Impermeability Of Blood-brain Barrier Research Articles

Transferrin-Conjugated Melittin-Loaded L-Arginine-Coated Iron Oxide Nanoparticles for Mitigating Beta-Amyloid Pathology of the 5XFAD Mouse Brain.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases and a major contributor to dementia. Although the cause of this condition has been identified long ago as aberrant aggregations of amyloid and tau proteins, effective therapies for it remain elusive. The complexities of drug development for AD treatment are often compounded by the impermeable blood-brain barrier and low-yield brain delivery. In addition, the use of high drug concentrations to overcome this challenge may entail side effects. To address these challenges and enhance the precision of delivery into brain regions affected by amyloid aggregation, we proposed a transferrin-conjugated nanoparticle-based drug delivery system. The transferrin-conjugated melittin-loaded L-arginine-coated iron oxide nanoparticles (Tf-MeLioNs) developed in this study successfully mitigated melittin-induced cytotoxicity and hemolysis in the cell culture system. In the 5XFAD mouse brain, Tf-MeLioNs remarkably reduced amyloid plaque accumulation, particularly in the hippocampus. This study suggested Tf-LioNs as a potential drug delivery platform and Tf-MeLioNs as a candidate for therapeutic drug targeting of amyloid plaques in AD. These findings provide a foundation for further exploration and advancement in AD therapeutics.

Local Delivery Strategies for Peptides and Proteins into the CNS: Status Quo, Challenges, and Future Perspectives.

Over the past decades, peptides and proteins have been increasingly important in the treatment of various human diseases and conditions owing to their specificity, potency, and minimized off-target toxicity. However, the existence of the practically impermeable blood brain barrier (BBB) limits the entry of macromolecular therapeutics into the central nervous systems (CNS). Consequently, clinical translation of peptide/protein therapeutics for the treatment of CNS diseases has been limited. Over the past decades, developing effective delivery strategies for peptides and proteins has gained extensive attention, in particular with localized delivery strategies, due to the fact that they are capable of circumventing the physiological barrier to directly introduce macromolecular therapeutics into the CNS to improve therapeutic effects and reduce systemic side effects. Here, we discuss various local administration and formulation strategies that have shown successes in the treatment of CNS diseases using peptide/protein therapeutics. Lastly, we discuss challenges and future perspectives of these approaches.

Peripheral Klotho protects the kidney and brain by regulating M2a/M2c macrophage polarization in d-gal-treated aged mice

In elderly individuals, aging can cause changes in the structure and function of one or more organs, increasing their susceptibility to various damage factors, especially the heart, kidney, brain and other important organs. Therefore, the incidence of cardiovascular disease, neurodegenerative diseases and chronic kidney disease in the elderly population is significantly higher than that in the general population. In our previous study, the hearts of aged mice did not express the antiaging protein Klotho (KL), but peripheral elevation of KL may significantly delay cardiac aging. The kidney and brain are the main organs that produce KL, but the effects and mechanism of peripheral KL supplementation on the kidney and hippocampus are still unclear. To study the effect and possible mechanism of KL against kidney and hippocampus aging, 60 male BALB/c mice were randomly divided into the Adult group, the KL group, the D-gal-induced Aged group, and the KL + Aged group. The results showed that KL increased anti-inflammatory M2a/M2c macrophages in the kidney and hippocampus of aging mice, significantly reduced tissue inflammation and oxidative stress, and improved organ function and aging status. More importantly, we demonstrate that despite the impermeable bloodbrain barrier in mice, peripherally administered KL surprisingly enhances M2-type microglia polarization, induces cognitive enhancement and reduces neuroinflammation. Cellular experimental results suggest that KL may play a role in delaying senescence by regulating the TLR4/Myd88/NF-κB signaling pathway to regulate macrophage polarization and reduce aging-related inflammation and oxidative stress.

