published_or_final_version / Orthopaedics and Traumatology / Master / Master of Medical Sciences

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Introduction. Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes that interferes with daily living and causes severe pain. Pharmacotherapy is the accepted treatment strategy, however, this strategy is associated with high cost, minimal reductions in pain, and adverse side effects. Thus, a critical need exists to develop alternative treatment strategies. Purpose. To determine if a 12-week whole-body vibration (WBV) intervention reduces pain in adults with DPN. Methods. Twenty-one adults with physician confirmed painful DPN volunteered to take part in a 26-week time series design study. Pain was assessed with the Brief Pain Inventory Short Form [BPI-sf] and a 0-10 numeric rating scale [NRS]. The BPI-sf contains two indices that respectively measure how pain interferes with daily living and severity. The intervention began after a 12-week control period. At week 13, participants were asked to stand on a WBV machine 3 d/week for 4, 3-min bouts at 30-50 Hz with 1-min rest intervals between bouts. Pain levels were reported using the NRS before and after each bout. Results. Comparing post- to pre-intervention, BPI-sf pain interference scores decreased from 5.61±1.40 to 2.39±1.82 (p≤0.001). BPI-sf pain severity scores decreased from 5.1±0.64 to 3.1±1.87 (p≤0.01). Analyses of the NRS scores indicate that pain decreased each week following WBV and that between weeks, pain continued to decrease. Conclusion. These findings demonstrate that whole-body vibration was effective at reducing pain in a sample of adults with painful DPN. / Graduation date: 2012

Indiana University-Purdue University Indianapolis (IUPUI) / Giant axonal neuropathy (GAN) is a rare genetic disease that causes progressive damage to the nervous system. Neurons in GAN patients develop an abnormal organization of cytoskeletal proteins called intermediate filaments (IFs), which normally provide strength and support for the overall cell structure. The irregular IF structure in GAN patient neurons leads to a progressive loss of motor skills in children and subsequent death in adolescence. GAN is caused by reduced levels of the gigaxonin (Giga) protein. Giga functions to control the degradation of other cellular proteins, and the loss of Giga in GAN cells results in significantly elevated levels of the galectin-1 (Gal-1) protein. Gal-1 stabilizes the active form of the Ras signaling protein, which functions as a molecular switch to regulate the phosphorylation and subsequent organization of IFs. The connection between these pathways led us to propose that Giga regulates IF phosphorylation and structure by modulating Ras signaling through the degradation of Gal-1. Using GAN patient cells, we demonstrated that restoring Giga reduced Gal-1 protein levels, decreased IF phosphorylation, and reestablished normal IF organization. Similar effects of reduced IF phosphorylation and improved IF structure were also obtained in GAN cells by directly decreasing the protein levels of either Gal-1, or downstream Ras signaling proteins. Taken together, these results demonstrate that the loss of Giga induces Gal-1 mediated activation of Ras signaling, thereby leading to the increased IF phosphorylation and abnormal IF structure observed in GAN cells. Identification of aberrant Ras signaling is significant because it is the first to specify a mechanism by which the loss of Giga leads to the development of GAN and provides targets for novel drug therapies for the treatment of this currently immedicable genetic disease.

Microtubule targeting agents (MTAs) are chemotherapeutics commonly used in the treatment of breast, ovarian, lung, and lymphoma cancers. There are two main classes of MTAs based upon their effects on microtubule stability. The two classes are the destabilizing agents, which include the drug vincristine, and the stabilizing agents, which include paclitaxel and epothilone B. These drugs are highly effective antineoplastics, but their use is often accompanied by several side effects, one of which is peripheral neuropathy. Peripheral neuropathy can be characterized by burning pain, tingling, loss of proprioception, or numbness in the hands and feet. In some patients, the MTA-induced peripheral neuropathy is debilitating and dose-limiting; however, there are no effective prevention strategies or treatment options for peripheral neuropathy as the mechanisms mediating this side effect are unknown. The goal of this work was to investigate MTA-induced effects on neuronal activity and morphology in order to elucidate the underlying mechanisms involved in the development of MTA-induced peripheral neuropathy. As an indicator of sensory neuronal activity, the basal and stimulated release of the putative nociceptive peptide, calcitonin gene-related peptide (CGRP), was measured from sensory neurons in culture after exposure to the MTAs paclitaxel, epothilone B, and vincristine. Neurite length and branching were also measured in sensory neuronal cultures after treatment with these MTAs. The results described in this thesis demonstrate that MTAs alter the stimulated release of CGRP from sensory neurons in differential ways depending on the MTA agent employed, the CGRP evoking-stimulus used, the concentration of the MTA agent, the duration of exposure to the MTA agent, and the presence of NGF. It was also observed that MTA agents decrease neurite length and branching, independent of the concentration of NGF in the culture media. Thus, this thesis describes MTA-induced alterations of sensory neuronal sensitivity and neurite morphology and begins to elucidate the underlying mechanisms involved in MTA-induced alterations of sensory neurons. These findings will undoubtedly be used to help elucidate the mechanisms underlying MTA-induced peripheral neuropathy.