Abstract
Objective: The antiepileptic drug valproate has been shown to affect the expression of carriers for essential compounds and drugs in extracerebral tissues. The aim of the current study was to evaluate in vivo the effect of valproate treatment on the cerebral expression of carriers and selected genes of the blood-brain barrier (BBB) in the rat.Methods: Male Wistar rats were treated daily for 7 days by intraperitoneal injections of valproate (75, 150, or 300 mg/kg/day) or the vehicle. mRNA was isolated from the cerebral cortex and the hippocampus. Transcript levels of 37 genes were measured using a customized gene expression assay. Quantitative histone acetylation was evaluated by western blotting. Glucose6-phosphate (G6P) tissue levels were used as a surrogate of cerebral glucose concentrations.Results: Valproate treatment was associated with significant reduction (up to 22%; P < 0.05) in cortical and hippocampal claudin 5-normalized Slc2a1 (Glut1) mRNA expression. G6P levels were not significantly altered, but were correlated with Slc2a1 transcript levels (r = 0.499; P < 0.02). None of the other 36 screened genes were significantly affected by valproate. Cortical histone hyperacetylation indicated cerebral activity of valproate on a major pathway regulating gene expression (P < 0.02).Significance: The effect of valproate on nutrient carriers appears to be tissue-specific and even brain area-specific. If validated in humans, the changes in Glut1 expression might have clinical implications in positron emission tomography (PET) imaging. Further studies are required for elucidating the relevance of these findings to the clinic.
Highlights
Valproic acid (VPA) is a broad-spectrum antiepileptic drug, whose exact mechanisms of therapeutic and adverse effects are still not fully understood (Tomson et al, 2016b).We and others have shown in extracerebral tissues that VPA can regulate the expression of membrane carriers involved in the cellular uptake and efflux of hormones, nutrients, and medications
VPA affected the expression of P-glycoprotein (ABCB1) in tumor cell lines and in rat livers (Eyal et al, 2006; Hauswald et al, 2009) and that of folate receptor α (FRα; FOLR1) in pregnant mice (Meir et al, 2016) and in a human placental cell line
We demonstrated that VPA selectively downregulated cerebral Glut1 mRNA expression, but did not significantly alter other 36 genes encoding nutrient transporters and blood-brain barrier (BBB) components
Summary
We and others have shown in extracerebral tissues that VPA can regulate the expression of membrane carriers involved in the cellular uptake and efflux of hormones, nutrients, and medications. VPA affected the expression of P-glycoprotein (ABCB1) in tumor cell lines and in rat livers (Eyal et al, 2006; Hauswald et al, 2009) and that of folate receptor α (FRα; FOLR1) in pregnant mice (Meir et al, 2016) and in a human placental cell line. VPA modulated the expression of genes encoding carriers for nutrients, including folate and glucose, in term human placentas (Rubinchik-Stern et al, 2018). We examined whether the effects of VPA on carrier expression are replicated in the brain. We conducted an initial screening which included key cerebral nutrient carriers and components of the blood-brain barrier (BBB), given its central role in controlling the levels of essential compounds and medications within the brain parenchyma
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