The effect of prolonged simvastatin application on serotonin uptake, membrane microviscosity and behavioral changes in the animal model

Vevera, Jan; Valeš, Karel; Fišar, Zdeněk; Hroudová, Jana; Singh, Namrata; Stuchlı́k, Aleš; Kačer, Petr; Nekovarova, Tereza

doi:10.1016/j.physbeh.2016.02.029

Cited by 23 publications

(22 citation statements)

References 50 publications

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“…At present, there are still strong indications of a relationship between cholesterol metabolism, serotonergic signaling, and behavioral effects, particularly violent and impulsive behavior. This is exemplified by a recent study on rats exposed to statins, which displayed increased impulsivity and cognitive difficulties after treatment with the statins (Vevera et al, 2016).…”

Section: Cholesterol and Serotoninmentioning

confidence: 89%

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Plasma apolipoprotein E and severity of suicidal behaviour

Asellus

Nordström

Jokinen

2016

Journal of Affective Disorders

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Section: Cholesterol and Serotoninmentioning

confidence: 89%

“…The link between low serum cholesterol and suicide, violent suicide attempts, impulsive behavior, or aggression, has long been considered to be mediated through alterations in the serotonergic system (Engelberg, 1992;Wallner and Machatschke, 2009;Vevera et al, 2016).…”

Section: Cholesterol and Serotoninmentioning

confidence: 99%

Plasma apolipoprotein E and severity of suicidal behaviour

Asellus

Nordström

Jokinen

2016

Journal of Affective Disorders

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“…STT produced a synergistic effect on level of 5HT when given along with FLX (Figure 4). Recent reports also revealed the elevated level of 5HT and synergistic antidepressant activity after treatment with the STT 47,48. It can be explained that statins dose-dependently attenuate the activity of indoleamine 2,3-dioxygenase (IDO), which is an interferon γ-inducible enzyme that degrades tryptophan in the kynurenine pathway.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous administration of fluoxetine and simvastatin ameliorates lipid profile, improves brain level of neurotransmitters, and increases bioavailability of simvastatin

Alasmari¹,

Ullah²,

Masoudi³

et al. 2017

JEP

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Simvastatin (STT), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is widely prescribed for dyslipidemia, whereas fluoxetine (FLX) is the first-choice drug for the treatment of depression and anxiety. A recent report suggests that selective serotonin reuptake inhibitors can interact with the cytochrome P450 3A4 substrate, and another one suggests that STT enhances the antidepressant activity of FLX. However, the data are inconclusive. The present study was designed to explore the pharmacokinetic and pharmacodynamic consequences of coadministration of STT and FLX in experimental animals. For this, Wistar rats weighing 250±10 g were divided into four groups, including control, STT (40 mg/kg/day), FLX (20 mg/kg/day), and STT+FLX group, respectively. After the dosing period of 4 weeks, the animals were sacrificed, and the blood and brain samples were collected for the analysis of STT, simvastatin acid (STA), FLX, total cholesterol, triglyceride, high-density lipoprotein (HDL), 5-hydroxytryptamine, dopamine, and hydroxy indole acetic acid. It was found that the coadministration resulted in a significant increase in the bioavailability of STT in the plasma (41.8%) and brain (68.7%) compared to administration of STT alone (p<0.05). The maximum drug concentration (Cmax) of STT was also found to be increased significantly in the plasma and brain compared to that achieved after monotherapy (p<0.05). However, STT failed to improve the pharmacokinetics of FLX up to a significant level. The results of this study showed that the combined regimen significantly reduced the level of cholesterol and triglyceride and increased the level of HDL when compared to STT monotherapy. Furthermore, the coadministration of STT with FLX led to an elevated level of neurotransmitters in the brain (p<0.05). FLX increased the concentration of STT in the plasma and brain. The coadministration of these drugs also led to an improved lipid profile. However, in the long-term, this interaction may have a vital clinical importance because the increase in STT level may lead to life-threatening side effects associated with statins.

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“…For example, simvastatin significantly reduces cellular cholesterol content in hypothalamic cells (Fukui et al ., ), in association with impaired insulin‐dependent Akt phospho‐activation (Fukui et al ., ). Such effects may arise throughout the CNS, as simvastatin reduced cholesterol content across brain regions, coupled with increased membrane fluidity, decreased serotonin transporter activity and behavioural changes (Vevera et al ., ). Atorvastatin treatment is also associated with alterations in membrane lipid raft proteins and behaviour or cognition (Schilling et al ., ).…”

Section: Strategic Manipulation Of Membrane‐dependent Protectionmentioning

confidence: 97%

Sarcolemmal dependence of cardiac protection and stress‐resistance: roles in aged or diseased hearts

Hoe

May

Headrick

et al. 2016

British J Pharmacology

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Disruption of the sarcolemmal membrane is a defining feature of oncotic death in cardiac ischaemia-reperfusion (I-R), and its molecular makeup not only fundamentally governs this process but also affects multiple determinants of both myocardial I-R injury and responsiveness to cardioprotective stimuli. Beyond the influences of membrane lipids on the cytoprotective (and death) receptors intimately embedded within this bilayer, myocardial ionic homeostasis, substrate metabolism, intercellular communication and electrical conduction are all sensitive to sarcolemmal makeup, and critical to outcomes from I-R. As will be outlined in this review, these crucial sarcolemmal dependencies may underlie not only the negative effects of age and common co-morbidities on myocardial ischaemic tolerance but also the on-going challenge of implementing efficacious cardioprotection in patients suffering accidental or surgically induced I-R. We review evidence for the involvement of sarcolemmal makeup changes in the impairment of stress-resistance and cardioprotection observed with ageing and highly prevalent co-morbid conditions including diabetes and hypercholesterolaemia. A greater understanding of membrane changes with age/disease, and the inter-dependences of ischaemic tolerance and cardioprotection on sarcolemmal makeup, can facilitate the development of strategies to preserve membrane integrity and cell viability, and advance the challenging goal of implementing efficacious 'cardioprotection' in clinically relevant patient cohorts. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein-Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc.

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The effect of prolonged simvastatin application on serotonin uptake, membrane microviscosity and behavioral changes in the animal model

Cited by 23 publications

References 50 publications

Plasma apolipoprotein E and severity of suicidal behaviour

Plasma apolipoprotein E and severity of suicidal behaviour

Simultaneous administration of fluoxetine and simvastatin ameliorates lipid profile, improves brain level of neurotransmitters, and increases bioavailability of simvastatin

Sarcolemmal dependence of cardiac protection and stress‐resistance: roles in aged or diseased hearts

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