Oral 5-aminolevulinic acid combined with sodium ferrous citrate prevents blood-aqueous barrier breakdown after anterior chamber paracentesis in healthy beagle dogs.

This study investigated the preventive effect of 5-aminolevulinic acid combined with sodium ferrous citrate (5-ALA/SFC) on blood-aqueous barrier (BAB) breakdown induced after anterior chamber paracentesis (ACP) in beagles. 5-ALA/SFC (1/0.64 mg/kg or 3/1.92 mg/kg) or carprofen (4.0 mg/kg) was orally administered daily for 7 days prior to ACP. Then, a sample of the aqueous humor (AH) was collected from one eye via ACP (first sample) and again 60 min later (second sample). The protein and prostaglandin E2 (PGE2) concentrations in both samples were measured. Compared with the control group, high-dose 5-ALA/SFC and carprofen significantly reduced the AH protein and PGE2 concentrations in the second sample. Our findings suggest that 5-ALA/SFC suppresses BAB breakdown in dogs.

Nanoscale delivery systems in treatment of posterior ocular neovascularization: strategies and potential applications.

Pathologic posterior neovascularization of eye is a major cause of irreversible vision loss and limitations of therapeutics to be successfully delivered to back of the eye has been a main obstacle for its effective treatment. Current pharmacological treatment using anti-VEGF agents being delivered intravitreally are effective but complicated due to anatomical and physiological barriers, as well as administration of high and frequent doses. With expanding horizons of nanotechnology, it can be possible to formulate promising nanoscale delivery system to improve penetration and sustained the release of therapeutic in posterior segment of the eye. Taking into consideration advances in the field of nanoscale delivery systems, this special report focuses on emerging strategies and their applications for treatment of posterior ocular neovascularization.

The Effect of Molecular Weight on Passage of Proteins Through the Blood-Aqueous Barrier.

Purpose: To determine the effect of molecular weight (MW) on the concentration of plasma-derived proteins in aqueous humor and to estimate the plasma-derived and eye-derived fractions for each protein. Methods: Aqueous humor and plasma samples were obtained during cataract surgery on an institutional review board-approved protocol. Protein concentrations were determined by ELISA and quantitative antibody microarrays. A total of 93 proteins were studied, with most proteins analyzed using 27 to 116 aqueous and 6 to 30 plasma samples. Results: Plasma proteins without evidence of intraocular expression by sequence tags were used to fit a logarithmic model relating aqueous-plasma ratio (AH:PL) to MW. The log(AH:PL) appears to be well predicted by the log(MW) (P < 0.0001), with smaller proteins such as cystatin C (13 kDa) having a higher AH:PL (1:6) than larger proteins such as albumin (66 kDa, 1:300) and complement component 5 (188 kDa, 1:2500). The logarithmic model was used to calculate the eye-derived intraocular fraction (IOF) for each protein. Based on the IOF, 66 proteins could be categorized as plasma-derived (IOF<20), whereas 10 proteins were primarily derived from eye tissue (IOF >80), and 17 proteins had contribution from both plasma and eye tissue (IOF 20-80). Conclusions: Protein concentration of plasma-derived proteins in aqueous is nonlinearly dependent on MW in favor of smaller proteins. Our study demonstrates that for proper interpretation of results, proteomic studies evaluating changes in aqueous humor protein levels should take into account the plasma and eye-derived fractions.

Primary angle closure glaucoma (PACG) susceptibility gene PLEKHA7 encodes a novel Rac1/Cdc42 GAP that modulates cell migration and blood-aqueous barrier function.