Brain-targeted delivery of Valsartan using solid lipid nanoparticles labeled with Rhodamine B; a promising technique for mitigating the negative effects of stroke

The brain is a vital organ that is protected from the general circulation and is distinguished by the presence of a relatively impermeable blood brain barrier (BBB). Blood brain barrier prevents the entry of foreign molecules. The current research aims to transport valsartan (Val) across BBB utilizing solid lipid nanoparticles (SLNs) approach to mitigate the adverse effects of stroke. Using a 32-factorial design, we could investigate and optimize the effect of several variables in order to improve brain permeability of valsartan in a target-specific and sustained-release manner, which led to alleviation of ischemia-induced brain damage. The impact of each of the following independent variables was investigated: lipid concentration (% w/v), surfactant concentration (% w/v), and homogenization speed (RPM) on particle size, zeta potential (ZP), entrapment efficiency (EE) %, and cumulative drug release percentage (CDR) %. TEM images revealed a spherical form of the optimized nanoparticles, with particle size (215.76 ± 7.63 nm), PDI (0.311 ± 0.02), ZP (-15.26 ± 0.58 mV), EE (59.45 ± 0.88%), and CDR (87.59 ± 1.67%) for 72 hours. SLNs formulations showed sustained drug release, which could effectively reduce the dose frequency and improve patient compliance. DSC and X-ray emphasize that Val was encapsulated in the amorphous form. The in-vivo results revealed that the optimized formula successfully delivered Val to the brain through intranasal rout as compared to a pure Val solution and evidenced by the photon imaging and florescence intensity quantification. In a conclusion, the optimized SLN formula (F9) could be a promising therapy for delivering Val to brain, alleviating the negative consequences associated with stroke.

Potentials of Neuropeptides as Therapeutic Agents for Neurological Diseases.

Despite recent leaps in modern medicine, progress in the treatment of neurological diseases remains slow. The near impermeable blood-brain barrier (BBB) that prevents the entry of therapeutics into the brain, and the complexity of neurological processes, limits the specificity of potential therapeutics. Moreover, a lack of etiological understanding and the irreversible nature of neurological conditions have resulted in low tolerability and high failure rates towards existing small molecule-based treatments. Neuropeptides, which are small proteinaceous molecules produced by the body, either in the nervous system or the peripheral organs, modulate neurological function. Although peptide-based therapeutics originated from the treatment of metabolic diseases in the 1920s, the adoption and development of peptide drugs for neurological conditions are relatively recent. In this review, we examine the natural roles of neuropeptides in the modulation of neurological function and the development of neurological disorders. Furthermore, we highlight the potential of these proteinaceous molecules in filling gaps in current therapeutics.

Poly(butyl cyanoacrylate) nanoparticles-delivered β-nerve growth factor promotes the neurite outgrowth and reduces the mortality in the rat after traumatic brain injury

Several transport vectors, including nanoparticles, have been reported to be used for the delivery of therapeutic medicines crossing the impermeable blood-brain barrier (BBB) to treat the diseases in the central nerve system (CNS), such as traumatic brain injury (TBI). Poly(n-butyl-2-cyanoacrylate) (PBCA) nanoparticles, made from biocompatible material, are regarded as a better potential delivery tool than others such as gold nanoparticles due to their degradability in vivo. However, little is known whether PBCA nanoparticles can be used to deliver neurotrophic factors into the brain to treat TBI. In this study, we first synthesized PBCA-carried β-nerve growth factor, a neurotrophic agent with a large molecular weight, and then intravenously injected the compound into TBI rats. We found that despite undergoing several synthesis steps and host circulation, β-NGF was able to be successfully delivered into the injured brain by PBCA nanoparticles, still maintain its neurotrophic activity for neurite outgrowth, and reduce the mortality of TBI rats. Our findings indicate that PBCA nanoparticles, with Tween 80, are an efficient delivery vector and a protective reservoir for large molecular therapeutic agents to treat TBI intravenously.

An In Vivo Mouse Model to Study Blood-Brain Barrier Destabilization in the Chronic Phase of Stroke.

