Experimental neurology
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Experimental neurology · Oct 2013
Comparative StudyA comparison of the behavioral and anatomical outcomes in sub-acute and chronic spinal cord injury models following treatment with human mesenchymal precursor cell transplantation and recombinant decorin.
This study assessed the potential of highly purified (Stro-1(+)) human mesenchymal precursor cells (hMPCs) in combination with the anti-scarring protein decorin to repair the injured spinal cord (SC). Donor hMPCs isolated from spinal cord injury (SCI) patients were transplanted into athymic rats as a suspension graft, alone or after previous treatment with, core (decorin(core)) and proteoglycan (decorin(pro)) isoforms of purified human recombinant decorin. Decorin was delivered via mini-osmotic pumps for 14 days following sub-acute (7 day) or chronic (1 month) SCI. hMPCs were delivered to the spinal cord at 3 weeks or 6 weeks after the initial injury at T9 level. ⋯ Decorin did not increase axonal outgrowth from that achieved by hMPCs. We provide evidence for the first time that (Stro-1(+)) hMPCs provide: i) an advantageous source of allografts for stem cell transplantation for sub-acute and chronic spinal cord therapy, and (ii) a positive host microenvironment that promotes tissue sparing/repair that subsequently improves behavioral outcomes after SCI. This was not measurably improved by recombinant decorin treatment, but does provide important information for the future development and potential use of decorin in contusive SCI therapy.
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Experimental neurology · Oct 2013
Canine degenerative myelopathy: biochemical characterization of superoxide dismutase 1 in the first naturally occurring non-human amyotrophic lateral sclerosis model.
Mutations in canine superoxide dismutase 1 (SOD1) have recently been shown to cause canine degenerative myelopathy, a disabling neurodegenerative disorder affecting specific breeds of dogs characterized by progressive motor neuron loss and paralysis until death, or more common, euthanasia. This discovery makes canine degenerative myelopathy the first and only naturally occurring non-human model of amyotrophic lateral sclerosis (ALS), closely paralleling the clinical, pathological, and genetic presentation of its human counterpart, SOD1-mediated familial ALS. To further understand the biochemical role that canine SOD1 plays in this disease and how it may be similar to human SOD1, we characterized the only two SOD1 mutations described in affected dogs to date, E40K and T18S. ⋯ Further studies show that these mutants, like most human SOD1 mutants, have an increased propensity to form aggregates in cell culture, with 10-20% of cells possessing visible aggregates. Creation of the E40K mutation in human SOD1 recapitulates the normal enzymatic activity but not the aggregation propensity seen with the canine mutant. Our findings lend strong biochemical support to the toxic role of SOD1 in canine degenerative myelopathy and establish close parallels for the role mutant SOD1 plays in both canine and human disorders.
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Experimental neurology · Oct 2013
A re-assessment of the effects of treatment with a non-steroidal anti-inflammatory (ibuprofen) on promoting axon regeneration via RhoA inhibition after spinal cord injury.
This study was undertaken as part of the NIH "Facilities of Research Excellence-Spinal Cord Injury" project to support independent replication of published studies. Here, we repeat key parts of a study reporting that rats treated with ibuprofen via subcutaneous minipump exhibited greater recovery of motor function and enhanced axonal growth after spinal cord injury. We carried out 3 separate experiments in which young adult female Sprague-Dawley rats received dorsal over-hemisections at T6-T7, and then were implanted with osmotic minipumps for subcutaneous delivery of ibuprofen or saline. ⋯ Rats that received Ibuprofen did not demonstrate statistically significant improvements in bladder function. Quantitative analyses of CST and 5HT axon distribution also did not reveal differences between ibuprofen-treated and control rats. Taken together, our results only partially replicate the findings that treatment with ibuprofen improves motor function after SCI but fail to replicate findings regarding enhanced axon growth.
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Experimental neurology · Oct 2013
The trade-off between wiring cost and network topology in white matter structural networks in health and migraine.
The human brain organization of cortical networks has optimized trade-off architecture for the economical minimization of connection distance and maximizing valuable topological properties; however, whether this network configuration is disrupted in chronic migraine remains unknown. Here, employing the diffusion tensor imaging and graph theory approaches to construct white matter networks in 26 patients with migraine (PM) and 26 gender-matched healthy controls (HC), we investigated relationships between structural connectivity, cortical network architecture and anatomical distance in the two groups separately. Compared with the HC group, the patients showed longer global distance connection in PM, with proportionally less short-distance and more medium-distance; correspondingly, the patients showed abnormal global topology in their structural networks, mainly presented as a higher clustering coefficient. ⋯ Intriguingly, the network measure that combined the nodal anatomical distance and network topology could distinguish PM from HC with high accuracy of 90.4%. We also demonstrated a high reproducibility of our findings across different parcellation schemes. Our results demonstrated that long-term migraine may result in a abnormal optimization of a trade-off between wiring cost and network topology in white matter structural networks and highlights the potential for combining spatial and topological aspects as a network marker, which may provide valuable insights into the understanding of brain network reorganization that could be attributed to the underlying pathophysiology resulting from migraine.
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Experimental neurology · Oct 2013
A non-cholinergic neuronal loss in the pedunculopontine nucleus of toxin-evoked parkinsonian rats.
The pedunculopontine nucleus (PPN) controls various physiological functions, whilst being deemed a suitable target for low-frequency stimulation therapy for alleviating aspects of Parkinson's disease (PD). Previous studies showed that the PPN contains mainly cholinergic, γ-aminobutyric acid (GABA)ergic and glutamatergic neurons. Here we report on the total number of PPN neurons in laboratory rats, a species frequently used as an experimental model for simulating aspects of human PD. ⋯ Our data also show a significant loss which affected PPN non-cholinergic cells, but not cholinergic ones in rats lesioned unilaterally in the Substantia Nigra pars compacta (SNpc) with a single injection of 6-hydroxydopamine (6-OHDA) compared to control animals. This result differs from previous studies which reported a substantial cholinergic cell loss in the PPN of post-mortem PD brains and in 6-OHDA-lesioned monkeys. Since a noted demise of dopaminergic neurons residing in the SN was confirmed in the 6-OHDA-lesioned rats, the current study suggests that a "dying-back" mechanism may underlie the cell death affecting non-cholinergic PPN neurons.