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What and Where Is the Blood–Brain Barrier? Joel Pachter, PhD, University of Connecticut Health Center
The theoretical concept of the blood–brain barrier (BBB) is now over one hundred years old. But while it is understood that the BBB strictly regulates the flux of soluble substances between the blood and the central nervous system (CNS), the full nature of the BBB still awaits description. In this regard, the microvascular endothelium is widely considered to be the anatomical substrate of the BBB, expressing tight junctions to restrict paracellular flow, and membrane transporters and cytoplasmic enzymes to modulate transcellular traffic of solutes into and out of the CNS. However, what of means to limit the traffic of cells; is this also a province of the BBB? If so, are there specific anatomic domains along the CNS microvascular tree that are responsible for different BBB properties? Increasing awareness that the microvascular endothelium is highly heterogeneous suggests a division of labor exists at the endothelial level, and that this might dictate the specialized activities of the BBB. Arterioles, capillaries and venules make up the microvascular tree, and it has long been known that these tributaries each perform specific functions in the peripheral circulation. Now, new evidence intimates that they also may be responsible for specialized attributes of the BBB. Further research in this area will enable more accurate modeling of the BBB and highlight means by which it might be therapeutically manipulated.
The BBB in Neurological Diseases: Clinical Relevance of Available Models Damir Janigro, PhD, Cleveland Clinic
This presentation will attempt to summarize the pharmacological and neuropathological aspects of BBB research, while at the same time providing insights into the models and experiments used in clinical subjects, animal models and in vitro. There are several aspects of BBB research that have translational and clinical relevance. The first acknowledged pathological role of the BBB was its unflattering role in multiple drug resistance. Drug resistance was and remains an unmet challenge for diseases as broad as brain neoplasms, depression and epilepsy. In vitro and animal models have proven useful yet ultimately insufficient to recapitulate clinical reality and a novel “ex situ” approach has been developed to study drug penetration in human brain. The management of drug resistance to chemotherapy has been facilitated by aggressive approaches such as the osmotic disruption of the BBB. Regardless of the merits of this procedure, its implementation demonstrated for the first time the huge clinical impact of even the most transient blood-brain barrier disruption. In fact, when the BBB was breached patients or animals experienced acute seizures, suggesting that seizure disorders may be due to a “BBB disease”. Further experiments revealed a surprising role for leukocytes in ictogenesis which in turn formed the basis of a mini-trial aimed at treating seizures with anti-inflammatory drugs.
The Blood–Brain versus Blood–CSF Barrier: Anatomical and Functional Differences and their Pathophysiological Implications Adam Chodobski, PhD, The Warren Alpert Medical School of Brown University
The blood-cerebrospinal fluid (CSF) barrier (BCSFB) primarily resides in the choroid plexus, a highly vascularized tissue known for its ability to produce CSF. Unlike the cerebrovascular endothelium which constitutes the blood–brain barrier (BBB), the endothelium of choroidal microvessels is fenestrated, but is enclosed by a single layer of cuboidal epithelial cells connected by tight junctions that form the BCSFB. The fenestrated phenotype of choroidal endothelium facilitates the penetration of blood-borne molecules across the walls of choroidal microvessels; however, the movement of hydrophilic molecules between the vascular and the CSF compartments is impeded by tight junction complexes whose protein composition is largely similar, yet distinct from that found in the BBB. This allows for selective uptake or extrusion of endogenous molecules or xenobiotics across the BCSFB in a manner similar to that found at the BBB, although noticeable differences in expression of various transporters occur between the two barriers. The surface area of the choroidal epithelium facing the CSF is comparable to that found for the BBB, which is a significant factor in the BCSFB-mediated removal of CSF-borne drugs and/or drug metabolites. In fact, these two barriers can frequently complement each other in their ability to eliminate xenobiotics from the CNS. In addition to their transport capabilities, both the brain endothelium and choroidal epithelium can produce a variety of polypeptides, and it is becoming increasingly recognized that not only the BBB, but also the BCSFB plays an important role in neuroinflammation. This suggests that both barriers may represent attractive targets for therapeutic intervention.
Drug Delivery to the Brain: The Case for Transcytosis David J Begley, PhD, Kings College London, London, United Kingdom
Drug penetration into the central nervous system (CNS) is severely limited by the presence of the blood–brain barrier (BBB). The BBB is formed by the endothelial cells of the capillaries in brain tissue and also by the epithelial cells of the choroid plexuses, which constitute the blood-cerebrospinal fluid barrier (BSCFB). At both barriers the endothelial and epithelial cells respectively form tight junctions between the cell boundaries which abolishes any aqueous paracellular diffusive pathway between the cells; a pathway which exists in the capillaries of most other tissues. Thus transport of solutes in and out of the brain has to be transcellular across the endothelial cells of the BBB and the epithelial cells of the BSCFB. Solutes may move into the brain passively down a concentration gradient if they are sufficiently lipid soluble to dissolve in the cell membrane, or if polar, such as glucose, amino acids and other essential nutrients they will require the presence of specific transport systems embedded in the cell membranes. Some lipid soluble molecules are actively effluxed from the barriers by ATP-binding cassette (ABC) transporters which transport these solutes out of the brain. Therapeutic drugs entering the CNS are also subject to these processes and the presence of the BBB is a major hurdle to the treatment of most CNS disease. This presentation will focus on transctosis at the BBB, both receptor and absorbtive-mediated, and will discuss the scope for macromolecule and drug/therapeutic vector transfer to the brain.