Cerebral ischemic injury evokes a complex cascade of pathophysiological events at the blood-vascular-parenchymal interface. These evolve over time and space and result in progressive neurological damage. Emerging evidence suggests that blood-brain barrier (BBB) recovery and reestablishment of BBB impermeability are incomplete and that these could influence stroke injury recovery, increase the risk of new stroke occurrence, and be a solid substrate for developing vascular dementia. Recent work from the author's laboratory has established the existence of incomplete BBB recovery in chronic stroke conditions that was induced by structural alterations to brain endothelial junctional complexes and persistent BBB leakage. The experimental methodology presented here is focused on modelling chronic stroke injury using an in vivo thromboembolic mouse stroke model and how to evaluate the kinetics and magnitude of BBB hyperpermeability in chronic stroke conditions using a combination of magnetic resonance imaging, tracer studies, and immunohistochemistry.

Pulsatile Bi-Directional Aerosol Flow Affects Aerosol Delivery to the Intranasal Olfactory Region: A Patient-Specific Computational Study.

The nasal olfactory region is a potential route for non-invasive delivery of drugs directly from the nasal epithelium to the brain, bypassing the often impermeable blood-brain barrier. However, efficient aerosol delivery to the olfactory region is challenging due to its location in the nose. Here we explore aerosol delivery with bi-directional pulsatile flow conditions for targeted drug delivery to the olfactory region using a computational fluid dynamics (CFD) model on the patient-specific nasal geometry. Aerosols with aerodynamic diameter of 1 µm, which is large enough for delivery of large enough drug doses and yet potentially small enough for non-inertial aerosol deposition due to, e.g., particle diffusion and flow oscillations, is inhaled for 1.98 s through one nostril and exhaled through the other one. The bi-directional aerosol delivery with steady flow rate of 4 L/min results in deposition efficiencies (DEs) of 50.9 and 0.48% in the nasal cavity and olfactory region, respectively. Pulsatile flow with average flow rate of 4 L/min (frequency: 45 Hz) reduces these values to 34.4 and 0.12%, respectively, and it mitigates the non-uniformity of right-left deposition in both the cavity (from 1.77- to 1.33-fold) and the olfactory region (from 624- to 53.2-fold). The average drug dose deposited in the nasal cavity and the olfactory epithelium region is very similar in the right nasal cavity independent of pulsation conditions (inhalation side). In contrast, the local aerosol dose in the olfactory region of the left side is at least 100-fold lower than that in the nasal cavity independent of pulsation condition. Hence, while pulsatile flow reduces the right-left (inhalation-exhalation) imbalance, it is not able to overcome it. However, the inhalation side (even with pulsation) allows for relatively high olfactory epithelium drug doses per area reaching the same level as in the total nasal cavity. Due to the relatively low drug deposition in olfactory region on the exhalation side, this allows either very efficient targeting of the inhalation side, or uniform drug delivery by performing bidirectional flow first from the one and then from the other side of the nose.

Does interventional MRI-guided brain cryotherapy cause a blood-brain barrier disruption? Radiological analysis and perspectives.

Glioblastoma is the most common primary malignant brain tumor with an incidence of 5/100,000 inhabitants/year and a 5-year survival rate of 6.8%. Despite recent advances in the molecular biology understanding of glioblastoma, CNS chemotherapy remains challenging because of the impermeable blood-brain barrier (BBB). Interventional MRI-guided brain cryotherapy (IMRgC) is technique that creates a tissue lesion by making a severe targeted hypothermia and possibly a BBB disruption. This study goal was to analyze the effect of IMRgC on human BBB glioblastoma through its gadolinium enhancing features. All patients harboring a local glioblastoma recurrence and meeting all the inclusion criteria were consecutively included into this retrospective study during a 2-year period. The primary endpoint was to analyze the modification of the gadolinium enhancement on MRI T1 sequences using MR perfusion weighted images during follow-up. The secondary endpoint was to assess any ischemic/hemorrhagic complication following cryotherapy procedure using diffusion weighted imaging (DWI), susceptibility weighted imaging (SWI), or fluid-attenuated inversion recovery (FLAIR). Among the 6 patients studied, all (100%) showed a BBB disruption on the cryotherapy site through the analysis of the perfusion weighted images with an average delay of 2.83months following the procedure. The gadolinium enhancement located around the cavity then spontaneously decreased in 4/6 patients (67%). No ischemic or hemorrhagic complication was recorded. This study confirms the IMRgC capacity to disrupt BBB as already suggested by the literature. IMRgC might represent a new option in the management of GBM allowing the combined effect of direct cryoablation and enhanced chemotherapy.

