Nasal to Brain Drug Delivery

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Nose to Brain Drug Delivery: New Perspectives for Old Problems An Enlightening Review

Nose to Brain Drug Delivery: New Perspectives for Old Problems An Enlightening Review

Solid lipid nanoparticles are colloidal substances. It composes biocompatible/biodegradable lipid medium which is solid in the body temperature and shows size ranges from 100 to 400 nm. It has many advantages like targeted delivery, controlled drug release, increased drug stability, smallest biotoxicity, and produced in large scale and easiness of sterilization [100]. SLN were introduced as submicron colloidal transporters (50-1000 nm) in 1991 as shown in Figure 6. SLN are used for hydrophilic and lipophilic drug(s) that are locked in biocompatible lipid core made by lipid or its combined form of lipids such as precirol ATO 5, Compritol 888 ATO, palmitic acid, glyceryl monostearate, stearic acid and stabilized by surfactant occur at the outer shell [101]. SLNs show an improvement to old drug delivery from nose to brain. As they are capable to guard the compressed drug from chemical or biological degradation and it also rises retention time of nasal because of an occlusive effect, adhesion and good application properties of the SLNs to mucous membranes [102].
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Role of Nanocarriers for Drug Delivery to Brain

Role of Nanocarriers for Drug Delivery to Brain

Through the olfactory or trigeminal nerve system that ends at olfactory neruoepithelium or respiratory epithelium drug delivery to brain can be possible through nasal route [131]. BBB can be crossed by using these nerve systems. Nose to brain drug delivery can reduce systemic toxicity but this route is inefficient. According to Illum et al. less than 0.1% of drug through nasal route will normally reaches to brain [132]. Poor nose to brain drug delivery can be improved using nanocarriers. Main barrier of this route is olfactory epithelium. Drug loaded nanocarriers can be used to achieve transmembrane transport across the barrier. Many studies have been done which suggests this strategy. A few studies have provided supportive data to this strategy. According to Betbeder et al. analgesic effect of morphine can be increased by administering morphine nasaly using 60 mm maltodextrin nanoparticles [133]. This study also concludes that Intransal nanoparticles formulation shows superior analgesic effect against subcutaneously administered morphine. Zhang et al. done same study using intranasally administered nanoparticles of nimodipine which shows improved results using nasal route [134]. Mucoadhesive nanopaticles can improve the olfactory drug delivery. Mainly Chitosan is used as mucoadhesive agent that can interact with junctional compleses between epithelial celles. Estradiol and risperidone were given intranasaly using Chitosan nanocarriers and their therapeutic effects were stronger than intravenously administered nanocarriers [135,136]. Lectins can also be used as mucoadhesive [137]. Lectin coated PLA nanoparticles can increase the coumarin concentration in brain by two folds instead of uncoated ones.
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A Review on Novel Techniques for Drug Delivery to the Brain

A Review on Novel Techniques for Drug Delivery to the Brain

In addition to targeted delivery, several alternative strategies have been developed to improve brain drug delivery by nanomedicine like efflux transporter inhibition 60,61 , nanocarrier cationization 62 , paracellular transport enhancement 63 , intranasal administration 64 , focused ultrasound and microbubbles with nanoparticles 65 . The brain and the nasal cavity are connected by the olfactory or trigeminal nerve system that terminates at the olfactory neuroepithelium or respiratory epithelium 64 . These two nerve systems can serve as the externally accessible points of the brain, and be exploited to bypass the BBB for direct nose-to-brain drug delivery. Along with this a number of groups have investigated enhanced delivery of drugs and antibodies using MRI- guided focused ultrasound with microbubbles and reported promising results. Despite these positive results and studies showing that ultrasound-induced BBB disruption does not cause substantial vascular damage that would result in ischemic or apoptotic death to neurons, there remain concerns over the safety of this strategy 65 .
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“EVALUATION OF BRAIN-TARGETING FOR THE NASAL
DELIVERY OF MIDAZOLAM” by Sapna Desai, Gali Vidyasagar, Anil Bhandhari,
India.

“EVALUATION OF BRAIN-TARGETING FOR THE NASAL DELIVERY OF MIDAZOLAM” by Sapna Desai, Gali Vidyasagar, Anil Bhandhari, India.