PLEKHA7, a gene recently associated with primary angle closure glaucoma (PACG), encodes an apical junctional protein expressed in components of the blood aqueous barrier (BAB). We found that PLEKHA7 is down-regulated in lens epithelial cells and in iris tissue of PACG patients. PLEKHA7 expression also correlated with the C risk allele of the sentinel SNP rs11024102 with the risk allele carrier groups having significantly reduced PLEKHA7 levels compared to non-risk allele carriers. Silencing of PLEKHA7 in human immortalized non-pigmented ciliary epithelium (h-iNPCE) and primary trabecular meshwork cells, which are intimately linked to BAB and aqueous humor outflow respectively, affected actin cytoskeleton organization. PLEKHA7 specifically interacts with GTP-bound Rac1 and Cdc42, but not RhoA, and the activation status of the two small GTPases is linked to PLEKHA7 expression levels. PLEKHA7 stimulates Rac1 and Cdc42 GTP hydrolysis, without affecting nucleotide exchange, identifying PLEKHA7 as a novel Rac1/Cdc42 GAP. Consistent with the regulatory role of Rac1 and Cdc42 in maintaining the tight junction permeability, silencing of PLEKHA7 compromises the paracellular barrier between h-iNPCE cells. Thus, downregulation of PLEKHA7 in PACG may affect BAB integrity and aqueous humor outflow via its Rac1/Cdc42 GAP activity, thereby contributing to disease etiology.

The blood-brain barrier fatty acid transport protein 1 (FATP1/SLC27A1) supplies docosahexaenoic acid to the brain, and insulin facilitates transport.

We purposed to clarify the contribution of fatty acid transport protein 1 (FATP1/SLC 27A1) to the supply of docosahexaenoic acid (DHA) to the brain across the blood-brain barrier in this study. Transport experiments showed that the uptake rate of [14 C]-DHA in human FATP1-expressing HEK293 cells was significantly greater than that in empty vector-transfected (mock) HEK293 cells. The steady-state intracellular DHA concentration was nearly 2-fold smaller in FATP1-expressing than in mock cells, suggesting that FATP1 works as not only an influx, but also an efflux transporter for DHA. [14 C]-DHA uptake by a human cerebral microvascular endothelial cell line (hCMEC/D3) increased in a time-dependent manner, and was inhibited by unlabeled DHA and a known FATP1 substrate, oleic acid. Knock-down of FATP1 in hCMEC/D3 cells with specific siRNA showed that FATP1-mediated uptake accounts for 59.2-73.0% of total [14 C]-DHA uptake by the cells. Insulin treatment for 30 min induced translocation of FATP1 protein to the plasma membrane in hCMEC/D3 cells and enhanced [14 C]-DHA uptake. Immunohistochemical analysis of mouse brain sections showed that FATP1 protein is preferentially localized at the basal membrane of brain microvessel endothelial cells. We found that two neuroprotective substances, taurine and biotin, in addition to DHA, undergo FATP1-mediated efflux. Overall, our results suggest that FATP1 localized at the basal membrane of brain microvessels contributes to the transport of DHA, taurine and biotin into the brain, and insulin rapidly increases DHA supply to the brain by promoting translocation of FATP1 to the membrane. Read the Editorial Comment for this article on page 324.

The influence of the time-of-day administration of sunitinib on the penetration through the blood-brain and blood-aqueous humour barriers in rabbits.

OBJECTIVE: Sunitinib is a multiple tyrosine kinase inhibitor (TKI) that exerts anti-tumor and antiangiogenic activity. It is used for the treatment of metastatic gastrointestinal stromal tumours, renal cell carcinoma and pancreatic neuroendocrine tumours. A few studies confirm the anti-tumour activity of sunitinib in brain tumours and uveal melanoma, as well as its efficacy in the reduction of brain metastases of some primary cancers. Therefore, the penetration of sunitinib through the blood-brain barrier (BBB) and blood-aqueous humour barrier (BAB) is an issue of growing interest. The aim of the study was to investigate the influence of the time-of-day administration on the penetration of sunitinib into the cerebrospinal fluid (CSF) and aqueous humour (AH). MATERIALS AND METHODS: The rabbits were divided into two groups: I (control group)--receiving sunitinib at 8 a.m., and II--receiving sunitinib at 8 p.m. Sunitinib was administered p.o. at a single dose of 25 mg. The concentrations of sunitinib and its active metabolite (SU12662) in the plasma, CSF, AH were measured with the validated HPLC-UV method. RESULTS: The plasma AUC0-t for sunitinib in group I was 2051.8 ng × h/mL, whereas in group II it was 3069.3 ng × h/mL. The aqueous humour AUC0-t for sunitinib in thr groups were 43.2 and 76.3 ng × h/mL, respectively. The cerebrospinal AUC0-t for sunitinib in groups I and II were 55.5 and 66.3 ng × h/mL, respectively. CONCLUSIONS: After the evening administration (8 p.m.) the exposure to sunitinib in the rabbits' plasma, AH and CSF was higher than after the morning administration (8 a.m.), but the degree of sunitinib penetration through the BAB and BBB was very low (< 5%) and comparable in both groups.

