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Barrier function of cultured BECs from WKYs and SHRSPs. The model using only BECs from either WKYs (Ew00 model) or SHRSPs (Esp00 model) was examined. a, b Barrier function was assessed by measuring TEER (a; n = 16) and permeability to Na-F (b; n = 8). c The images are representative blots, and the bar graphs are pooled densitometry data from three separate experiments (n = 7 to 9). *p < 0.05, **p < 0.01
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The blood–brain barrier (BBB) comprises three cell types: brain capillary endothelial cells (BECs), astrocytes, and pericytes. Abnormal interaction among these cells may induce BBB dysfunction and lead to cerebrovascular diseases. The stroke-prone spontaneously hypertensive rat (SHRSP) harbors a defective BBB, so we designed the present study to ex...
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... OT was measured using a 96-plate commercial OT-ELISA kit (Enzo Life Sciences, Farmingdale, NY, USA), as described previously. 73 The optical density of the samples and standards was measured at wavelengths of 405 and 590 nm using a microplate reader (Bio-Rad, Richmond, CA, USA). Sample concentrations were calculated using Matlab, version 7 (MathWorks, Natick, MA, USA) according to the relevant standard curve. ...
... The cannulae were inserted into the mPFC as shown in a representative image (see Supporting information, Figure S1). The extracellular fluid that is separated from the blood by the endothelial barrier in neurovascular units 73,74 was collected in male mice at F I G U R E 1 Transport of oxytocin (OT) into the medial prefrontal cortex (mPFC). A, OT concentrations in microperfusates of the mPFC of wild-type (Ager +/+ ) or receptor for advanced glycation endproducts (RAGE) knockout (KO) (Ager -/-) male mice before and 30, 60 and 90 min after intranasal administration of 20 µL of 1000 ng mL -1 OT (20 ng each nasal cavity) or 20 µL of saline (n = 5-6 data points). ...
Oxytocin (OT) is a neuropeptide hormone. Single and repetitive administration of OT increases social interaction and maternal behaviour in humans and mammals. Recently, it was found that the receptor for advanced glycation end‐products (RAGE) is an OT‐binding protein and plays a critical role in the uptake of OT to the brain after peripheral OT administration. Here, we address some unanswered questions on RAGE‐dependent OT transport. First, we found that, after intranasal OT administration, the OT concentration increased in the extracellular space of the medial prefrontal cortex (mPFC) of wild‐type male mice, as measured by push‐pull microperfusion. No increase of OT in the mPFC was observed in RAGE knockout male mice. Second, in a reconstituted in vitro blood‐brain barrier system, inclusion of the soluble form of RAGE (endogenous secretory RAGE [esRAGE]), an alternative splicing variant, in the luminal (blood) side had no effect on the transport of OT to the abluminal (brain) chamber. Third, OT concentrations in the cerebrospinal fluid after i.p. OT injection were slightly higher in male mice overexpressing esRAGE (esRAGE transgenic) compared to those in wild‐type male mice, although this did not reach statistical significance. Although more extensive confirmation is necessary because of the small number of experiments in the present study, the reported data support the hypothesis that RAGE may be involved in the transport of OT to the mPFC from the circulation. These results suggest that the soluble form of RAGE in the plasma does not function as a decoy in vitro. RAGE is involved in the transport of oxytocin to the brain from the circulation. The soluble forms of RAGE in the plasma do not inhibit nor facilitate membrane RAGE‐dependent oxytocin transport, but may function as a buffer of plasma oxytocin.
Growing evidence has proved that alterations in the gut microbiota have been linked to neurological disorders including stroke. Structural and functional disruption of the blood-brain barrier (BBB) is observed after stroke. In this context, there is pioneering evidence supporting that gut microbiota may be involved in the pathogenesis of stroke by regulating the BBB function. However, only a few experimental studies have been performed on stroke models to observe the BBB by altering the structure of gut microbiota, which warrant further exploration. Therefore, in order to provide a novel mechanism for stroke and highlight new insights into BBB modification as a stroke intervention, this review summarizes existing evidence of the relationship between gut microbiota and BBB integrity and discusses the mechanisms of gut microbiota on BBB dysfunction and its role in stroke.
Globally, stroke is a leading cause of death and long-term disability. Over the past decades, several efforts have attempted to discover new drugs or repurpose existing therapeutics to promote post-stroke neurological recovery. Preclinical stroke studies have reported successes in identifying novel neuroprotective agents; however, none of these compounds have advanced beyond a phase III clinical trial. One reason for these failures is the lack of consideration of blood-brain barrier (BBB) transport mechanisms that can enable these drugs to achieve efficacious concentrations in ischemic brain tissue. Despite the knowledge that drugs with neuroprotective properties (i.e., statins, memantine, metformin) are substrates for endogenous BBB transporters, preclinical stroke research has not extensively studied the role of transporters in central nervous system (CNS) drug delivery. Here, we review current knowledge on specific BBB uptake transporters (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents); organic cation transporters (OCTs in humans; Octs in rodents) that can be targeted for improved neuroprotective drug delivery. Additionally, we provide state-of-the-art perspectives on how transporter pharmacology can be integrated into preclinical stroke research. Specifically, we discuss the utility of in vivo stroke models to transporter studies and considerations (i.e., species selection, co-morbid conditions) that will optimize the translational success of stroke pharmacotherapeutic experiments.
