Peripheral blood mononuclear cell activation sustains seizure activity

Abstract

Objective: The influx of immune cells and serum proteins from the periphery into the brain due to a dysfunctional blood-brain barrier (BBB) has been proposed to contribute to the pathogenesis of seizures in various forms of epilepsy and encephalitis.We evaluated the pathophysiological impact of activated peripheral blood mononuclear cells (PBMCs) and serum albumin on neuronal excitability in an in vitro brain preparation. Methods: A condition of mild endothelial activation induced by arterial perfusion of lipopolysaccharide (LPS) was induced in the whole brain preparation of guinea pigs maintained in vitro by arterial perfusion. We analyzed the effects of co-perfusion of human recombinant serum albumin with human PBMCs activated with concanavalin A on neuronal excitability, BBB permeability (measured by FITC-albumin extravasation), and microglial activation. Results: Bioplex analysis in supernatants of concanavalin A-stimulated PBMCs revealed increased levels of several inflammatory mediators, in particular interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (INF)-γ, IL-6, IL-10, IL-17A, and MIP3α. LPS and human albumin arterially co-perfused with either concanavalin A-activated PBMCs or the cytokine-enriched supernatant of activated PBMCs (1) modulated calcium-calmodulin-dependent protein kinase II at excitatory synapses, (2) enhanced BBB permeability, (3) induced microglial activation, and (4) promoted seizure-like events. Separate perfusions of either nonactivated PBMCs or concanavalin A-activated PBMCs without LPS/human albumin (hALB) failed to induce inflammatory and excitability changes. Significance: Activated peripheral immune cells, such as PBMCs, and the extravasation of serum proteins in a condition of BBB impairment contribute to seizure generation.

Effect of inactivated COVID-19 vaccines on seizure frequency in patients with epilepsy: A multicenter, prospective study

“…SARS-COV-2 may severely hamper cerebral homeostasis upon entry into the CNS by destroying the blood-brain barrier (BBB) and glial limiting factor, activating the toll-like receptor (TLR), and ultimately leading to neuronal death ( 26 ). Several studies have reported that activation of TLR may promote epilepsy ( 27 , 28 ), while others have reported that immune cell and serum protein infiltration due to BBB destruction also exacerbates epilepsy ( 28 , 29 ). Moreover, SARS-COV-2 entry into the CNS could hamper the respiratory regulation center in the brain stem ( 30 ), which would significantly increase the risk of sudden epileptic death ( 31 ), and potentially contribute to increased mortality in SARS-COV-2 infected PWE.…”

A Preliminary Report: The Hippocampus and Surrounding Temporal Cortex of Patients With Schizophrenia Have Impaired Blood-Brain Barrier

“…Since this is critical information necessary for comparing BBB function among the Ctrl and subjects with SZ, we have developed a semi-quantitative protocol using the Cavalieri estimator stereological function in Stereo Investigator software (MBF Bioscience, VT, United States). Similar to previous studies, our semi-quantitative protocol relies on the immunoreactivity demonstrated by the extravasated IgGs with neurons and neuropil ( Librizzi et al, 2021 ; Vila Verde et al, 2021 ). The Cavalieri estimator method is a proven unbiased stereological method used to calculate areas in tissue sections, and we have adopted it to estimate IgG leaked area fraction or the extent of BBB leak ( Cohen, 1992 ; No authors, 2021 ).…”

The correlation of temporal changes of neutrophil-lymphocyte ratio with seizure severity and the following seizure tendency in patients with epilepsy

“…This indicated that inflammation reflected by NLR was involved in the pathophysiology of epilepsy. It is reported that serum albumin can extravasate from blood vessel into the brain parenchyma when the blood-brain barrier is dysfunctional, and this has been suggested to be involved in the pathogenesis of various types of epilepsy ( 33 – 35 ). In this study, we found that low serum albumin was associated with acute seizures, which effectively confirmed albumin extravasation after acute seizures.…”

“…Subsequently, the activated microglia, reactive astrocytes and infiltrating immune cells release large amounts of pro-inflammatory mediators including IL-6, IL-1β, TNF-α, COX-2, HMGB1 and chemokines, inducing neuroinflammation through multiple signaling pathways. And the neuroinflammation can further increase excitability of the CNS, along with serum albumin extravasation ( 14 , 35 , 36 ). Thus, neuroinflammation can aggravate the severity, duration, and frequency of epileptic seizures and even lead to new-onset seizures ( 13 , 15 , 37 ).…”