| Dissertation |
Thesis (M.Sc.) --NUI, 2015 at Department of Anatomy and Neuroscience, UCC. |
| Summary |
Abstract Neuroinflammation has emerged as a central player in progressive neurodegeneration. The innate immune system, orchestrated by Toll-like receptors (TLRs) and downstream effectors, has received much interest in the progression of neuroinflammatory diseases such as Multiple Sclerosis (MS). Baclofen, a gamma-aminobutyric acid (GABA)B receptor agonist, is currently prescribed for the management of spasticity associated with MS, but whether baclofen also has disease-modifying or anti-inflammatory effects in MS or in mixed glial models of neuroinflammation is not yet clear. Both glial cells of the central nervous system (CNS) and mononuclear cells of the peripheral immune system express the GABAB receptor, thus suggesting that activity of this receptor might play a role in central and peripheral inflammatory responses. In the present study we set out to determine whether modulation of GABAB receptors using baclofen can exert anti-inflammatory effects by impacting TLR3 and TLR4-induced inflammatory signalling in murine glial cells and human peripheral blood mononuclear cells (PBMCs) isolated from healthy control individuals and MS patients. The results indicate that the previously reported effects of GABAB receptor activation on TLR4-induced inflammatory processes in microglia and astrocytes do not translate to a mixed glial model of innate neuroinflammatory activity. In addition although baclofen was found to impact TLR3-induced intracellular signalling events, baclofen was not found to alter TLR3 induced inflammatory cytokine release. Analysis of peripheral mononuclear cells isolated from healthy control subjects and treatment-naïve Relapse Remitting (RR) MS patients revealed increased basal inflammatory activity among RRMS subjects as well as increased sensitivity to TLR4-induced inflammation. Investigation of the effects of baclofen on human cells revealed a modest anti-inflammatory activity in peripheral mononuclear cells isolated from healthy controls, but this effect was not observed in peripheral mononuclear cells isolated from RRMS subjects. These results suggest that although baclofen may modulate peripheral innate immune processes, it remains to be seen whether this extends to MS pathogenesis. |
| Subject |
Nervous system -- Degeneration.
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| Collection |
Theses Masters (Research)
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Theses Anatomy and Neuroscience Department
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| Description |
118 pages ; 30 cm. |
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