Mesenchymal Epithelial Transition Factor Signaling in Pediatric Nervous System Tumors: Implications for Malignancy and Cancer Stem Cell Enrichment.

Malignant nervous system cancers in children are the most devastating and worrisome diseases, specifically due to their aggressive nature and, in some cases, inoperable location in critical regions of the brain and spinal cord, and the impermeable blood-brain barrier that hinders delivery of pharmaco-therapeutic compounds into the tumor site. Moreover, the delicate developmental processes of the nervous system throughout the childhood years adds another limitation to the therapeutic modalities and doses used to treat these malignant cancers. Therefore, pediatric oncologists are charged with the daunting responsibility of attempting to deliver effective cures to these children, yet with limited doses of the currently available therapeutic options in order to mitigate the imminent neurotoxicity of radio- and chemotherapy on the developing nervous system. Various studies reported that c-Met/HGF signaling is affiliated with increased malignancy and stem cell enrichment in various cancers such as high-grade gliomas, high-risk medulloblastomas, and MYCN-amplified, high-risk neuroblastomas. Therapeutic interventions that are utilized to target c-Met signaling in these malignant nervous system cancers have shown benefits in basic translational studies and preclinical trials, but failed to yield significant clinical benefits in patients. While numerous pre-clinical data reported promising results with the use of combinatorial therapy that targets c-Met with other tumorigenic pathways, therapeutic resistance remains a problem, and long-term cures are rare. The possible mechanisms, including the overexpression and activation of compensatory tumorigenic mechanisms within the tumors or ineffective drug delivery methods that may contribute to therapeutic resistance observed in clinical trials are elaborated in this review.

A Murine Ommaya Xenograft Model to Study Direct-Targeted Therapy of Leptomeningeal Disease.

Leptomeningeal disease (LMD) is an uncommon type of central nervous system (CNS) metastasis to the cerebral spinal fluid (CSF). The most common cancers that cause LMD are breast and lung cancers and melanoma. Patients diagnosed with LMD have a very poor prognosis and generally survive for only a few weeks or months. One possible reason for the lack of efficacy of systemic therapy against LMD is the failure to achieve therapeutically effective concentrations of drug in the CSF because of an intact and relatively impermeable blood-brain barrier (BBB) or blood-CSF barrier across the choroid plexus. Therefore, directly administering drugs intrathecally or intraventricularly may overcome these barriers. This group has developed a model that allows for the effective delivery of therapeutics (i.e., drugs, antibodies, and cellular therapies) chronically and the repeated sampling of CSF to determine drug concentrations and target modulation in the CSF (when the tumor microenvironment is targeted in mice). The model is the murine equivalent of a magnetic resonance imaging-compatible Ommaya reservoir, which is used clinically. This model, which is affixed to the skull, has been designated as the “Murine Ommaya.” As a therapeutic proof of concept, human epidermal growth factor receptor 2 antibodies (clone 7.16.4) were delivered into the CSF via the Murine Ommaya to treat mice with LMD from human epidermal growth factor receptor 2-positive breast cancer. The Murine Ommaya increases the efficiency of drug delivery using a miniature access port and prevents the wastage of excess drug; it does not interfere with CSF sampling for molecular and immunological studies. The Murine Ommaya is useful for testing novel therapeutics in experimental models of LMD.