Midazolam is chemically 8-chloro- 6-(2-fluorophenyl)- 1- methyl- 4H-imidazo[1,5-a] [1,4]benzodiazepine . It is used to produce sleepiness or drowsiness and to relieve anxiety before surgery. Midazolam is also given to produce amnesia so that the patient will not remember any discomfort or undesirable effects that may occur after a surgery or procedure. Midazolam undergoes first pass metabolism and it is generally given by oral or parenteral routes. An alternative route of drug delivery is needed since oral and intravenous routes for delivering drugs are sometimes impractical and/or inconvenient. Direct transport of drugs to the brain circumventing the brain-barriers following intranasal administration provides a unique feature and better option to target drugs to brain. The plasma half life of midazolam is 4 hrs and that is the reason it was used for the nose to brain drug delivery and the use of bioadhesive microspheres gives more residence time to facilitate absorption. Chitosan-gelatin was used to prepare the midazolam microspheres for the nose to brain drug delivery so as to increase the residence time and by pass the first pass metabolism by liver. Intranasal administration has drawn considerable interest in the last decade since it provides a non-invasive method for bypassing hepatic first-pass effect and possibly the blood brain barrier (BBB). Therefore, it might be a feasible way of both enhancing midazolam bioavailability and achieving its brain- targeting. Drugs administered to the nasal cavity can travel along the olfactory and trigeminal nerves to reach many regions within CNS. Many substances, including tracer materials, heavy metals, low molecular weight drugs and peptides have been shown to reach the CSF, the olfactory bulb (OB) and in some case other parts of the brain, after nasal administration. Drugs have been shown to reach the CNS from the nasal cavity by a direct transport across the olfactory region situated at the loft
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Nano formulation: A novel approach for nose to brain drug delivery

Nano formulation: A novel approach for nose to brain drug delivery

There has been growing interest and focus on the use of nasal route for systemic delivery & Brain targeting. Drug which undergoes first pass metabolism to avoid this and increases there bioavailability of drug nasal route is preferred[19]. It is useful for the drug which are active at low doses & show very less oral bioavailability such as Protein and peptide, central nervous system diseases such as Epilepsies, meningitis, migraine, Parkinson diseases, Alzheimer diseases has difficulty in targeting because of the transport through Blood Brain Barrier [20]. From literature it shows that such diseases can be treated by transporting exogenous material to brain by nose or it’s an effective route by passing BBB [21]. The result of concentration time Profile of intranasal administration drug is similar to the Intravenous route [22]. The pathway employed for the delivery of particular drug from the nose to brain is highly dependent on various factors, such as existence of specific receptor on the olfactory neurons, the lipophilicity and molecular, weight of the drug [23]. Intra nasal delivery is non-invasive & painless delivery and it does not required sterile preparation & it is easy method of drug administration for patient or physician. The nasal route offers improve delivery for “non-Lipinski” drug [24]. Lipophilic drug can easy cross BBB by travelling throw transcellular pathway. Hydrophilic drug transport throw paracellular pathway so they have very less chance to pass BBB. Polar molecule have very less chance to pass from respiratory region to blood stream so they have some chances to reach brain by passing or travelling throw olfactory mucosa in nose [25]. Many novel nasal products for systemic delivery on various diseases are launched in market but still no drug exploiting the nasal route to treat CNS diseases. Development of drug delivery throw nose to enable rapid & effective concentration in Brain challenges for Researchers.
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BRAIN DRUG DELIVERY SYSTEM: A COMPREHENSIVE REVIEW ON RECENT EXPERIMENTAL AND CLINICAL FINDINGS

BRAIN DRUG DELIVERY SYSTEM: A COMPREHENSIVE REVIEW ON RECENT EXPERIMENTAL AND CLINICAL FINDINGS

Most of the lipid soluble molecules can readily enter the blood stream from the nasal mucosa and subsequently reach the CNS by crossing the BBB. [33] But majority of the pharmaceutical drug molecules are hydrophilic, which becomes another rate limiting barrier for drug targeting, as highly lipid soluble drug molecules show easier and better targeting ability due to higher partition coefficient. It has been reported that the drugs other than lipid soluble molecule can cross nasal mucosa if there is a local injury as that can lead to breakdown of the nasal mucosal barrier 34 . In the recent years several drugs as well as peptides have been delivered effectively using intranasal route. Administration of NAD+ greatly decreased brain injury in a rat model of transient focal ischemia and profoundly decreased oxidative cell death 35 .
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Numerical Simulation of Airflow, Particle Deposition and Drug Delivery in a Representative Human Nasal Airway Model