Determinants of impairment in lung diffusing capacity in patients with systemic sclerosis.

OBJECTIVES: Lung diffusing capacity for carbon monoxide (DLCO) is impaired in interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) associated to systemic sclerosis (SSc), but the mechanism of DLCO reduction remains controversial. We hypothesised that the determinants of DLCO impairment differ in interstitial or vascular involvement of the lung of SSc patients. METHODS: DLCO was partitioned into alveolar-capillary membrane conductance (Dm) and pulmonary capillary blood volume (Vc) using combined single-breath DLNO and DLCO measurements. Seventeen SSc patients without pulmonary involvement (SSc), 20 SSc patients with ILD (SSc-ILD), with and without PAH, and 21 healthy controls were included. RESULTS: DLNO and Dm were reduced in SSc patients as compared with controls, whereas Vc was not significantly different. SSc-ILD patients showed a highly significant decrease in Dm and Vc as compared with SSc patients and controls. Vc tended to be more reduced than Dm in SSc-ILD patients with PAH. Dm and Vc were negatively correlated with PAPs and HCRT scores, but the relationship with the HRCT score was stronger. CONCLUSIONS: DLNO is more sensitive than DLCO in detecting functional impairment in SSc without radiologic or haemodynamic alterations. A disproportional reduction of Dm relative to Vc suggests a thickening of the blood-gas diffusion barrier in these patients. In SSc patients with detectable ILD, the gas exchange impairment is due to both components of lung diffusing capacity, and partitioning of DLCO in Dm and Vc is of little use in distinguishing the patients with only ILD from those with ILD complicated by PAH.

Death following traumatic brain injury in Drosophila is associated with intestinal barrier dysfunction.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Unfavorable TBI outcomes result from primary mechanical injuries to the brain and ensuing secondary non-mechanical injuries that are not limited to the brain. Our genome-wide association study of Drosophila melanogaster revealed that the probability of death following TBI is associated with single nucleotide polymorphisms in genes involved in tissue barrier function and glucose homeostasis. We found that TBI causes intestinal and blood-brain barrier dysfunction and that intestinal barrier dysfunction is highly correlated with the probability of death. Furthermore, we found that ingestion of glucose after a primary injury increases the probability of death through a secondary injury mechanism that exacerbates intestinal barrier dysfunction. Our results indicate that natural variation in the probability of death following TBI is due in part to genetic differences that affect intestinal barrier dysfunction.

Undefined role of mucus as a barrier in ocular drug delivery.

Mucus layer covers the ocular surface, and soluble mucins are also present in the tear fluid. After topical ocular drug administration, the drugs and formulations may interact with mucus layer that may act as a barrier in ocular drug delivery. In this mini-review, we illustrate the mucin composition of the ocular surface and discuss the influence of mucus layer on ocular drug absorption. Based on the current knowledge the role of mucus barrier in drug delivery is still undefined. Furthermore, interactions with mucus may prolong the retention of drug formulations on the ocular surface. Mucus may decrease or increase ocular bioavailability depending on the magnitude of its role as barrier or retention site, respectively. Mechanistic studies are needed to clarify the role of mucin in ocular drug delivery.

Effects of repeated Cr(VI) intratracheal instillation on club (Clara) cells and activation of nuclear factor-kappa B pathway via oxidative stress.

