Differences in statin associated neuroprotection corresponds with either decreased production of IL-1β or TNF-α in an in vitro model of neuroinflammation-induced neurodegeneration

A. J. McFarland, A. K. Davey, C. M. McDermott, G. D. Grant, J. Lewohl, S. Anoopkumar-Dukie

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2 Citations (Scopus)

Abstract

3-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.

Original languageEnglish
Pages (from-to)56-73
Number of pages18
JournalToxicology and Applied Pharmacology
Volume344
Early online date6 Mar 2018
DOIs
Publication statusPublished - 1 Apr 2018

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Interleukin-1
Pravastatin
Neurology
Lipopolysaccharides
Reactive Oxygen Species
Central Nervous System
fluvastatin
Neuroprotection
In Vitro Techniques
Caspase 7
Simvastatin
Autophagy
Mitochondrial Membranes
Microglia
Neuroprotective Agents
Cell death
Conditioned Culture Medium
Vacuoles
Neuroblastoma

Cite this

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title = "Differences in statin associated neuroprotection corresponds with either decreased production of IL-1β or TNF-α in an in vitro model of neuroinflammation-induced neurodegeneration",
abstract = "3-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.",
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Differences in statin associated neuroprotection corresponds with either decreased production of IL-1β or TNF-α in an in vitro model of neuroinflammation-induced neurodegeneration. / McFarland, A. J.; Davey, A. K.; McDermott, C. M.; Grant, G. D.; Lewohl, J.; Anoopkumar-Dukie, S.

In: Toxicology and Applied Pharmacology, Vol. 344, 01.04.2018, p. 56-73.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Differences in statin associated neuroprotection corresponds with either decreased production of IL-1β or TNF-α in an in vitro model of neuroinflammation-induced neurodegeneration

AU - McFarland, A. J.

AU - Davey, A. K.

AU - McDermott, C. M.

AU - Grant, G. D.

AU - Lewohl, J.

AU - Anoopkumar-Dukie, S.

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