Numerical Simulation of Airflow, Particle Deposition and Drug Delivery in a Representative Human Nasal Airway Model

The human nasal airways constitute one of the more complex airflow domains found in nature. Thus, generally all basic flow phenomena and flow regimes may be encountered within the effective length of a nasal cavity which is only 10 cm. If the inhaled air also contains nanoparticles or microparticles, it is of interest to determine how much the nasal airways filter out and where the particles deposit at what concentrations, considering both particles being highly toxic or therapeutic. Specifically, metal-oxide or carbon-based nanomaterials depositing in the airways (Service, 2003) rapidly diffuse into soft tissue and across semi-permeable membranes (Oberdörster and Utell, 2002) with toxic effects. Microparticles, e.g., JP-8 fuel wildly used in military aircrafts, constitutes a significant health hazard to Air Force personnel, fuelers, as well as people living near military fields (Zhang et al., 2004; Pleil et al., 2000). Therapeutically for most intranasal drug delivery systems, e.g., nasal sprays, the drug aerosol diameter is in the micro-size range. One possible nasal drug delivery is to target the olfactory region which is separated by a thin neural membrane from the brain, and finally drug can pass along neural pathway into the brain (Frey, 2002). For both toxic and therapeutic scenarios, deposition of nano- and microparticles is important either to determine the local pollutant concentrations in the nasal airway or the efficiency of nasal drug delivery. Thus, a detailed characterization of nasal airflow and particle/vapor deposition patterns are most desirable to answer questions related to these challenging fluid-particle transport phenomena.
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Potential for intranasal drug delivery to alter cerebrospinal fluid outflow via the nasal turbinate lymphatics

Potential for intranasal drug delivery to alter cerebrospinal fluid outflow via the nasal turbinate lymphatics

Expansion of the ventricular space due to a deficit in CSF absorption can lead to an increase in ICP and a de- crease in cerebral perfusion pressure, these scenarios being commonly seen in traumatic brain injury and hydrocephalus. With regards to the latter, the most com- mon solution is either CSF diversion with a shunt or endoscopic third ventriculostomy (ETV), both being highly invasive with potential long-term negative conse- quences. From a theoretical perspective, the intranasal delivery route for pharmacological agents may provide a means to modulate CSF outflow in a non-invasive manner by targeting the lymphatic vasculature at the cribriform plate. In this report we provide proof-of- concept that supports the above hypothesis using well- characterized albeit not necessarily clinically-applicable pharmacological agents that modulate the lymphatic vasculature resulting in a change in CSF outflow.
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NASAL DRUG DELIVERY  AN OVERVIEW

NASAL DRUG DELIVERY AN OVERVIEW

ABSTRACT: Over the past few decades the nasal route has gained widespread interest as a promising and an alternative route to oral and parenteral drug delivery. The nasal mucosa being highly vascularized and permeable provides a rapid onset of therapeutic action. It is a convenient, compliant and needleless mode of drug delivery suitable for the treatment of both acute and chronic diseases. In addition, nasal drug delivery circumvents the issues of poor and slow absorption, first pass hepatic metabolism, blood brain barrier. Intranasal administration can be used to deliver small polar molecules, hormones, vaccines, proteins and peptides. Despite the several potential advantages the nasal route has certain limitations. The present review outlines the various merits and demerits of intranasal administration, the relevant anatomy and physiology of the nasal cavity. The present article gives a detailed description of the factors affecting drug absorption and the different strategies that can be used to improve the drug absorption . INTRODUCTION: Conventionally, the oral route
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STRATEGIES AND PROSPECTS OF NASAL DRUG DELIVERY SYSTEMS