Hexavalent chromium [Cr(VI)] exposure is known to induce respiratory inflammation and contribute to lung cancer development, but little is known about its target cell type in lung. In the current study, we investigated the effects of repeated Cr(VI) intratracheal instillation on club (Clara) cells and club (Clara) cell secretory protein (CC16) in rats and explored whether the nuclear factor-kappa B (NF-κB) related pathway was involved. We also studied the role of orally delivered Zn against Cr-induced adverse health effects. For four weeks, sixty Sprague-Dawley male rats received weekly intratracheal instillation of potassium dichromate (K2Cr2O7) at 0, 0.063 and 0.630mgCr/kg with or without daily intragastric administration of zinc sulfate (ZnSO4) at 10mg Zn/kg. Results showed that exposure to Cr(VI) significantly increased the organ coefficient of lung (organ weight as a percentage of body weight), albumin and total protein level in bronchoalveolar lavage fluid (BALF), indicating lung injury and compromised bronchoalveolar/blood barrier (BA/BB) integrity. With increasing Cr(VI) dose, the secretion of CC16 decreased in a dose-dependent manner, suggesting that CC16 can serve as a peripheral biomarker for club cell damage during early lung injury induced by Cr(VI). Increased expression of NF-κB were observed in club cells in both Cr-exposed groups, indicating upregulation of NF-κB, which can be induced by reactive oxygen species (ROS) generated by club cells during Cr reduction with repetitive Cr(VI) exposure. Cr-induced DNA damage was also observed, as significant increase of 8-OHdG was found with Cr exposure at 0.630mg/kg week. Oral Zn supplementation did not alleviate changes in serum CC16 level under Cr(VI) exposure, indicating its failure in protecting against Cr(VI)-induced club cell damage.

Repeated anterior chamber fluorophotometric evaluation of the eyes of ophthalmologically normal dogs.

OBJECTIVE: To perform repeated anterior chamber fluorophotometry on both eyes of ophthalmologically normal dogs to measure fluorescein concentrations over a 5-day period and identify any change in the degree of anterior chamber fluorescence over time or difference between eyes. ANIMALS: 9 healthy adult dogs (18 eyes). PROCEDURES: Each dog received an IV injection of 10% fluorescein solution, and anterior chamber fluorophotometry was performed 1 hour later on both eyes. This procedure was repeated at the same time each day for 5 consecutive days. RESULTS: A significant increase in fluorescein concentration was evident in the anterior chamber on day 5 in the right eye and days 2, 3, 4, and 5 in the left eye. There was no significant difference in concentration between the left and the right eyes on any day. CONCLUSIONS AND CLINICAL RELEVANCE: The increase in ocular fluorescein concentration in the study dogs was unlikely to be of clinical importance and is only pertinent for subsequent research studies. This is a limitation that should be considered when reporting fluorophotometry data as fluorescein concentration or as change in fluorescein concentration from baseline.

[Mek1 and Mek2 functions in the formation of the blood placental barrier]. / Le rôle des kinases Mek1 et Mek2 dans la formation de la barrière hématoplacentaire chez la souris.

The ERK/MAPK signaling pathway is involved in several cellular functions. Inactivation in mice of genes encoding members of this pathway is often associated with embryonic death resulting from abnormal placental development. The placenta is essential for nutritional and gaseous exchanges between maternal and embryonic circulations, as well as for the removal of metabolic wastes. These exchanges take place without direct contact between the two circulations. In mice, the hematoplacental barrier consists in a triple layer of trophoblast cells and endothelial cells of the embryo. MEK1 and MEK2 are double specificity serine-threonine/tyrosine kinases responsible for the activation of ERK1 and ERK2. Mek1 inactivation results in placental anomalies due to trophoblast cell proliferation and differentiation defects leading to severe delays in the development of placenta and causing the death of the embryo. Although Mek2(-/-) mutant mice survived without any apparent phenotype, double heterozygous Mek1(+/-)Mek2(+/-) mutants die during gestation from placental malformations. Together, these data emphasize the crucial role of the ERK/MAPK cascade in the formation of extraembryonic structures.

Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice.

BACKGROUND: Loss-of-function mutations in filaggrin are major predisposing factors for atopic dermatitis. Although various reports suggest a critical role for filaggrin in stratum corneum (SC) barrier formation, the lack of filaggrin-null (Flg(-/-)) mice has hampered detailed in vivo analysis of filaggrin's functions. OBJECTIVE: We sought to generate Flg(-/-) mice and to assess the effect of filaggrin loss on SC barrier function and percutaneous immune responses. METHODS: We generated Flg(-/-) mice using gene targeting and assessed the morphology, hydration, mechanical strength, and antigen permeability of their SC. Percutaneous immune responses were evaluated through irritant- and hapten-induced contact hypersensitivity studies and by measuring humoral responses to epicutaneous sensitization with protein antigen. RESULTS: Newborn Flg(-/-) mice exhibited dry scaly skin. Despite marked decreases in natural moisturizing factor levels, which are filaggrin degradation products, SC hydration and transepidermal water loss were normal. Microscopic analyses suggested premature shedding of SC layers, and indeed, increased desquamation under mechanical stress was demonstrated. Loss of keratin patterns, which are critical for corneocyte stabilization, is likely attributable to fragility in the Flg(-/-) SC. Antigens penetrated the Flg(-/-) SC more efficiently, leading to enhanced responses in hapten-induced contact hypersensitivity and higher serum levels of anti-ovalbumin IgG(1) and IgE. CONCLUSION: Complete filaggrin deficiency led to altered barrier integrity and enhanced sensitization, which are important factors in early-phase atopic dermatitis. Flg(-/-) mice should provide a valuable tool to further explore additional factors the dysfunction of which leads to uncontrolled inflammation in patients with atopic diseases.

Role of vascular endothelial growth factor in the breakdown of the blood-aqueous barrier after retinal laser photocoagulation in pigmented rabbits.

PURPOSE: Retinal laser photocoagulation is used to treat a variety of retinal diseases. Breakdown of the blood-aqueous barrier has been noted after retinal laser photocoagulation. The effect of vascular endothelial growth factor (VEGF) on the function of the blood-aqueous barrier after retinal laser photocoagulation remains undetermined. The current study was designed to evaluate the relationship between intraocular levels of VEGF and breakdown of the blood-aqueous barrier after retinal laser photocoagulation in rabbits. METHODS: Pigmented rabbits were treated with retinal laser photocoagulation in one eye; the other served as control. Laser flare photometry was carried out on post-treatment days 1, 3, 7, and 14. Animals were sacrificed at the time period just mentioned postlaser, the eyes were removed, and samples of vitreous and aqueous humor were collected. Intraocular VEGF levels were measured by using an immunoassay. An intravitreal injection of VEGF was administered, and the aqueous flare intensity and VEGF levels in the aqueous and vitreous humor were measured at the time periods just mentioned. RESULTS: A significant increase in the aqueous flare intensity after retinal laser photocoagulation was noticed on postoperative day 1, with the values returning to baseline levels on day 14. The VEGF levels in the vitreous of the lasered eyes were significantly increased on day 1 compared with the nonlasered control eyes. The VEGF levels in the aqueous humor of the lasered eyes were also significantly increased on day 1 compared with the control eyes. An intravitreal injection of VEGF induced a significant increase in the aqueous flare intensity and VEGF levels in the aqueous and vitreous humor. CONCLUSIONS: The current results suggested that retinal laser photocoagulation can produce a breakdown of the blood-aqueous barrier. VEGF may play a role in the blood-aqueous barrier dysfunction after retinal laser photocoagulation.

The effects of anthrax lethal toxin on host barrier function.

