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  • Investigating the Effects of Statins in Neuroinflammation-induced Neurodegeneration

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    McFarland, Amelia_Final Thesis_Redacted.pdf (15.83Mb)
    Author(s)
    McFarland, Amelia J.
    Primary Supervisor
    Anoopkumar-Dukie, Shailendra
    Other Supervisors
    Lewohl, Joanne
    Grant, Gary
    McDermott, Catherine
    Davey, Andrew
    Year published
    2017-11
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    Abstract
    Statins are widely used in primary and secondary prevention of atherosclerotic cardiovascular disease. Despite being generally considered as safe for use, current clinical evidence regarding the neurological effects of statins is conflicting. Although a number of large-scale studies suggest that statins are largely neuroprotective, case reports suggest a possible association between statins and adverse cognitive effects in the form of cognitive decline or memory impairment. There are numerous limitations surrounding existing in vitro and in vivo studies investigating statins’ central nervous system (CNS) effects, including ...
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    Statins are widely used in primary and secondary prevention of atherosclerotic cardiovascular disease. Despite being generally considered as safe for use, current clinical evidence regarding the neurological effects of statins is conflicting. Although a number of large-scale studies suggest that statins are largely neuroprotective, case reports suggest a possible association between statins and adverse cognitive effects in the form of cognitive decline or memory impairment. There are numerous limitations surrounding existing in vitro and in vivo studies investigating statins’ central nervous system (CNS) effects, including a lack of comparison between the different statin compounds. Consequently, a thorough understanding of statins’ mechanistic effects within the CNS has not been possible to date. The overall aim of this project was to determine the mechanisms underlying the effects of multiple structurally and pharmacologically diverse statins in neuroinflammation and subsequent neurodegeneration. This was achieved through a combination of in vitro and in vivo studies. Firstly, the effects of six (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) on the inflammatory response were investigated in vitro using differentiated THP-1 monocytes as surrogate microglia. This study identified that all statins (0-100 μM) significantly reduced lipopolysaccharide (LPS)-induced interleukin (IL)-1β (p<0.05) and tumour necrosis factor (TNF)-α release (p<0.001), as well as decrease LPS-induced prostaglandin E2 (PGE2; p<0.05). Similarly, global reactive oxygen species (ROS) and nitric oxide (NO) production were decreased following pre-treatment with all statins (p<0.05). To confirm the anti-inflammatory and antioxidant effects of statins which were observed in the microglial-like cells, a model IV of LPS-induced inflammation was established in brain-derived highly aggressive Similarly to differentiated THP-1 cells, it was found that all statins significantly decreased LPS-induced IL-1β, TNF-α, and PGE2 release in HAPI microglia (p<0.05). Furthermore all statins reduced both LPS-induced oxidative and nitrosative stress in HAPI microglia (p<0.05). In contrast to observations in differentiated THP-1 cells, statins effects in HAPI microglia demonstrated less consistency, with subtle differences between each statins’ anti-inflammatory ability observed. To determine the significance of these differences, LPS-conditioned media (CM) from HAPI microglia was used to treat SH-SY5Y neuroblastoma cells in an in vitro model of neuroinflammation-induced neurodegeneration. When statin-pre-treated HAPI-CM was applied to SH-SY5Y cells, only atorvastatin (100 μM, p<0.01), pravastatin (1-100 μM, p<0.05) and rosuvastatin (100 μM, p<0.01) pre-treatment significantly protected SH-SY5Y cells from LPS-induced decreases in cellular proliferation. In contrast, simvastatin pre-treatment (10 and 100 μM) augmented HAPI-CM induced toxicity (p<0.001). Reductions in TNF-α (atorvastatin, pravastatin and rosuvastatin) and IL-1β (atorvastatin and pravastatin only) were consistent with protection of SH-SY5Y cells against LPS-induced cytotoxicity and To confirm whether in vitro findings translated to an in vivo model, effects of atorvastatin, pravastatin, rosuvastatin and simvastatin on acute LPS-induced neuroinflammation were investigated in mice. Clinically relevant human-equivalent doses were used across short-term (3-day) and long-term (21-day) administration periods. Although all statins were associated with improvements in LPS-induced behavioural deficit after 3-day and 21-day regimens (p<0.05), only rosuvastatin proliferating immortalized (HAPI) rat microglia. caspase-3 elevations. V improved locomotor activity (LMA) after 3 days (p<0.01), which correlated with reduced brain IL-1β (p<0.05) and TNF-α (p<0.01). When treatment period was extended to 21 days, LPS-induced decreases in LMA were improved by atorvastatin (p<0.001), pravastatin (p<0.001) and rosuvastatin (p<0.05), which correlated with reduced brain IL-1β (p<0.001), TNF-α (p<0.05) and lipid peroxidation (p<0.001). Although simvastatin was associated with a reduction in LPS-induced behavioural deficit in vivo and demonstrating anti-inflammatory activity in brain homogenates, this compound had no effects on LMA, suggesting alternate neuropharmacological mechanisms to the other three statins. Ultimately, findings from this thesis suggest that while all tested statins exhibit anti-inflammatory and anti-oxidant activity, subtle pharmacological differences across the statin class results in differing effects on neuroinflammation and subsequent neurodegeneration both in vitro and in vivo. Furthermore, this thesis suggests that, of the statins examined, atorvastatin, pravastatin and rosuvastatin exhibit consistent protective effects both in vitro and in vivo against acute neuroinflammatory insult at doses which can be considered clinically relevant. Based on these findings, it is recommended that individual statins be considered as possessing distinct neurological effects, which are not necessarily applicable to the statin class.
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    Thesis Type
    Thesis (PhD Doctorate)
    Degree Program
    Doctor of Philosophy (PhD)
    School
    School of Pharmacy and Pharmac
    DOI
    https://doi.org/10.25904/1912/633
    Copyright Statement
    The author owns the copyright in this thesis, unless stated otherwise.
    Subject
    Statins
    Neuroinflammation
    Neurodegeneration
    Atorvastatin
    Pravastatin
    Rosuvastatin
    Simvastatin
    Publication URI
    http://hdl.handle.net/10072/375746
    Collection
    • Theses - Higher Degree by Research

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