STRATEGIES AND PROSPECTS OF NASAL DRUG DELIVERY SYSTEMS

Peptides & proteins have generally a low oral bioavailability because of their physicochemical instability and susceptibility to hepato- gastrointestinal first pass elimination. Examples are insulin, calcitonin, pituitary hormones etc 24 . These peptides and proteins are hydrophilic polar molecules of relatively high molecular weight, are poorly absorbed across biological membranes with bioavailabilities obtained in the region of 1–2% concentrations when administered as simple solutions. To overcome this problem, with the use of absorption enhancers like surfactants, glycosides, cyclodextrin and glycols will increase the bioavailability. Nasal route is proving to be the best route for such biotechnological products.  Delivery of Drugs to Brain through Nasal Cavity:
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<p>Integration of PEG 400 into a self-nanoemulsifying drug delivery system improves drug loading capacity and nasal mucosa permeability and prolongs the survival of rats with malignant brain tumors</p>

<p>Integration of PEG 400 into a self-nanoemulsifying drug delivery system improves drug loading capacity and nasal mucosa permeability and prolongs the survival of rats with malignant brain tumors</p>

Results: The optimized formulation involved the integration of polyethylene glycol 400 (PEG 400) in K-EL to encapsulate Bdph dissolved in dimethyl sulfoxide (DMSO), and it exhibited higher drug loading capacity and drug solubility in water than the old formulation, which did not contain PEG 400. Incorporation of PEG 400 as a co-surfactant increased Bdph loading capacity to up to 50% (v/v), even in formulations using Kolliphor ® HS 15 (K-HS15) as a surfactant, which is less compatible with Bdph than K-EL. The optimized Bdph formulation presented 5- and 2.5-fold higher permeability and cytotoxicity, respectively, in human GBM than stock Bdph. This could be attributed to the high drug loading capacity and the high polarity index due to DMSO, which increases the compatibility between the drug and the cell. Rats bearing a brain glioma treated with 160 mg/kg intranasal emulsi fi ed Bdph had a mean survival of 37 days, which is the same survival time achieved by treatment with 320 mg/kg stock Bdph. This implies that the optimized emulsi fi ed formulation required only half the Bdph dose to achieve an ef fi cacy similar to that of stock Bdph in the treatment of animals with malignant brain tumor.
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IN  SITU NASAL GEL: MODERNISTIC ADVANCEMENT IN DRUG DELIVERY

IN SITU NASAL GEL: MODERNISTIC ADVANCEMENT IN DRUG DELIVERY

Therapy through IN administration has been an accepted as a form of treatment in the ayurvedic system of Indian medicine and is called “Nasya Karma”. Drug delivery through the nose is uncomplicated and convenient and can include the delivery of solutions, suspensions, powders, in situ gel and ointments. The avoidance of first pass metabolism, quick onset of action and lowered systemic exposure to drug are the main advantages of IN delivery. Nose- to-brain delivery of drug moieties are possible through the olfactory region, by neuronal and extracellular pathways located at the roof of the nasal cavity, whose neuroepithelium is the only part of the central nervous system (CNS) that is directly exposed to the external environment. The therapeutic agents are carried to the CNS through the olfactory neuroepithelium by the trigeminal nerve systems and olfactory nerve pathways. In both intravenous as well as oral administration, the blood-brain barrier (BBB) restricts the brain’s access to the drug.
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MODERN ENCROACHMENT AND PROVOCATION IN NASAL DRUG DELIVERY SYSTEM

MODERN ENCROACHMENT AND PROVOCATION IN NASAL DRUG DELIVERY SYSTEM

ABSTRACT: Nasal drug delivery has occupied an important place in the field of drug delivery technology. Transmucosal nasal delivery is a promising drug delivery option where common drug administration’s (e.g. intravenous, intramuscular, and oral) are inapplicable. This route is also advisable for drugs undergoing extensive first pass effect. The physiology of the nose presents obstacles, but offers a promising route for non-invasive systemic delivery of numerous therapies and debatably drug delivery route to the brain. Nasal route is easily accessible for self- administration without the help of health professionals and no needle stick hazards are associated with nasal administration. To overcome these problems in nasal drug delivery, deep understanding and study of the various factors affecting nasal delivery is muust. Thus present review focuses on various aspects of nasal drug delivery with special emphasis on various formulations available, obstacles, advancement and future prospects in nasal drug delivery .
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 SLN BRAIN TARGETING DRUG DELIVERY FOR CNS: A NOVEL APPROACH

