Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

Elmorsy, Ekramy; Smith, Paul A.

doi:10.1016/j.bbrc.2015.03.122

Cited by 26 publications

(18 citation statements)

References 25 publications

(33 reference statements)

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“…As a direct measure of bioenergetic potential, intracellular ATP was measured as previously described (Elmorsy and Smith, 2015). Data was corrected for background luminescence by subtraction of the values measured in media alone.…”

Section: Intracellular Atp Contentmentioning

confidence: 99%

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Editor’s Highlight: Therapeutic Concentrations of Antidepressants Inhibit Pancreatic Beta-Cell Function via Mitochondrial Complex Inhibition

Elmorsy

Al‐Ghafari

Helaly

et al. 2017

Toxicological Sciences

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Diabetes mellitus risk is increased by prolonged usage of antidepressants (ADs). Although various mechanisms are suggested for their diabetogenic potential, whether a direct effect of ADs on pancreatic β-cells is involved is unclear. We examined this idea for three ADs:paroxetine, clomipramine and, with particular emphasis, fluoxetine, on insulin secretion, mitochondrial function, cellular bioenergetics, K ATP channel activity and caspase activity in murine and human cell-line models of pancreatic β-cells. Metabolic assays showed that these ADs decreased the redox, oxidative respiration and energetic potential of β-cells in a time and concentration dependent manner at concentrations (100 nM) well within their plasma therapeutic window. These effects were related to inhibition of mitochondrial complex I and III activity.Consistent with impaired mitochondrial function, lactate output was increased and insulin secretion decreased. Neither fluoxetine, antimycin nor rotenone could reactivate K ATP channel activity blocked by glucose unlike the mitochondrial uncoupler, FCCP. Chronic, but not acute, AD increased oxidative stress and activated caspases, 3, 8 and 9. To conclude, paroxetine, clomipramine and fluoxetine were all found to be cytotoxic at therapeutic concentrations on pancreatic beta-cells; an action suggested to arise by inhibition of mitochondrial bioenergetics, oxidative stress and induction of apoptosis. These actions may help explain the diabetogenic potential of these ADs in humans.

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Section: Intracellular Atp Contentmentioning

confidence: 99%

“…The effect of ADs on MIN6 cells mitochondrial complexes I and III were assessed as previously described (Elmorsy and Smith, 2015). To maximize event detection, concentrations of ADs were chosen that inhibited MTT reduction/ATP production by ~ 50% after 24 hours incubation.…”

Section: Mitochondrial Complex Activitymentioning

confidence: 99%

Editor’s Highlight: Therapeutic Concentrations of Antidepressants Inhibit Pancreatic Beta-Cell Function via Mitochondrial Complex Inhibition

Elmorsy

Al‐Ghafari

Helaly

et al. 2017

Toxicological Sciences

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“…Furthermore, our group has previously reported that CPZ, HAL, CLZ and RIS significantly decreased ATP production in brain microvascular cells in concentrations and exposure durations dependent manner (Elmorsy and Smith, 2015).…”

Section: Discussionmentioning

confidence: 82%

“…Several APs (CPZ, HAL, RIS and CLZ) have been shown to decrease the mitochondrial trans-membrane potential (Neustadt andPieczenik, 2008, Elmorsy andSmith, 2015). Furthermore, Donohoe et al, (2006) showed APs to have an affect on the Calciumcalmodulin system, which is known to affect the mitochondrial membrane potential and ATP synthesis.…”

Section: Discussionmentioning

confidence: 99%

Effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells

Elmorsy

Al‐Ghafari

Aggour³

et al. 2017

Toxicology Letters

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MANUSCRIPT: "Effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells" Highlights: This study investigated the effects of four antipsychotics (APs) on mitochondrial bioenergetics and steroidogenesis of rats isolated ovarian theca interstitial cells (TICs) as a possible mechanism of reproductive toxicity. The APs used in this experiment include chlorpromazine (CPZ) haloperidol (HAL), risperidone (RIS) clozapine (CLZ).  All four APs seem to inhibit mitochondrial bioenergetics and steroidogenesis in rat's TICs.  These findings support the hypothesis that APs-induced reproductive toxicity may be through mechanisms involving mitochondrial insult. Abstract:Background: Antipsychotics (APs) are widely prescribed drugs, which are well known to cause

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“…These vascular changes, even though insufficient to trigger CVAE in adults without SVD, suggest an association between APDs and brain microvascular dysfunctions. Indeed, studies in rodents documented cerebral small vessel lesions in APDs-exposed animals (42, 43). …”

Section: Cerebral Small Vessel Disease the First Cvae Strikementioning

confidence: 99%

The Ticking of the Epigenetic Clock: Antipsychotic Drugs in Old Age

et al. 2016

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BackgroundExposed to antipsychotic drugs (APDs), older individuals with dementing illness are at risk of cerebrovascular adverse effects (CVAE), including sudden death. Transient microvascular dysfunctions are known to occur in younger persons exposed to APDs; however, they seldom progress to CVAE, suggesting that APDs alone are insufficient for engendering this untoward effect. It is, therefore, believed that a preexistent microvascular damage is necessary for CVAE to take place, but the exact nature of this lesion remains unclear. CNS small vessel disease (SVD) is a well-known age-related risk factor for strokes, dementia, and sudden death, which may constitute the initial CVAE-predisposing pathology. Therefore, we propose the two strikes CVAE paradigm, in which SVD represents the first strike, while exposure to APDs, the second. In this model, both strikes must be present for CVAE to take place, and the neuroimaging load of white matter hyperintensities may be directly proportional with the CVAE risk. To investigate this hypothesis at the molecular level, we focused on a seemingly unrelated phenomenon: both APDs and SVD were found protective against a similar repertoire of cancers and their spread to the brain (1–4). Since microRNA-29 has shown efficacy against the same malignancies and has been associated with small vessels pathology, we narrowed our search down to this miR, hypothesizing that the APDs mechanism of action includes miR-29 upregulation, which in turn facilitates the development of SVD.AimTo assess whether miR-29 can be utilized as a peripheral blood biomarker for SVD and CVAE risk.MethodWe conducted a search of experimentally verified miR-29 target genes utilizing the public domain tools miRanda, RNA22 and Weizemann Institute of Science miRNA Analysis. We identified in total 67 experimentally verified target genes for miR-29 family, 18 of which correlate with microvascular integrity and may be relevant for CVAE.ConclusionUpregulated microRNA-29 silences the expression of 18 genes connected with capillary stability, engendering a major vulnerability for SVD (first strike) which in turn increases the risk for CVAE after exposure to APDs (second strike).

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Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

Cited by 26 publications

References 25 publications

Editor’s Highlight: Therapeutic Concentrations of Antidepressants Inhibit Pancreatic Beta-Cell Function via Mitochondrial Complex Inhibition

Editor’s Highlight: Therapeutic Concentrations of Antidepressants Inhibit Pancreatic Beta-Cell Function via Mitochondrial Complex Inhibition

Effect of antipsychotics on mitochondrial bioenergetics of rat ovarian theca cells

The Ticking of the Epigenetic Clock: Antipsychotic Drugs in Old Age

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