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Molecular Mechanisms and Experimental Therapies of Pain in Multiple Sclerosis

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Title: Molecular Mechanisms and Experimental Therapies of Pain in Multiple Sclerosis
Author(s): Hu, Xiaoyu
Advisor(s): Wang, Zaijie Jim
Contributor(s): Brodie, Mark S; Molokie, Robert E; Park, Thomas; Schlemmer, Francis; Wang, Zaijie Jim
Department / Program: Biopharmaceutical Sciences
Degree Granting Institution: University of Illinois at Chicago
Degree: PhD, Doctor of Philosophy
Genre: Doctoral
Subject(s): pain multiple sclerosis CaMKII curcumin
Abstract: Multiple sclerosis is an autoimmune disorder in central nervous system with manifestations of neuroinflammation and demyelination. Pain associated with multiple sclerosis is a common and severe symptom, but is barely studied in the pharmacological and medicinal researches compared with the motor dysfunction of this disease. In this study, we focused on investigating the molecular and cellular mechanisms underlying multiple sclerosis associated pain, and also on exploring the potential therapeutic interventions. To study the pain behavior of multiple sclerosis, an animal model of EAE, widely used for pathology study of multiple sclerosis, has been established and evaluated to present evoked mechanical and thermal hyperalgesia and non-evoked ongoing pain in mice. We discovered that inhibition of spinal CaMKIIα, a multifunctional serine/threonine kinase, is able to attenuate the pain in EAE mice. A role of IL-17, an immune factor, in initiating the EAE pain and regulating CaMKIIα was also identified. Specific targeting CaMKIIα in dorsal horn of spinal cord can be a potential therapy for multiple sclerosis associated pain. Curcumin was also studied as a potential therapeutics for pain. A novel nanoformulation has been employed to improve the solubility and bioavailability of curcumin, which is the main problem that hindered the medical use of curcumin for years. A dose-dependent effect of curcumin in attenuating opioid tolerance and dependence, and opioid-induced hyperalgesia was observed in this study, and this behavior observation was consistently linked to the pharmacological inhibition of CaMKIIα in brain and spinal dorsal horn. These findings provide better insights into the pharmacological mechanisms underlying the multiple sclerosis associated pain, and offered promising targeted experimental therapies for future development of effective treatment for pain management in multiple sclerosis.
Issue Date: 2017-03-17
Type: Thesis
Date Available in INDIGO: 2017-10-27
Date Deposited: May 2017

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