Effects of valproate on the entry of inert hydrophilic markers and expression of tight junction associated genes in the neonatal brain and choroid plexus of a rat model of epilepsy (GAERS).

Abstract

Background: The integrity of blood-brain and blood-cerebrospinal fluid (CSF) barriers is characterised by their ability to restrict transcellular passage of inert, hydrophilic markers of different molecular sizes by tight junctions between barrier forming cells. Compromised barrier integrity has been linked to many pathologies, including epilepsy.

Methods: Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and Sprague-Dawley (SD) rats between embryonic day 19 and 21-week were administered an injection of radiolabelled sucrose (342 Da) or dextran (70 kDa) intravenously. After 5 min, plasma, CSF and brain samples were collected for radioactivity measurement. Experiments were performed in drug naïve and valproate (an antiseizure medication) exposed animals. Postnatal rats were provided with a valproate diet (20 g/kg), and fetal animals were exposed to the drug via placental transfer from pregnant dams consuming the diet. Brain cortex and choroid plexus transcriptomes from both rat strains were examined and compared for the expression of tight junction associated proteins. Additionally, differential expression analyses were performed on valproate exposed and control postnatal GAERS pups.

Results: Brain/plasma and CSF/plasma concentration ratios of 70 kDa dextran were elevated during a specific period of postnatal development (newborn to 13-week-old) in GAERS compared to age-matched SD rats. In contrast, brain and CSF distribution spaces of sucrose, as well as expression of most transcripts for tight junction associated proteins in cortex and choroid plexus were similar between the strains. Long term postnatal or fetal exposure to valproate reduced the elevated apparent brain distribution space of dextran in GAERS to levels similar to SD rats and correlated with some changes in gene expression in the cortex and choroid plexus.

Conclusions: Increased apparent brain and CSF distribution spaces of a large hydrophilic molecule, dextran, but not of a smaller marker sucrose in GAERS implied that while the integrity of brain barriers did not appear to be compromised, its phenotype was distinctly different from that of Sprague Dawley rats. Exposure of GAERS to valproate induced a change in brain barriers phenotype to one more similar to that in Sprague Dawley rats. Understanding potential link between this barrier phenotype and postnatal onset of seizures may shed light on common factor(s) affecting development of cerebral blood vessels and neurons, and their relevance to epileptic seizures.