Ultrasound-Induced Blood-Brain Barrier OpeningElisa Konofagou, PhD, Columbia University
Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, remains a unique technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this presentation is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD) in both mice and non-human primates, and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It will be shown that the BBB can be disrupted safely and transiently under specific acoustic (pressures under 0.45 MPa) and microbubble (diameter under 8 μm) conditions. The permeability of the BBB has been measured to increase by at least two orders of magnitude while closing is highly dependent on the pressure amplitude and microbubble diameter used and can vary between 3 hours and 5 days. Finally, delivery of different molecular weights and constituency including therapeutic compounds through the opened blood-brain barrier will be shown with specific examples and evidence of neuronal uptake.
Keywords: Blood-brain barrier; brain drug delivery; disruption; focused ultrasound; microbubble; opening; safety.
Gene Delivery Across the Blood–Brain Barrier for Treating Neurological Disorders Brian Kaspar, PhD, Research Institute at Nationwide Children's Hospital
The blood–brain barrier (BBB) acts as a protective barrier for the central nervous system (CNS) by helping to maintain appropriate concentration gradients and acting as a defense shield against pathogens. In serving this vital role, the BBB denies most systemically administered molecules entry to the CNS. Therein lays the problem in treating CNS disorders, delivery. Therapeutic drug delivery is a common problem shared by both pharmacologists and gene therapists, but the field of viral gene delivery to the CNS has recently demonstrated the remarkable ability for adeno-associated virus 9 (AAV9) to traverse the BBB when given as an intravenous (IV) infusion in both neonate and adult animals, now reported by multiple groups. We have utilized this breakthrough to treat neurological disorders using models of spinal muscular atrophy and amyotrophic lateral sclerosis. Additionally, we have examined the translation of these findings in larger species and will report on the potential for AAV9 to target the brain and spinal cord in non-human primates at various ages. Furthermore, key safety studies have demonstrated that systemically delivered virus is safe and well tolerated. In this presentation, we will demonstrate the ability to non-invasively deliver a product through the blood stream to target the brain and spinal cord, opening a plethora of basic research and therapeutic opportunities.
Intranasal Insulin, Small Molecules, Biopharmaceuticals and Stem Cells Bypass the Blood-Brain Barrier to Treat Alzheimer’s, Stroke, Brain Tumors, Parkinson’s and Other CNS DisordersWilliam H. Frey II, PhD, Alzheimer's Research Center
Intranasal delivery provides a practical, noninvasive, method of bypassing the blood-brain barrier to deliver therapeutic agents to the brain and spinal cord [Dhuria et al. (2010) J Pharm Sci 99(4): 1654-1673]. This method allows drugs that do not cross the blood-brain barrier to be delivered to the central nervous system (CNS) within minutes. It also directly targets drugs that do cross the blood-brain barrier to the CNS, eliminating the need for systemic delivery and thereby reducing unwanted systemic side effects. This is possible because of the unique connection that the olfactory and trigeminal nerves provide between the brain and external environment. Intranasal delivery does not require any modification of therapeutic agents. A wide variety of therapeutics, including small molecules, macromolecules and stem cells are rapidly delivered intranasally to the brain. Using this intranasal delivery method, which I first introduced in 1989, both the treatment of and protection against stroke in animals have been demonstrated with IGF-I, deferoxamine and erythropoietin. Intranasal FGF-2 and EGF stimulate neurogenesis in the brains of adult animals, and intranasal GRN163 doubles the lifespan of animals with brain tumors, etc. Intranasal insulin treatment, which I first developed in 1989, has been reported to improve memory and mood in healthy adults and improve memory, attention and functioning in patients with Alzheimer's disease without altering blood levels of insulin or glucose. This is not surprising as Alzheimer's patients have a brain deficiency of insulin, and without insulin, key brain areas are starved for energy and degenerate. My colleagues in Germany and I have shown that intranasal stem cells bypass the blood-brain barrier by migrating from the nasal mucosa through the cribriform plate along the olfactory neural pathway into the brain and spinal cord. Using intranasal bone marrow-derived stem cells, we have shown major improvement in Parkinson’s while others have reported improvement in neonatal ischemia in animal models. Intranasal delivery is changing the way we treat CNS disorders.