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dc.contributor.authorMcFarland, AJ
dc.contributor.authorDavey, AK
dc.contributor.authorMcDermott, CM
dc.contributor.authorGrant, GD
dc.contributor.authorLewohl, J
dc.contributor.authorAnoopkumar-Dukie, S
dc.date.accessioned2019-07-04T12:38:11Z
dc.date.available2019-07-04T12:38:11Z
dc.date.issued2018
dc.identifier.issn0041-008X
dc.identifier.doi10.1016/j.taap.2018.03.005
dc.identifier.urihttp://hdl.handle.net/10072/385101
dc.description.abstract3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been associated with conflicting effects within the central nervous system (CNS), with underlying mechanisms remaining unclear. Although differences between individual statins' CNS effects have been reported clinically, few studies to date have compared multiple statins' neuroprotective effects. This study aimed to compare six statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin; 0–100 μM) using an in vitro model of lipopolysaccharide (LPS)-induced neuroinflammation and subsequent neurodegeneration. To achieve this, HAPI microglia were treated with LPS (0.1 μg/mL; 24 h), resulting in increased reactive oxygen species (ROS), nitric oxide, and IL-1β, TNF-α and PGE2 release. Conditioned media (“HAPI-CM”) was then transferred to SH-SY5Y neuroblastoma cells, and effects on cellular viability, mitochondrial membrane permeability, apoptosis, autophagy and ROS production assessed. Of the statins investigated, only atorvastatin, pravastatin and rosuvastatin protected SH-SY5Y cells from LPS-induced decreases in cellular viability; this appeared mediated through reduced caspase 3/7 activation and was associated with decreased IL-1β (atorvastatin, pravastatin) and/or TNF-α (atorvastatin, pravastatin, rosuvastatin). Only pravastatin conferred protection at all tested concentrations. ROS production and autophagic vacuole formation was decreased by all statins, suggesting these two mechanisms are unlikely to be sole mediators of neuroprotection seen with selected statins. Ultimately, our model suggests that despite all statins reducing microglial inflammation, subsequent effects on neuronal viability and cell death signalling pathways varies between statins. Our findings highlight the need to consider individual statins as inducing discrete pharmacological effects within the CNS in future in vitro/in vivo studies and in clinical practice.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier
dc.publisher.placeUnited States
dc.relation.ispartofpagefrom56
dc.relation.ispartofpageto73
dc.relation.ispartofjournalToxicology and Applied Pharmacology
dc.relation.ispartofvolume344
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences not elsewhere classified
dc.subject.fieldofresearchcode3214
dc.subject.fieldofresearchcode321499
dc.titleDifferences in statin associated neuroprotection corresponds with either decreased production of IL-1? or TNF-? in an in vitro model of neuroinflammation-induced neurodegeneration
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dc.description.versionAccepted Manuscript (AM)
gro.rights.copyright© 2018 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorLewohl, Joanne M.
gro.griffith.authorGrant, Gary D.
gro.griffith.authorAnoopkumar-Dukie, Shailendra
gro.griffith.authorDavey, Andrew


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