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.

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.

Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-ß(1-42) deposition.

Previous studies have reported immunoglobulin-positive neurons in Alzheimer's disease (AD) brains, an observation indicative of blood-brain barrier (BBB) breakdown. Recently, we demonstrated the nearly ubiquitous presence of brain-reactive autoantibodies in human sera. The significance of these observations to AD pathology is unknown. Here, we show that IgG-immunopositive neurons are abundant in brain regions exhibiting AD pathology, including intraneuronal amyloid-ß(42) (Aß(42)) and amyloid plaques, and confirm by western analysis that brain-reactive autoantibodies are nearly ubiquitous in human serum. To investigate a possible interrelationship between neuronal antibody binding and Aß pathology, we tested the effects of human serum autoantibodies on the intraneuronal deposition of soluble Aß(42) peptide in adult mouse neurons in vitro (organotypic brain slice cultures). Binding of human autoantibodies to mouse neurons dramatically increased the rate and extent of intraneuronal Aß(42) accumulation in the mouse cerebral cortex and hippocampus. Additionally, individual sera exhibited variable potency related to their capacity to enhance intraneuronal Aß(42) peptide accumulation and immunolabel neurons in AD brain sections. Replacement of human sera with antibodies targeting abundant neuronal surface proteins resulted in a comparable enhancement of Aß(42) accumulation in mouse neurons. Overall, results suggest that brain-reactive autoantibodies are ubiquitous in the blood and that a defective BBB allows these antibodies to access the brain interstitium, bind to neuronal surfaces and enhance intraneuronal deposition of Aß(42) in AD brains. Thus, in the context of BBB compromise, brain-reactive autoantibodies may be an important risk factor for the initiation and/or progression of AD as well as other neurodegenerative diseases.