Blood–brain barrier dysfunction can contribute to pharmacoresistance of seizures

Abstract

SUMMARYObjective: We tested the hypothesis that interstitial albumin can contribute to pharmacoresistance, which is common among patients with focal epilepsies. These patients often present with an open blood-brain barrier (BBB), resulting in diffusion of drug-binding albumin into the brain interstitial space. Methods: Seizure-like events (SLEs) induced by 100 lM 4-aminopyridine (4-AP) were monitored using extracellular field potential recordings from acute rat entorhinal cortex-hippocampus slices. Effects of standard antiepileptic drugs (phenytoin, valproic acid, carbamazepine, and phenobarbital) were studied in the presence of albumin applied acutely or by intraventricular injection. Unbound antiepileptic drugs (AEDs) were detected by ultrafiltration and high-performance liquid chromatography (HPLC). Results: Contrary to the absence of albumin, conventional AEDs failed to suppress SLEs in the rat entorhinal cortex in the presence of albumin. This effect was partially caused by buffering of phenytoin and carbamazepine (CBZ) by albumin. Increasing CBZ concentration from 50 lM to 100 lM resulted in block of SLEs. In slices obtained from animals that were pretreated with intraventricular albumin application 24 h prior to experiment, CBZ suppressed SLEs similar to control slices. We also found that application of serum-like electrolytes transformed SLEs into late recurrent discharges (LRDs), which were no longer responding to CBZ. Significance: A dysfunctional BBB with acute extravasation of serum albumin into the brain's interstitial space could contribute to pharmacoresistance. In such instances, choice of an AED with low albumin binding affinity may help in seizure control.

Glial source of nitric oxide in epileptogenesis: A target for disease modification in epilepsy

“…The serum albumin (SA) is considered as a biomarker for BBB leakage (Frigerio et al, 2012). Increased SA and glutamate levels induce reactive astrogliosis that causes hyperexcitability of neurons and hence seizures (Boje, 1996; Frigerio et al, 2012; Liu et al, 2012; Salar et al, 2014; Weissberg et al, 2015). Our previous studies from the rat and mouse epilepsy models have shown an increased SA and GFAP levels in the hippocampus at 7 day post-SE, and 1400W treatment reduced their levels (Puttachary et al, 2016a and b).…”

WONOEP appraisal: Development of epilepsy biomarkers—What we can learn from our patients?

“…It has been suggested that enhancement of a transcellular pathway rather than paracellular opening of tight junctions accounts for the increase in BBB permeability in epileptic conditions as evidenced by ultrastructural observations . Given these many converging studies, a disrupted BBB, such as enhancement on imaging studies, could be a biomarker for the detection of epileptogenesis and translatable from animal studies to humans …”

“…[29][30][31] Given these many converging studies, a disrupted BBB, such as enhancement on imaging studies, could be a biomarker for the detection of epileptogenesis and translatable from animal studies to humans. 21,26,32,33 Another potential biomarker comes from miRNAs as they could contribute to the development of epilepsy and may be detectable as circulating biomarkers in the blood. miRNAs are small (~22 nucleotides) noncoding RNAs that regulate the expression of target messenger RNAs (mRNAs) at the posttranscriptional level.…”

The blood–brain barrier—Gatekeeper to neuronal homeostasis: Clinical implications in the setting of stroke

“…Differential alterations to trans-and paracellular passage similarly occur in the transient medial cerebral artery occlusion stroke model, with increased transcellular transport preceding TJ rearrangement [46]. The migration of albumin across the BBB may also have important consequences for drug efficacy as it can bind many drugs and may buffer agents which support drug actions [47].…”