The pathological actions of anthrax toxin require the activities of its edema factor (EF) and lethal factor (LF) enzyme components, which gain intracellular access via its receptor-binding component, protective antigen (PA). LF is a metalloproteinase with specificity for selected mitogen-activated protein kinase kinases (MKKs), but its activity is not directly lethal to many types of primary and transformed cells in vitro. Nevertheless, in vivo treatment of several animal species with the combination of LF and PA (termed lethal toxin or LT) leads to morbidity and mortality, suggesting that LT-dependent toxicity is mediated by cellular interactions between host cells. Decades of research have revealed that a central hallmark of this toxicity is the disruption of key cellular barriers required to maintain homeostasis. This review will focus on the current understanding of the effects of LT on barrier function, highlighting recent progress in establishing the molecular mechanisms underlying these effects.

Alterations in the aqueous humor proteome in patients with a glaucoma shunt device.

PURPOSE: To investigate whether implantation of a glaucoma shunt device leads to inappropriate accumulation of plasma derived proteins in the aqueous humor. METHODS: Aqueous humor samples were collected from 11 patients (study group) with a glaucoma shunt device undergoing either cataract surgery or a corneal transplant and 11 patients (control) with senile cataract undergoing routine cataract extraction. Of the study group, 9 had an Ahmed valve implant and 2 eyes had a Baerveldt implant. Tryptic digests of the mixture of proteins in aqueous humor (AH) were analyzed using Liquid Chromatography/Mass Spectrometry (LC-MS/MS). Proteins were identified with high confidence using stringent criteria and compared quantitatively using a label-free platform (IdentiQuantXL™). RESULTS: We identified 135 proteins in the albumin-depleted fraction in both the study and control group AH. Using stringent criteria, 13 proteins were detected at a significantly higher level compared to controls. These proteins are known to play a role in oxidative stress, apoptosis, inflammation and/or immunity and include gelsolin (p=0.00005), plasminogen (p=0.00009), angiotensinogen (p=0.0001), apolipoprotein A-II (p=0.0002), beta-2-microglobulin (p=0.0002), dickkopf-3 (DKK-3; p=0.0002), pigment epithelium-derived factor (p=0.0002), RIG-like 7-1 (p=0.0002), afamin (p=0.0003), fibronectin 1 (FN1; p=0.0003), apolipoprotein A-I (p=0.0004), activated complement C4 protein (C4a; p=0.0004) and prothrombin (p=0.0004). Many of the identified proteins were novel proteins that have not been associated with glaucoma in prior studies. All but C4a (complement C4 is a plasma protein but not in an activated form) are known plasma proteins and the elevated levels of these proteins in the aqueous humor suggests a breach in the blood-aqueous barrier with passive influx into the anterior chamber of the eye. CONCLUSIONS: The presence of these proteins in the aqueous humor suggests that glaucoma shunt device causes either a breach in blood-aqueous barrier or chronic trauma, increasing influx of oxidative, apoptotic and inflammatory proteins that could potentially cause corneal endothelial damage.

Evaluation of drug efflux transporter liabilities of darifenacin in cell culture models of the blood-brain and blood-ocular barriers.

AIMS: The objective of the present study was to evaluate drug efflux transporter interactions of darifenacin and examine the impact of such transporter interactions on darifenacin permeability in an in vitro model of the blood-brain barrier (BBB) and blood-ocular barrier (BOB). METHODS: Cell membranes expressing human P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) were examined for ATPase activity following darifenacin exposure (0-10 µM). Primary cultured bovine brain microvessel endothelial cells (BBMEC) and P-gp transfected Manin-Darby canine kidney epithelial cells (MDCKMDR1) were used to examine darifenacin permeability and drug efflux transporter responses. RESULTS: Concentration-dependent increases in ATPase activity was observed in P-gp membranes following darifenacin exposure. Both MRP and BCRP membrane preparations were unresponsive to darifenacin. Studies in both BBMEC and MDCKMDR1 monolayers confirmed a P-gp interaction for darifenacin and significantly greater efflux (basolateral to apical) permeability for darifenacin that was reduced by the P-gp inhibitor, elacridar. CONCLUSIONS: Darifenacin is a substrate for the P-gp drug efflux transporter present in both BBB and BOB. The P-gp drug efflux transporter liabilities of darifenacin may limit its penetration into brain and ocular tissue thereby reducing side effect potential.