 SLN BRAIN TARGETING DRUG DELIVERY FOR CNS: A NOVEL APPROACH

As reviewed above nearly 98 % of therapeutics for treatment of neurological disorders available in the market is not ideal for transport across the BBB. CNS drugs molecule difficult transport across the BBB, There for various novel drug delivery methodologies used for transport drug in to brain. However, need idea that drugs reach the right site in the body, at the right time, at right concentration. It should not exert side effects, neither on its way to the therapeutic target, nor at the target site, nor during the clearance process. The SLNs have the potential to achieve, at least partially, these broad objectives. Numerous study on SLNs as carrier system had been made and concluded that SLN are rational approach in various systems where to input active compounds or therapeutically difficult molecules such as proteins, peptides, hormones, genes, DNA, RNA or viral vectors for targeting to get their related merits. The appropriate characterization of the complex surfactant/lipid dispersions SLN requires several analytical methods in addition to the determination of the particle size. The kinetic Aspects are taken into account. SLN administration to various organs and tissues as brain, nasal route has been providinga new path for fewer indiscriminate bio distribution and increase the bioavailability of hydrophobic molecules in specific sites in body. SLNs provide a new approach for an effective delivery of various drug moieties as analgesics, anti-TB, Chemotherapeutics, anti-ageing, antiepileptic, neuroleptics, antibiotics, antiviral agents etc. into the brain. Safety parameters and biodegradability property shows the SLN technology as strong tool which will provide and carve best among other conventional delivery systems for next coming era.
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NOVEL DRUG DELIVERY SYSTEM THROUGH NASAL (NON INVASIVE)

NOVEL DRUG DELIVERY SYSTEM THROUGH NASAL (NON INVASIVE)

Intranasal route is the best method for high absorption and direct delivery to the brain. The interests and importance, of this route, are that the systemic effects of drugs when administered through the nasal route, have expanded over recent decades and it used for therapeutic and recreational purposes. In comparison with the parenteral route of drug administration, intra-nasal administration of drugs offers an interesting alternative for achieving systemic therapeutic effects of drugs. The oral administration of the drug produces low drug bioavailability, and this can be minimized using this nasal route. Moreover, the advantage of this route is that it can bypass the first-pass metabolism. Therefore, it is important to understand the potential and limitations of various nasal drug delivery systems. The aim of this review article is to discuss the various pharmaceutical dosage forms that have the potential to be utilized for local or systemic drug administration. It is assumingly expected that this review will help to understand about this route and also to develop suitable intra-nasal formulations to achieve specific therapeutic objectives. The different types of nasal drug formulations that can be used are nasal drops, nasal sprays, nasal gels, nasal suspensions and emulsion, and nasal powders.
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Drug delivery in overcoming the blood&ndash;brain barrier: role of nasal mucosal grafting

Drug delivery in overcoming the blood&ndash;brain barrier: role of nasal mucosal grafting

Abstract: The blood–brain barrier (BBB) plays a fundamental role in protecting and maintaining the homeostasis of the brain. For this reason, drug delivery to the brain is much more difficult than that to other compartments of the body. In order to bypass or cross the BBB, many strategies have been developed: invasive techniques, such as temporary disrup- tion of the BBB or direct intraventricular and intracerebral administration of the drug, as well as noninvasive techniques. Preliminary results, reported in the large number of stud- ies on the potential strategies for brain delivery, are encouraging, but it is far too early to draw any conclusion about the actual use of these therapeutic approaches. Among the most recent, but still pioneering, approaches related to the nasal mucosa properties, the permea- bilization of the BBB via nasal mucosal engrafting can offer new potential opportunities. It should be emphasized that this surgical procedure is quite invasive, but the implication for patient outcome needs to be compared to the gold standard of direct intracranial injection, and evaluated whilst keeping in mind that central nervous system diseases and lysosomal storage diseases are chronic and severely debilitating and that up to now no therapy seems to be completely successful.
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In situ gel for nasal drug delivery

