Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood–brain barrier

Elmorsy, Ekramy; El-Zalabany, Laila; Elsheikha, Hany M.; Smith, Paul A.

doi:10.1016/j.brainres.2014.08.011

Cited by 49 publications

(41 citation statements)

References 46 publications

(43 reference statements)

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“…HBVECs were grown and maintained in RPMI-1640 medium which also contained heat inactivated 20% Foetal Bovine Serum, 2mM L-glutamine, 1mM sodium pyruvate, 1% minimum essential media (MEM) vitamins, 1% MEM non-essential amino acids, 100 units of penicillin-G ml -1 , and 100 µg of streptomycin sulphate ml -1 as previously described [4]. When confluent, our HBVECs demonstrated morphological and transport properties consistent with a functional endothelium identity [4].…”

Section: Cellsmentioning

confidence: 92%

“…Their ability to cross the BBB from the blood plasma to the CSF is prevented by the BBB [1] and compromised by the counter-transport activities of PGP and MRP, consequently a tipping point is envisaged where if a drug reaches a sufficiently high enough intracellular concentration to impair the mitochondrial function of BBB endothelial cells then a combined action of a decrease in intracellular ATP and ATPase-dependent pump activities will culminate in a catastrophic failure of the endothelial cell to act as an effective barrier for that drug; a process manifest as a drug permeable conduit from the plasma into the CNS with associated neuropathologies [4]. Indeed, we have recently shown that a variety of APs can impair BBB functions at concentrations seen at the higher end of their therapeutic windows and with over-dosage [4]. The fact that this effect was associated with decreased cellular redox potential and increased ROS production, implicates that the adverse action of APs on endothelial cells of the BBB was most likely mediated by mitochondrial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

Elmorsy

Smith

2015

Biochemical and Biophysical Research Communications

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Antipsychotics (APs) are widely used medications, however these are not without side effects such as disruption of blood brain barrier function (BBB). To investigate this further we have studied the chronic effects of the typical APs, chlorpromazine (CPZ) and haloperidol (HAL) and the atypical APs, risperidone (RIS) and clozapine (CLZ), on the bioenergetics of human micro-vascular endothelial cells (HBVECs) of the BBB. Alamar blue (AB) and ATP assays showed that these APs impair bioenergenesis in HBVECs in a concentration and time dependent manner. However since these effects were incomplete they suggest a population of cell bioenergetically heterogeneous, an idea supported by the bistable nature by which APs affected the mitochondrial transmembrane potential. CPZ, HAL and CLZ inhibited the activity of mitochondrial complexes I and III.Our data demonstrates that at therapeutic concentrations, APs can impair the bioenergetic status of HBVECs, an action that help explains the adverse side effects of these drugs when used clinically.

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Section: Cellsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

Elmorsy

Smith

2015

Biochemical and Biophysical Research Communications

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“…As such it is a facile indicator of cell viability that results from the product of cell number and redox status (Elmorsy et al, 2014). The MTT assay was employed in accord with the manufacturer's protocol (CellTiter 96 Non-Radioactive Cell Proliferation Assay; Promega, UK).…”

Section: Measurement Of Cell Viability With Mttmentioning

confidence: 99%

“…Cells were incubated for 4, 24, 48 or 72 hours in the presence of ADs or vehicle. In one set of experiments, this assay was repeated in the presence of 10 mM reduced glutathione (GSH) with a concentration of AD that inhibited MTT reduction by ~ 50% after 24 hours incubation (Elmorsy et al, 2014).…”

Section: Measurement Of Cell Viability With Mttmentioning

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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Sex‐dependent alterations of dopamine receptor and glucose transporter density in rat hypothalamus under long‐term clozapine and haloperidol medication

et al. 2020

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Objective Sex‐dependent disturbances of peripheral glucose metabolism are known complications of antipsychotic drug treatment. The influence of long‐term clozapine and haloperidol medication on hypothalamus, maintaining aspects of internal body homeostasis, has not yet been completely clarified. Methods After puberty, male and female Sprague Dawley rats were fed orally with ground pellets containing haloperidol (1 mg/kgBW/day) or clozapine (20 mg/kgBW/day) for 12 weeks. The hypothalamic protein expression of dopamine receptors D2R and D4R, melanocortin receptor MC4R, and glucose transporters Glut1 and Glut3 was examined. Glucose, glycogen, lactate, and pyruvate levels were determined, also malondialdehyde equivalents as markers of oxidative stress. Results D2R expression was increased in the male haloperidol and clozapine group but decreased in females medicated with clozapine. D4R expression was upregulated under clozapine medication. While females showed increased Glut1, Glut3 was elevated in both male and female clozapine‐medicated animals. We found no changes of hypothalamic malondialdehyde, glycogen, and MC4R. Hypothalamic lactate was elevated in the female clozapine group. Conclusion Clozapine sex‐dependently affects the expression of D2R, Glut1, and Glut3. The upregulation of the glucose transporters indicates glucose deprivation in the endothelial cells and consequently in astrocytes and neurons. Increased hypothalamic lactate in females under clozapine points to enhanced glycolysis with a higher glucose demand to produce the required energy. Haloperidol did not change the expression of the glucose transporters and upregulated D2R only in males.

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Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood–brain barrier

Cited by 49 publications

References 46 publications

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

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

Sex‐dependent alterations of dopamine receptor and glucose transporter density in rat hypothalamus under long‐term clozapine and haloperidol medication

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