Current state of cerebral microangiopathy in hypertension

Hypertension is the main cause and the most important risk factor for both acute cerebrovascular accident and chronic progressive cerebrovascular insufficiency that is accompanied by severe neurological and mental disorders even to the extent of developing dementia. They are based on hypertension-induced pathology of the intracerebral arteries and cerebral microvasculature - cerebral microangiopathy that leads to small deep (lacunar) infarcts (SDIs) and diffuse cerebral white matter diseases. This review highlights the morphology, pathogenesis, clinical and neuroimaging diagnosis of hypertensive SDIs, and their differential diagnosis with atherosclerotic SDIs in the historical aspect. It is emphasized that the lacunar state of the brain in hypertension is a predictor of massive cerebral hemorrhages. Special attention is paid to current studies of the morphology and pathogenesis of diffuse changes in white matter and to the role of blood-brain barrier impermeability in the development of progressive leukoencephalopathy.

Exploring the Molecular Mechanisms of 17β-HSD5-induced Carcinogenicity of Catha edulis via Molecular Modeling Approach.

The tradition of khat chewing has been deep-rooted in the African and Arabian Peninsula for centuries. Due to its amphetamine-like psycho-stimulant or euphoric effect, khat has been used by millions in Somalia, Ethiopia, Saudi Arabia and Yemen. The long-term use of khat can induce many major health outcomes, which may be serious and irreversible. Prolonged use of khat constituents has been associated with different types of cancers such as prostatic, breast and ovarian cancer. However, it has been very difficult to identify the molecular targets involved in khat carcinogenesis that interact with the Khat constituents by in vitro/in vivo experimental tools. In silico tools were used to predict potential targets involved in the carcinogenesis of khat. Pass on-line prediction server was used for the prediction of a potential molecular target for khat constituents. Molecular Dynamics simulation and MM-GBSA calculation of the predicted target were carried out. Molecular Dynamics simulation and MM-GBSA calculation revealed that among khat constituents, β-sitosterol showed a high binding affinity towards 17β-HSD5. On the other hand, this study highlights for the first time some new interactions, which were observed in the case of cathine, cathinone and nerol during the simulation. In silico molecular dynamic simulation tools were used for the first time to investigate the molecular mechanism of widely used leaves of psychoactive khat (Catha edulis) constituent. The present study provides deep insight to understand the effect of khat constituents involved in the impairment of the reproductive system and its binding to 17β-HSD5. ADMET profiling also suggested that few khat constituents do not fulfill the requirements of the Lipinski rule of five i.e. poor absorption and blood-brain barrier impermeability.

Targeting nanoparticles to the brain by exploiting the blood–brain barrier impermeability to selectively label the brain endothelium

Current strategies to direct therapy-loaded nanoparticles to the brain rely on functionalizing nanoparticles with ligands which bind target proteins associated with the blood-brain barrier (BBB). However, such strategies have significant brain-specificity limitations, as target proteins are not exclusively expressed at the brain microvasculature. Therefore, novel strategies which exploit alternative characteristics of the BBB are required to overcome nonspecific nanoparticle targeting to the periphery, thereby increasing drug efficacy and reducing detrimental peripheral side effects. Here, we present a simple, yet counterintuitive, brain-targeting strategy which exploits the higher impermeability of the BBB to selectively label the brain endothelium. This is achieved by harnessing the lower endocytic rate of brain endothelial cells (a key feature of the high BBB impermeability) to promote selective retention of free, unconjugated protein-binding ligands on the surface of brain endothelial cells compared to peripheral endothelial cells. Nanoparticles capable of efficiently binding to the displayed ligands (i.e., labeled endothelium) are consequently targeted specifically to the brain microvasculature with minimal "off-target" accumulation in peripheral organs. This approach therefore revolutionizes brain-targeting strategies by implementing a two-step targeting method which exploits the physiology of the BBB to generate the required brain specificity for nanoparticle delivery, paving the way to overcome targeting limitations and achieve clinical translation of neurological therapies. In addition, this work demonstrates that protein targets for brain delivery may be identified based not on differential tissue expression, but on differential endocytic rates between the brain and periphery.

