title: Sevoflurane and Isoflurane induce structural changes in brain vascular endothelial cells and increase blood-brain barrier permeability: Possible link to postoperative delirium and cognitive decline.
abstract: A large percentage of patients subjected to general anesthesia at 65 years and older exhibit postoperative delirium (POD). Here, we test the hypothesis that inhaled anesthetics (IAs), such as Sevoflurane and Isoflurane, act directly on brain vascular endothelial cells (BVECs) to increase blood-brain barrier (BBB) permeability, thereby contributing to POD. Rats of young (3-5 months), middle (10-12 months) and old (17-19 months) ages were anesthetized with Sevoflurane or Isoflurane for 3h. After exposure, some were euthanized immediately; others were allowed to recover for 24h before sacrifice. Immunohistochemistry was employed to monitor the extent of BBB breach, and scanning electron microscopy (SEM) was used to examine changes in the luminal surfaces of BVECs. Quantitative immunohistochemistry revealed increased BBB permeability in older animals treated with Sevoflurane, but not Isoflurane. Extravasated immunoglobulin G showed selective affinity for pyramidal neurons. SEM demonstrated marked flattening of the luminal surfaces of BVECs in anesthetic-treated rats. Results suggest an aging-linked BBB compromise resulting from exposure to Sevoflurane. Changes in the luminal surface topology of BVECs indicate a direct effect on the plasma membrane, which may weaken or disrupt their BBB-associated tight junctions. Disruption of brain homeostasis due to plasma influx into the brain parenchyma and binding of plasma components (e.g., immunoglobulins) to neurons may contribute to POD. We propose that, in the elderly, exposure to some IAs can cause BBB compromise that disrupts brain homeostasis, perturbs neuronal function and thereby contributes to POD. If unresolved, this may progress to postoperative cognitive decline and later dementia.
authors.affiliation: Biomarker Discovery Center, New Jersey Institute for Successful Aging, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA; Department of Geriatrics and Gerontology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA.
authors.forename: Nimish K
authors.initials: NK
authors.lastname: Acharya
authors.affiliation: Biomarker Discovery Center, New Jersey Institute for Successful Aging, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA; Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ 08084, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Goldwaser
authors.affiliation: Department of Geriatrics and Gerontology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Forsberg
authors.affiliation: Biomarker Discovery Center, New Jersey Institute for Successful Aging, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA; Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ 08084, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Godsey
authors.affiliation: Biomarker Discovery Center, New Jersey Institute for Successful Aging, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA; Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ 08084, USA.
authors.forename: Cristina A
authors.initials: CA
authors.lastname: Johnson
authors.affiliation: Biomarker Discovery Center, New Jersey Institute for Successful Aging, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA; Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ 08084, USA.
authors.forename: Abhirup
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: Biomarker Discovery Center, New Jersey Institute for Successful Aging, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA; Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ 08084, USA.
authors.forename: Cassandra
authors.initials: C
authors.lastname: DeMarshall
authors.affiliation: Biomarker Discovery Center, New Jersey Institute for Successful Aging, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA; Department of Geriatrics and Gerontology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Kosciuk
authors.affiliation: Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ 08084, USA; Department of Geriatrics and Gerontology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Dash
authors.affiliation: Department of Geriatrics and Gerontology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA.
authors.forename: Caitlin P
authors.initials: CP
authors.lastname: Hale
authors.affiliation: Department of Psychiatry, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Leonard
authors.affiliation: Philadelphia College of Osteopathic Medicine, , PA, USA, Philadelphia, PA 19131, USA.
authors.forename: Denah M
authors.initials: DM
authors.lastname: Appelt
authors.affiliation: Biomarker Discovery Center, New Jersey Institute for Successful Aging, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA; Department of Geriatrics and Gerontology, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA. Electronic address: nagelero@rowan.edu.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nagele
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000139:chemically induced / Q000209:etiology; D003693:Delirium / Q000139:chemically induced / Q000209:etiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007074:Immunoglobulin G / Q000378:metabolism; D007150:Immunohistochemistry; D007530:Isoflurane / Q000633:toxicity*; D008738:Methyl Ethers / Q000633:toxicity*; D008855:Microscopy, Electron, Scanning; D011183:Postoperative Complications / Q000139:chemically induced; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane; D013997:Time Factors
chemical_list: D018685:Anesthetics, Inhalation; D007074:Immunoglobulin G; D008738:Methyl Ethers; D000077149:Sevoflurane; D007530:Isoflurane
keywords: Anesthesia; Blood−brain barrier; Delirium; Isoflurane; Postoperative delirium; Sevoflurane