Browsing by Author "Motsch, Melanie"

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    Early-onset treadmill training reduces mechanical allodynia and modulates calcitonin gene-related peptide fiber density in lamina III/IV in a mouse model of spinal cord contusion injury
    (Lippincott, Williams, and Wilkins, 2016-03) Nees, Timo A.; Tappe-Theodor, Anke; Sliwinski, Christopher; Motsch, Melanie; Rupp, Rüdiger; Kuner, Rohini; Weidner, Norbert; Blesch, Armin; Department of Neurological Surgery, IU School of Medicine
    Abstract: Below-level central neuropathic pain (CNP) affects a large proportion of spinal cord injured individuals. To better define the dynamic changes of the spinal cord neural network contributing to the development of CNP after spinal cord injury (SCI), we characterized the morphological and behavioral correlates of CNP in female C57BL/6 mice after a moderate T11 contusion SCI (50 kdyn) and the influence of moderate physical activity. Compared with sham-operated animals, injured mice developed mechanical allodynia 2 weeks post injury when tested with small-diameter von Frey hair filaments (0.16 g and 0.4 g filament), but presented hyporesponsiveness to noxious mechanical stimuli (1.4 g filament). The mechano-sensory alterations lasted up to 35 days post injury, the longest time point examined. The response latency to heat stimuli already decreased significantly 10 days post injury reaching a plateau 2 weeks later. In contrast, injured mice developed remarkable hyposensitivity to cold stimuli. Animals that underwent moderate treadmill training (2 × 15 minutes; 5 d/wk) showed a significant reduction in the response rate to light mechanical stimuli as early as 6 days after training. Calcitonin gene-related peptide (CGRP) labeling in lamina III-IV of the dorsal horn revealed significant increases in CGRP-labeling density in injured animals compared with sham control animals. Importantly, treadmill training reduced CGRP-labeling density by about 50% (P < 0.01), partially reducing the injury-induced increases. Analysis of IB4-labeled nonpeptidergic sensory fibers revealed no differences between experimental groups. Abnormalities in temperature sensation were not influenced by physical activity. Thus, treadmill training partially resolves signs of below-level CNP after SCI and modulates the density of CGRP-labeled fibers.
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    An Inducible Tyrosine Kinase Receptor for Axonal Regeneration
    (2016) Deng, Ming; McCall, Julianne; Goganau, Ioana; Motsch, Melanie; Weidner, Norbert; Blesch, Armin; Department of Neurological Surgery, IU School of Medicine
    The prevention or reduction of neuronal degeneration remains a challenge in neurotrophins therapy. An inducible trkA (ItrkA) system has been shown to regulate embryonic dorsal root ganglion (DRG) neuronal survival and neurite outgrowth in vitro. A new ItrkA plasmid ItrkA-membrane (ItrkAmemb) with one adenine at 3’ terminal was established by correcting the sequence of the original plasmid ItrkA-cytosol (ItrkAcyto). Adult DRGs were dissected from adult Fischer 344 rats (8-14 weeks) for the treatment with AP20187 (membrane-permeable small-molecule ligand), vehicle or NGF (Nerve Growth Factor). Neurite outgrowth assessments were done by manually tracing the longest neurite of each neuron. Cell diameters were also measured and averaged for each well. Protein expression after ItrkAmemb transfection and trkA downstream signaling were investigated by Western-blotting. Neurite length of ItrkAmemb transfected DRGs was not influenced by AP20187 or NGF but cells displayed shorter neurites compared to GFP control groups. While ItrkAcyto transfected DRGs cultured with AP20187 had the longest neurite growth compared to ItrkAmemb transfected neurons and ItrkAcyto transfected cells treated with vehicle or NGF, no significant difference to GFP controls was detected. Quantification of the mean diameter of transfected DRGs demonstrated that ItrkAmemb electroporation significantly increased cell diameter, while the diameter of ItrkAcyto transfected neurons and GFP controls were almost the same as naïve neurons. In contrast to electroporated adult DRG neurons, ItrkAmemb virus transfection did not affect the diameter of infected adult DRG Neurons. No obvious difference was observed between the ItrkAmemb and GFP electroporated cells, and only cells transduced with ItrkAmemb treated with AP20187 seemed to show higher phosphorylation both of Akt and Erk1/2. The effect of adult DRG neurons after ItrkA transfection differs, which depends on the change of cell soma size and/or neurite growth, gene delivery technique, expression level and the localization of ItrkA.
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    Systemic epothilone D improves hindlimb function after spinal cord contusion injury in rats
    (Elsevier, 2018) Sandner, Beatrice; Puttagunta, Radhika; Motsch, Melanie; Bradke, Frank; Ruschel, Jörg; Blesch, Armin; Weidner, Norbert; Neurological Surgery, School of Medicine
    Following a spinal cord injury (SCI) a growth aversive environment forms, consisting of a fibroglial scar and inhibitory factors, further restricting the already low intrinsic growth potential of injured adult central nervous system (CNS) neurons. Previous studies have shown that local administration of the microtubule-stabilizing drug paclitaxel or epothilone B (Epo B) reduce fibrotic scar formation and axonal dieback as well as induce axonal growth/sprouting after SCI. Likewise, systemic administration of Epo B promoted functional recovery. In this study, we investigated the effects of epothilone D (Epo D), an analog of Epo B with a possible greater therapeutic index, on fibrotic scarring, axonal sprouting and functional recovery after SCI. Delayed systemic administration of Epo D after a moderate contusion injury (150 kDyn) in female Fischer 344 rats resulted in a reduced number of footfalls when crossing a horizontal ladder at 4 and 8 weeks post-injury. Hindlimb motor function assessed with the BBB open field locomotor rating scale and Catwalk gait analysis were not significantly altered. Moreover, formation of laminin positive fibrotic scar tissue and 5-HT positive serotonergic fiber length caudal to the lesion site were not altered after treatment with Epo D. These findings recapitulate a functional benefit after systemic administration of a microtubule-stabilizing drug in rat contusion SCI.