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Old drugs in a new light : investigating the gold Rheumatoid Arthritis medications as novel inhibitors of neuroinflammation

University of British Columbia

Several degenerative disorders of the central nervous system including Alzheimer’s and Parkinson’s diseases are characterized by chronic inflammation. The main contributors to this inflammation are glial cells, including microglia and astrocytes. Even though they are normally protective, disease specific stimuli can activate glial cells to start secreting neurotoxic molecules. There is no effective treatment for neurodegenerative diseases, though it is hypothesized that reducing neuroinflammation may diminish neuronal loss. Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) has been linked with lower incidence of neurodegenerative disorders, though mixed results have been obtained in clinical trials of NSAIDs when these drugs are used for treatment of established disease. Gold thiol compounds, including aurothiomalate, aurothioglucose, and auranofin, comprise another class of medications effective at reducing peripheral inflammation in rheumatoid arthritis patients. Their effects on neuroinflammation are unknown. In this thesis I demonstrate that 0.1 – 5 µM auranofin, but not the other gold thiol compounds, inhibits human microglia and astrocyte-mediated neurotoxicity in vitro. The anti-neurotoxic properties of auranofin are selective; treatment with auranofin does not inhibit expression or secretion of several cytokines by glia but does upregulate heme-oxygenase (HOX)-1. Interestingly, low micromolar concentrations of auranofin directly protect neuronal cells from toxicity induced by hydrogen peroxide or stimulated glial supernatants, possibly through the upregulation of HOX-1. Lastly, laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) was used to demonstrate that auranofin reaches low micromolar concentrations in mouse brains following daily oral administration for one week. Since auranofin can protect against neuroinflammation by inhibiting glial toxicity and is directly neuroprotective, it may be useful in neurodegenerative diseases where sustained inflammation contributes to disease progression including neuronal loss.

Text

2012-11-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/43622

Biology

University of British Columbia

UBCO

http://creativecommons.org/licenses/by-nc-nd/4.0/