In situ gel for nasal drug delivery

They observed an increase in bioadhesion strength on increasing the concentration of bioadhesive polymers, but at the same time a decrease in spreadability was documented. Mehta et al. developed thermally triggered in situ nasal gel of pheniramine and phenylephrine HCl using poloxamer as gelling polymer and HPMC and xanthan gum as mucoadhesive agents. The results revealed that the formulation containing HPMC E-15 was able to form a consistent mucoadhesive gel. Temperature-mediated in situ nasal gel of ropinirole was reported by Khan et al. In vivo bioavailability and its efficiency in brain targeting were assessed in rats following intranasal administration of 99mTc-ropinorole in situ gel. The bioavailability measured as (AUCbrain) after nasal administration of ropinirole in situ nasal gel was 8.5 times more than that obtained following intravenous administration of ropinirole solution. Park et al. designed an intranasal delivery system for plasmid DNA composed of in situ gelling polymer (poloxamer 407) and mucoadhesive polymer vehicle (polycarbophil or polyethylene oxide) which could effectively and safely improve the nasal retention and absorption of plasmid DNA. Three hours post dose, the nasal tissue levels of plasmid DNA given in poloxamer/polycarbophil and poloxamer/ polyethylene oxide (0.8%) were 10- and 40-fold higher than saline. From the results it was been observed that the gelation temperature of the formulations decreased slightly by the mucoadhesive polymers, but not by plasmid DNA. When poloxamer/polycarbophil (0.2%) was used, highest absorption was observed with an area under the curve value 11-fold higher than saline (conventional vehicle). The absorption of plasmid DNA varied with the contents and type of mucoadhesive polymers. The in vitro release of plasmid DNA from the gels followed Fickian diffusion.
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The nasal delivery of nanoencapsulated statins &ndash; an approach for brain delivery

The nasal delivery of nanoencapsulated statins &ndash; an approach for brain delivery

to their optimal EE of drug and suitable physicochemical features, and a suspension of simvastatin was used as control. The simvastatin release profile from SVT-LCN_MaiLab can be seen in Figure 6. A simulated nasal fluid at pH 6.5, containing sodium, potassium, and calcium salts, was used to simulate the nasal conditions. Due to the low solubility of simvastatin in aqueous solution, BSA was used to increase simvastatin solubility in the dissolution medium outside the dialysis bag to achieve sink conditions throughout the experi- ment. BSA was selected for being closer to physiological conditions in comparison to surfactants or co-solvents gener- ally used to increase the solubility of poorly soluble drugs. The in vitro release tests were performed over 24 hours for SVT-LCN_MaiLab and simvastatin suspension. For the sus- pension, after an initial rapid release in the first hour, a plateau characterized by a very low dissolution rate was reached. This was not observed for the nanoparticle formulation. In fact, the nanoparticles kept releasing simvastatin at a constant release rate from the second hour to the end of the experiment. As shown in Figure 6, 40% of simvastatin was released from
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DESIGN AND IN VITRO CHARACTERIZATION OF PHASE TRANSITION SYSTEM USING RIVASTIGMINE TARTRATE FOR NASAL DRUG DELIVERY SYSTEM

DESIGN AND IN VITRO CHARACTERIZATION OF PHASE TRANSITION SYSTEM USING RIVASTIGMINE TARTRATE FOR NASAL DRUG DELIVERY SYSTEM

preparations and crosses the blood brain barrier. It undergoes extensive first pass metabolism in liver. With the advent of new era of pharmaceutical dosage forms, nasal drug delivery system has established itself as an integral part of novel drug delivery system. Nasal gel is prepared by using gelling agent such as Chitosan HCL, HPMC K4M, Carbopol 934, Sodium alginate, Gellun gum and Sod. β-Glycerophosphate and other excipients. It was observed that Phase transition system has best fitted to peppas model. Phase transition nasal gel has r2 value (0.9343) and n value (1.1566). Also, it was observed that nasal gel FF9 a formulation has best fitted to order release. Hence revealed that FF9 optimized formulation.
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NANOPARTICLES AS SPECIFIED CARRIERS IN TARGETED BRAIN DRUG DELIVERY SYSTEM

NANOPARTICLES AS SPECIFIED CARRIERS IN TARGETED BRAIN DRUG DELIVERY SYSTEM

The BBB is not one single structure or membrane in the brain, but it is created by the way the blood vessels in the brain are organized. Thus, understanding the BBB requires an understanding of the anatomy and physiology of the blood vessels in the brain. Both large and small capillaries form a richly branched and complex network throughout the entire brain tissue. Like a chimney made of individual bricks, the brain blood vessels consist of a monolayer of endothelial cells that are connected with each other by tight junctions. The part of the cells membrane facing the bloodstream is called the "luminal" membrane, and the side which is exposed to the actual brain tissue is called the "abluminal" membrane. This part faces the extracellular liquid of the brain parenchyma where pericytes
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