Inhibitory effects of alcohol on glucose transport across the blood-brain barrier leads to neurodegeneration: preventive role of acetyl-L: -carnitine.

PURPOSE: Evidence shows that alcohol intake causes oxidative neuronal injury and neurocognitive deficits that are distinct from the classical Wernicke-Korsakoff neuropathy. Our previous findings indicated that alcohol-elicited blood-brain barrier (BBB) damage leads to neuroinflammation and neuronal loss. The dynamic function of the BBB requires a constant supply and utilization of glucose. Here we examined whether interference of glucose uptake and transport at the endothelium by alcohol leads to BBB dysfunction and neuronal degeneration. MATERIAL AND METHODS: We tested the hypothesis in cell culture of human brain endothelial cells, neurons and alcohol intake in animal by immunofluorescence, Western blotting and glucose uptake assay methods. RESULTS: We found that decrease in glucose uptake correlates the reduction of glucose transporter protein 1 (GLUT1) in cell culture after 50 mM ethanol exposure. Decrease in GLUT1 protein levels was regulated at the translation process. In animal, chronic alcohol intake suppresses the transport of glucose into the frontal and occipital regions of the brain. This finding is validated by a marked decrease in GLUT1 protein expression in brain microvessel (the BBB). In parallel, alcohol intake impairs the BBB tight junction proteins occludin, zonula occludens-1, and claudin-5 in the brain microvessel. Permeability of sodium fluorescein and Evans Blue confirms the leakiness of the BBB. Further, depletion of trans-endothelial electrical resistance of the cell monolayer supports the disruption of BBB integrity. Administration of acetyl-L: -carnitine (a neuroprotective agent) significantly prevents the adverse effects of alcohol on glucose uptake, BBB damage and neuronal degeneration. CONCLUSION: These findings suggest that alcohol-elicited inhibition of glucose transport at the blood-brain interface leads to BBB malfunction and neurological complications.

Nanoparticle-mediated brain-specific drug delivery, imaging, and diagnosis.

Central nervous system (CNS) diseases represent the largest and fastest-growing area of unmet medical need. Nanotechnology plays a unique instrumental role in the revolutionary development of brain-specific drug delivery, imaging, and diagnosis. With the aid of nanoparticles of high specificity and multifunctionality, such as dendrimers and quantum dots, therapeutics, imaging agents, and diagnostic molecules can be delivered to the brain across the blood-brain barrier (BBB), enabling considerable progress in the understanding, diagnosis, and treatment of CNS diseases. Nanoparticles used in the CNS for drug delivery, imaging, and diagnosis are reviewed, as well as their administration routes, toxicity, and routes to cross the BBB. Future directions and major challenges are outlined.

The role of blood-ocular barrier transporters in retinal drug disposition: an overview.

IMPORTANCE OF THE FIELD: Delivery of drugs to the retina remains a major challenge which needs to be addressed urgently because retinal disorders are leading causes of visual impairment and significantly affect a patient's quality of life. Systemic drug administration is one possible route for treating retinal disorders; however, retinal transfer of drugs from the circulating blood is strictly regulated by two blood-ocular barrier systems, the blood-aqueous barrier and the blood-retinal barrier. AREAS COVERED IN THIS REVIEW: This review summarizes the latest biological research regarding blood-ocular barrier drug transporters. WHAT THE READER WILL GAIN: The blood-ocular barrier sites and their respective roles in aqueous humor dynamics and retinal homeostasis are briefly presented. The potential impact of ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, such as ABCB, ABCC, ABCG, SLC7, SLC16, SLC19, SLCO/SLC21A, SLC22A and SLC29 transporters, on the permeability of drugs across the blood-ocular barriers is then illustrated. TAKE HOME MESSAGE: As more information becomes available regarding the blood-ocular barrier transporters, we may be able to design simpler and more effective routes for drug delivery to the retina and, consequently, improve the treatment of retinal diseases.