Isoflurane increases cell membrane fluidity significantly at clinical concentrations

Patel, Jigesh; Chowdhury, Ekram Ahmed; Noorani, Behnam; Bickel, Ulrich; Huang, Juyang

doi:10.1016/j.bbamem.2019.183140

Cited by 18 publications

(24 citation statements)

References 44 publications

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“… 14 In model membranes, isoflurane interferes with the organization of lipid domains, which leads to disturbances in lipid mobility and increased membrane fluidity. 15 , 16 We therefore hypothesized that in primary EC, isoflurane exposure could affect lipid nanodomains, which would result in enhanced transcytosis in our in vitro system. We stained primary ECs with BCtheta that binds cholesterol, predominantly when located in membrane lipid nanodomains.…”

Section: Resultsmentioning

confidence: 99%

“…This is compatible with our in vitro findings and with isoflurane-mediated perturbation of model membranes. 15 , 16 …”

Section: Resultsmentioning

confidence: 99%

“… 20 , 21 , 26 , 34 In model membranes, the hydrophobic isoflurane molecule dissolves in the bilayer and rapidly destabilizes especially compact liquid-ordered membrane regions by interfering with both hydrophobic membrane cores as well as glycerol backbones. 15 , 16 The correlate of liquid-ordered domains in model membranes are membrane lipid rafts/lipid nanodomains in cellular membranes. We show that isoflurane enlarged the size of membrane lipid nanodomains in cultured primary brain endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

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Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport

Spieth

Berghoff

Stumpf

et al. 2021

Neuro-Oncology Advances

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Background Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood-brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery. Methods Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis. Results Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy. Conclusions Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching therapeutic implications for CNS malignancies.

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Section: Resultsmentioning

confidence: 99%

“…This is compatible with our in vitro findings and with isoflurane-mediated perturbation of model membranes. 15 , 16 …”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport

Spieth

Berghoff

Stumpf

et al. 2021

Neuro-Oncology Advances

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“…Patel et al investigated the membrane effects of isoflurane using different membrane systems such as POPC/cholesterol liposomal membranes, erythrocyte ghosts and brain endothelial cell-mimetic membranes (34). FA measurements indicated that isoflurane increases the membrane fluidity at 1 and 5 mM.…”

Section: Inhalational Anestheticsmentioning

confidence: 99%

Interaction of drugs with lipid raft membrane domains as a possible target

Tsuchiya

Mizogami

2020

dti

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Introduction: Plasma membranes are not the homogeneous bilayers of uniformly distributed lipids but the lipid complex with laterally separated lipid raft membrane domains, which provide receptor, ion channel and enzyme proteins with a platform. The aim of this article is to review the mechanistic interaction of drugs with membrane lipid rafts and address the question whether drugs induce physicochemical changes in raft-constituting and raft-surrounding membranes. Methods: Literature searches of PubMed/MEDLINE and Google Scholar databases from 2000 to 2020 were conducted to include articles published in English in internationally recognized journals. Collected articles were independently reviewed by title, abstract and text for relevance. Results: The literature search indicated that pharmacologically diverse drugs interact with raft model membranes and cellular membrane lipid rafts. They could physicochemically modify functional protein-localizing membrane lipid rafts and the membranes surrounding such domains, affecting the raft organizational integrity with the resultant exhibition of pharmacological activity. Raft-acting drugs were characterized as ones to decrease membrane fluidity, induce liquid-ordered phase or order plasma membranes, leading to lipid raft formation; and ones to increase membrane fluidity, induce liquid-disordered phase or reduce phase transition temperature, leading to lipid raft disruption. Conclusion: Targeting lipid raft membrane domains would open a new way for drug design and development. Since angiotensin-converting enzyme 2 receptors which are a cell-specific target of and responsible for the cellular entry of novel coronavirus are localized in lipid rafts, agents that specifically disrupt the relevant rafts may be a drug against coronavirus disease 2019.

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“…BBB dysfunction is an important feature of the pathological cascades associated with different neurological disorders such as Alzheimer's disease, 116,117 stroke, 118,119 traumatic brain injury, 120,121 multiple sclerosis, 122,123 and even while anesthetized with volatile anesthetics. [124][125][126] Disruption of the BBB results in the infiltration of serum components and immune cells into the CNS parenchyma leading to the loss of CNS homeostasis, ultimately damaging the surrounding tissue. Even though BBB leakage is observed in most conditions, the degree of leakage has been found to vary from widespread leakage to localized small leaks in different brain regions.…”

Section: Clinical Techniques For Measuring Brain Permeabilitymentioning

confidence: 99%

Understanding the brain uptake and permeability of small molecules through the BBB: A technical overview

Chowdhury

Noorani

Alqahtani

et al. 2021

J Cereb Blood Flow Metab

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The brain is the most important organ in our body requiring its unique microenvironment. By the virtue of its function, the blood-brain barrier poses a significant hurdle in drug delivery for the treatment of neurological diseases. There are also different theories regarding how molecules are typically effluxed from the brain. In this review, we comprehensively discuss how the different pharmacokinetic techniques used for measuring brain uptake/permeability of small molecules have evolved with time. We also discuss the advantages and disadvantages associated with these different techniques as well as the importance to utilize the right method to properly assess CNS exposure to drug molecules. Even though very strong advances have been made we still have a long way to go to ensure a reduction in failures in central nervous system drug development programs.

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Isoflurane increases cell membrane fluidity significantly at clinical concentrations

Cited by 18 publications

References 44 publications

Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport

Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport

Interaction of drugs with lipid raft membrane domains as a possible target

Understanding the brain uptake and permeability of small molecules through the BBB: A technical overview

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