Atorvastatin activates autophagy and promotes neurological function recovery after spinal cord injury

Gao, Shuang; Zhang, Zhongming; Shen, Zhaoliang; Gao, Kai; Chang, Liang; Guo, Yuanqiang; Li, Zhuo; Wang, Wei; Wang, Ai-mei

doi:10.4103/1673-5374.184498

Cited by 33 publications

(23 citation statements)

References 39 publications

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“…Interestingly, while our model suggests that high-dose simvastatin appeared to augment LPS- [80,81]. It is important to note that autophagy is a complex, evolutionarily preserved process, and the effects of statins on this pathway are poorly understood [82,83].…”

Section: Discussionmentioning

confidence: 74%

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

Davey

McDermott

et al. 2018

Toxicology and Applied Pharmacology

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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 PGE 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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Section: Discussionmentioning

confidence: 74%

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

Davey

McDermott

et al. 2018

Toxicology and Applied Pharmacology

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“…The β2-adrenergic receptor is a major activator of autophagy 60 , and we found that β2 antagonist led to a significant increase in the splice correction activity. Furthermore, autophagy induction by atorvastatin 61 significantly reduced the splice correction activity mediated by PF14 transfection system. Prostaglandin E2 (PGE2) induces autophagy 62 and is capable of diminishing splice correction as well.…”

Section: Discussionmentioning

confidence: 95%

Role of autophagy in cell-penetrating peptide transfection model

Dowaidar

Gestin

Cerrato

et al. 2017

Sci Rep

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Cell-penetrating peptides (CPPs) uptake mechanism is still in need of more clarification to have a better understanding of their action in the mediation of oligonucleotide transfection. In this study, the effect on early events (1 h treatment) in transfection by PepFect14 (PF14), with or without oligonucleotide cargo on gene expression, in HeLa cells, have been investigated. The RNA expression profile was characterized by RNA sequencing and confirmed by qPCR analysis. The gene regulations were then related to the biological processes by the study of signaling pathways that showed the induction of autophagy-related genes in early transfection. A ligand library interfering with the detected intracellular pathways showed concentration-dependent effects on the transfection efficiency of splice correction oligonucleotide complexed with PepFect14, proving that the autophagy process is induced upon the uptake of complexes. Finally, the autophagy induction and colocalization with autophagosomes have been confirmed by confocal microscopy and transmission electron microscopy. We conclude that autophagy, an inherent cellular response process, is triggered by the cellular uptake of CPP-based transfection system. This finding opens novel possibilities to use autophagy modifiers in future gene therapy.

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“…Some of the pleiotropic effects attributed to statins may related to their potential role regulating essential proteins involved in autophagy (Ashrafizadeh, Ahmadi, Farkhondeh, & Samarghandian, 2020). Atorvastatin induced autophagy by enhancing Beclin1 and LC3-II (Gao et al, 2016) gene and protein expression or via the AMPK/mTOR pathway (Zhang et al, 2013). In cancer cells, lovastatin induced autophagy by up-regulating LC3-II (Shi, Felley-Bosco, Marti, & Stahel, 2012), and atorvastatin through LC3-I to LC3-II conversion (Hu et al, 2018).…”

Section: Role Of Statins In the Autophagy Responsementioning

confidence: 99%

Statins: Could an old friend help in the fight against COVID‐19?

Rodrigues-Díez

Tejera‐Muñoz

Márquez‐Expósito

et al. 2020

British J Pharmacology

113

114

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The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has overwhelmed healthcare systems requiring the rapid development of treatments, at least, to reduce COVID-19 severity. Drug repurposing offers a fast track. Here, we discuss the potential beneficial effects of statins in COVID-19 patients based on evidence that they may target virus receptors, replication, degradation, and downstream responses in infected cells, addressing both basic research and epidemiological information. Briefly, statins could modulate virus entry, acting on the SARS-CoV-2 receptors, ACE2 and CD147, and/or lipid rafts engagement. Statins, by inducing autophagy activation, could regulate virus replication or degradation, exerting protective effects. The well-known anti-inflammatory properties of statins, by blocking several molecular mechanisms, including NF-κB and NLRP3 inflammasomes, could limit the "cytokine storm" in severe COVID-19 patients which is linked to fatal outcome. Finally, statin moderation of coagulation response activation may also contribute to improving COVID-19 outcomes.

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Atorvastatin activates autophagy and promotes neurological function recovery after spinal cord injury

Cited by 33 publications

References 39 publications

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

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

Role of autophagy in cell-penetrating peptide transfection model

Statins: Could an old friend help in the fight against COVID‐19?

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