Heterogeneity and vascular permeability of breast cancer brain metastases.

Improvements in the diagnosis and treatment of systemic breast cancer have led to a prolongation in patient survival. Unfortunately, these advances are also associated with an increased incidence of brain metastases (BM), with the result that many patients succumb due to BM treatment failure. Intracranial delivery of many chemotherapeutic agents and other therapeutics is hindered by the presence of an impermeable blood-brain barrier (BBB) designed to protect the brain from harmful substances. The formation of BM compromises the integrity of the BBB, resulting in a highly heterogeneous blood-tumor barrier (BTB) with varying degrees of vascular permeability. Here, we discuss how blood vessels play an important role in the formation of brain micrometastases as well as in the transformation from poorly permeable BM to highly permeable BM. We then review the role of BTB vascular permeability in the diagnostics and the choice of treatment regimens for breast cancer brain metastases (BCBM) and discuss whether the vasculature of primary breast cancers can serve as a biomarker for BM. Specifically, we examine the association between the vascular permeability of BCBM and their accumulation of large molecules such as antibodies, which remains largely unexplored.

ABC Transporter Inhibition Plus Dexamethasone Enhances the Efficacy of Convection Enhanced Delivery in H3.3K27M Mutant Diffuse Intrinsic Pontine Glioma.

An impermeable blood-brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG). To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG. The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed. Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P=.0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P<.001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P<.001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P=.0305). ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib, resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27M mutant DIPG.

Biodistribution of TAT or QLPVM coupled to receptor targeted liposomes for delivery of anticancer therapeutics to brain in vitro and in vivo

Combination therapy has emerged as an efficient way to deliver chemotherapeutics for treatment of glioblastoma. It provides collaborative approach of targeting cancer cells by acting via multiple mechanisms, thereby reducing drug resistance. However, the presence of impermeable blood brain barrier (BBB) restricts the delivery of chemotherapeutic drugs into the brain. To overcome this limitation, we designed a dual functionalized liposomes by modifying their surface with transferrin (Tf) and a cell penetrating peptide (CPP) for receptor and adsorptive mediated transcytosis, respectively. In this study, we used two different CPPs (based on physicochemical properties) and investigated the influence of insertion of CPP to Tf-liposomes on biocompatibility, cellular uptake, and transport across the BBB both in vitro and in vivo. The biodistribution profile of Tf-CPP liposomes showed more than 10 and 2.7 fold increase in doxorubicin and erlotinib accumulation in mice brain, respectively as compared to free drugs with no signs of toxicity.

Claudin-1-Dependent Destabilization of the Blood-Brain Barrier in Chronic Stroke.

Recent evidence suggests that blood-brain barrier (BBB) recovery and reestablishment of BBB impermeability after stroke is incomplete. This could influence stroke recovery, increase the risk of repeat stroke, and be a solid substrate for developing vascular dementia. Although accumulating evidence has defined morphological alterations and underlying mechanisms of tight junction (TJ) changes during BBB breakdown in acute stroke, very little is known about the type of alterations and mechanisms in BBB "leakage" found subacutely or chronically. The current study examined BBB structural alterations during the "BBB leakage" associated with the chronic phase of stroke in male mice and both genders of humans. We found significant upregulation of claudin-1 mRNA and protein, a nonspecific claudin for blood vessels, and downregulation in claudin-5 expression. Morphological and biochemical as well as fluorescence resonance energy transfer and fluorescence recovery after photobleaching analysis of postischemic brain endothelial cells and cells overexpressing claudin-1 indicated that newly synthesized claudin-1 was present on the cell membrane (∼45%), was incorporated into the TJ complex with established interaction with zonula occludens-1 (ZO-1), and was building homophilic cis- and trans-interactions. The appearance of claudin-1 in the TJ complex reduced claudin-5 strands (homophilic claudin-5 cis- and trans-interactions) and claudin-5/ZO-1 interaction affecting claudin-5 incorporation into the TJ complex. Moreover, claudin-1 induction was associated with an endothelial proinflammatory phenotype. Targeting claudin-1 with a specific C1C2 peptide improved brain endothelial barrier permeability and functional recovery in chronic stroke condition. This study highlights a potential "defect" in postischemic barrier formation that may underlie prolonged vessel leakiness.SIGNIFICANCE STATEMENT Although rarely expressed at the normal blood-brain barrier (BBB), claudin-1 is expressed in pathological conditions. Analyzing poststroke human and mouse blood microvessels we have identified that claudin-1 is highly expressed in leaky brain microvessels. Our results reveal that claudin-1 is incorporated in BBB tight junction complex, impeding BBB recovery and causing BBB leakiness during poststroke recovery. Targeting claudin-1 with a claudin-1 peptide improves brain endothelial barrier permeability and consequently functional neurological recovery after stroke.

