Sodium Caprate Transiently Opens Claudin-5-Containing Barriers at Tight Junctions of Epithelial and Endothelial Cells

Abstract

Claudin-5 is a tight junction (TJ) protein which limits the diffusion of small hydrophilic molecules. Thus, it represents a potential pharmacological target to improve drug delivery to the tissues protected by claudin-5-dependent barriers. Sodium caprate is known as an absorption enhancer which opens the paracellular space acting on TJ proteins and actin cytoskeleton. Its action on claudin-5 is not understood so far. Epithelial and endothelial systems were used to evaluate the effect of caprate on claudin-5 in TJ-free cells and on claudin-5 fully integrated in TJ. To this aim, confocal microscopy on live and fixed cells and isolated mouse brain capillaries, Western blotting and permeability assays were employed. Caprate reversibly reduced claudin-5 trans-interactions in TJ-free human embryonic kidney-293 cells expressing claudin-5-YFP. It decreased the membranous claudin-5 and the F-actin content in Madin-Darby canine kidney-II cells expressing Flag-claudin-5, thereby increasing the permeability to the small molecule lucifer yellow. Interestingly, zonula occludens protein 1 (ZO-1), which links transmembranous TJ proteins to the actin cytoskeleton, was not affected by caprate treatment. Similarly, endogenous claudin-5 in the membrane of brain endothelia was displaced together with F-actin, whereas ZO-1 remained unaffected. Caprate transiently opens the paracellular space, reducing the intercellular claudin-5/claudin-5 interactions and the polymerized actin at the perijunctional region of endothelial and epithelial cells. In conclusion, the study further elucidates the cellular effects of caprate at the tight junctions.

Acute anticonvulsant effects of capric acid in seizure tests in mice

“…Of note, increasing the number of carbons should be expected to result in higher efficacy (Chang et al, 2013;Nakamura et al, 1990), which is not the case when CA8 and CA10 (present study) are compared. Of note, CA10 has been reported, albeit at higher doses, to affect the blood-brain-barrier by making it more permeable to drugs (Del Vecchio et al, 2012;Ohnishi et al, 1999;Preston et al, 2008). If that were the case in the present study, CA10 would make PTZ to more rapidly entering the brain, which is predicted to result in shorter latencies to convulsions given there is a positive correlation between rate of uptake of PTZ into the brain and latencies to PTZ-induced convulsions (Yonekawa et al, 1980).…”

Recent progress in tight junction modulation for improving bioavailability

“…The promising TJ modulators Clostridium perfringens enterotoxin [46][47][48], sodium caprate [48,49] and the claudin-1 peptidomimetics [50] have also been evaluated in vivo, but do not fit entirely the definition of MB TJ modulators given above and are thus beyond the scope of this review.…”

Trends in drug delivery through tissue barriers containing tight junctions

“…These studies have mostly used cells from the colon 53 , 54 or kidney, 55 , 56 but also freshly isolated brain capillaries 55 and excised rat intestinal mucosa 57 . In these experiments TER decreased and/or the permeability of molecules with a molecular weight between 182 and 10,000 Da increased after incubation with C 10 (Table 2).…”

“…Furthermore, the effect of C 10 could not be blocked with inhibitors of the actin-myosin interaction, phospholipase C, Rho-kinase or by Ca 2+ chelators 54 . The redistribution of the TJ-complex is under discussion as well, since several studies have reported that the membrane localization of ZO-1 is unchanged (30 mM C 10 65 ; 7.5 mM C 10 55 ). However, claudin-1, claudin-4, junctional adhesion molecule and β-catenin in human airway epithelial cells and claudin-5 in brain endothelial cells were reduced after C 10 treatment 55 , 65 .…”