal role in the genesis of chronic pain conditions such as inflammatory and neuropathic pain. PGE2-prolonged sensitization of nociceptive dorsal root ganglion (DRG) neurons (nociceptors) may contribute to the transition from acute to chronic pain. However, the underlying cellular mechanisms are poorly understood. ⋯ EP4 was expressed in almost half of IB4-binding nociceptors of L4-6 DRG. Taken together, our data suggest that stimulating the synthesis and anterograde axonal trafficking to increase EP4 availability at the axonal terminals of nociceptors is likely a novel mechanism underlying PGE2-prolonged nociceptor sensitization. Blocking COX2/PGE2/EP4 signaling at an earlier stage of inflammation or injury is crucial for preventing the transition from acute pain to a chronic state.
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Experimental neurology · Nov 2014
Role of striatal NMDA receptor subunits in a model of paroxysmal dystonia.
Dystonia is a movement disorder in which abnormal plasticity in the basal ganglia has been hypothesized to play a critical role. In a model of paroxysmal dystonia, the dt(sz) mutant hamster, previous studies indicated striatal dysfunctions, including an increased long-term potentiation (LTP). Beneficial effects were exerted by subunit-unspecific antagonists at NMDA receptors, which blocked LTP. ⋯ By using quantitative RT-PCR, the NR2A/NR2B ratio was found to be increased in the striatum, but not in the cortex of mutant hamsters in comparison to non-dystonic controls. These data indicate that NR2A-mediated activation may be involved in the pathophysiology of paroxysmal dystonia. Since significant antidystonic effects were observed after systemic administration of NVP-AAM077 already at well tolerated doses, antagonists with preferential activity on NR2A-containing NMDA receptors could be interesting candidates for the treatment of dystonia.
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Experimental neurology · Nov 2014
Low brain iron effects and reversibility on striatal dopamine dynamics.
Iron deficiency (ID) in rodents leads to decreased ventral midbrain (VMB) iron concentrations and to changes in the dopamine (DA) system that mimic many of the dopaminergic changes seen in RLS patient where low substantia nigra iron is a known pathology of the disease. The ID-rodent model, therefore, has been used to explore the effects that low VMB iron can have on striatal DA dynamics with the hopes of better understanding the nature of iron-dopamine interaction in Restless Legs Syndrome (RLS). Using a post-weaning, diet-induced, ID condition in rats, the No-Net-Flux microdialysis technique was used to examine the effect of ID on striatal DA dynamics and it reversibility with acute infusion of physiological concentrations of iron into the VMB. ⋯ In summary, the ID-rodent model provides highly reproducible changes in striatal DA dynamics that remarkably parallel dopaminergic changes seen in RLS patients. Some but not all of these ID-induced changes in striatal DA dynamics were reversible with physiological increases in VMB iron. The small changes in VMB iron induced by iron infusion likely represent biologically relevant changes in the non-transferrin-bound labile iron pool and may mimic circadian-dependent changes that have been found in VBM extracellular iron.