Lipid Nanoparticles: A Novel Approach for Brain Targeting.

Brain is a delicate organ, separated from general circulation and is characterized by the presence of relatively impermeable Blood Brain Barrier (BBB). The BBB maintains homeostasis in the brain thus restricting the entrance of foreign bodies and several molecules from reaching the brain. As a result several promising molecules do not reach the target site and fail to produce in vivo response. Nevertheless, lipid nanoparticles are taken up readily by the brain because of their lipophilic nature. The bioacceptable and biodegradable nature of lipid nanoparticles makes them less toxic and suited for brain targeting. In the present review the BBB, mechanism of transport across the BBB, strategies to bypass the blood-brain barrier have been presented. The aptness of lipid nanoparticles for brain targeting has been highlighted. The proposed mechanism of uptake of the lipid nanoparticles, methods of prolonging the plasma retention and various methods of preparation for formulation of effective delivery systems for brain targeting have been included and dealt in this review. Lipid based formulations can be designated as the current and future generation of drug delivery systems as these possess tremendous potential to bypass BBB and reach the target site due to their small size and ability to dodge the reticular endothelial system. However, these nanostructures need to be investigated intensively to successfully reach the clinical trials stage.

The Matrix Metalloproteinases Panel in Multiple Sclerosis Patients Treated with Natalizumab: A Possible Answer to Natalizumab Non- Responders.

In the lymphocyte migration across the blood-brain barrier (BBB) in multiple sclerosis (MS), matrix metalloproteinases (MMPs) play an important role in the degradation of the basal membrane. Natalizumab (NAT), a monoclonal antibody, binds to the alpha-4 (α4) integrin leading to BBB impermeability. Approximately 30% of NAT-treated patients show clinical or MRI signs of BBB disruption. To determine whether NAT significantly influences the MMPs serum levels and to what extent these could be used as biomarkers in relapsing-remitting MS (RRMS) patients. This prospective study over a period of 8 months of NAT treatment, included 30 RRMS patients (mean age 38 ± 6 years; mean MS duration 12 ± 5 years), of which ten were initially naive to NAT and 15 were healthy controls. We determined the serum levels of the MMPs Panel (MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP12, and MMP13) quantified by a multiplex method at the beginning and end of the study. After 8 months of NAT treatment, a statistically significant decrease was found in MMP9, MMP2, MMP3, MMP8, and MMP10 levels. Relapses during the study were correlated with a variation of MMP12 and MMP13 serum levels. MMP9 had the most numerous correlations with the EDSS score, Rio score, and duration of NAT treatment. MMPs signature (the sum of all MMPs) and the MMP9/MMP2 ratio significantly decreased during the study. 1. The serum level of MMP9 significantly decreased by NAT treatment and correlates with MS activity; 2. After eight months of NAT treatment, the MMPs signature and the MMP9/MMP2 ratio decreased; 3. MMP9 might be used as a biomarker in MS patients treated with NAT.