Drug Targeting to the Brain

The Brain as a Drug Target

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"In vitro" evaluation of blood-brain barrier transport

Brain distribution spaces of mannitol-3H, inulin-14C, and dextran-14C in the rat.

Delivery of drugs into the brain is one of the most interesting and challenging areas of research. The blood-brain barrier (BBB) is a highly selective semipermeable membrane that separates blood from the brain in the central nervous system. It acts as a barrier to protect the brain from microbes, neurotoxins and other chemical substances and also blocks the entry of many drugs into the brain. An estimated 6.8 billion people die every year from CNS diseases like Parkinson’s disease, Alzheimer’s disease, sclerosis, brain stroke, dementia and others. According to WHO, one billion people are affected worldwide, about 50 million suffer from epilepsy and 24 million suffer from Alzheimer and other dementias. This indicates the importance of the delivery of drugs into the brain for treating various neurological diseases and psychological disorders. In drug targeting, a concept was introduced by Dr. Paul Ehrlich as a ‘magic bullet’ that gave tremendous hope for the researches to deliver drugs into the brain. This review discuses about various drug targeting strategies and applications of nanotechnology in designing drug delivery systems with the ability to cross through the BBB for treating neurological diseases.

Ascorbic acid homeostasis in the central nervous system.

During inflammatory conditions in the central nervous system (CNS), immune cells immigrate into the CNS and can be detected in the CNS parenchyma and in the cerebrospinal fluid (CSF). The most comprehensively investigated model for CNS inflammation is experimental autoimmune encephalomyelitis (EAE), which is considered the prototype model for the human disease multiple sclerosis (MS). In EAE autoagressive CD4(+), T cells gain access to the CNS and initiate the molecular and cellular events leading to edema, inflammation, and demyelination in the CNS. The endothelial blood-brain barrier (BBB) has been considered the obvious place of entry for the circulating immune cells into the CNS. A role of the choroid plexus in the pathogenesis of EAE or MS, i.e., as an alternative entry site for circulating lymphocytes directly into the CSF, has not been seriously considered before. However, during EAE, we observed massive ultrastructural changes within the choroid plexus, which are different from changes observed during hypoxia. Using immunohistochemistry and in situ hybridization, we observed expression of VCAM-1 and ICAM-1 in the choroid plexus and demonstrated their upregulation and also de novo expression of MAdCAM-1 during EAE. Ultrastructural studies revealed polar localization of ICAM-1, VCAM-1, and MAdCAM-1 on the apical surface of choroid plexus epithelial cells and their complete absence on the fenestrated endothelial cells within the choroid plexus parenchyme. Furthermore, ICAM-1, VCAM-1, and MAdCAM-1 expressed in choroid plexus epithelium mediated binding of lymphocytes via their known ligands. In vitro, choroid plexus epithelial cells can be induced to express ICAM-1, VCAM-1, MAdCAM-1, and, additionally, MHC class I and II molecules on their surface. Taken together, our observations imply a previously unappreciated function of the choroid plexus in the immunosurveillance of the CNS.

BackgroundP-glycoprotein (P-gp) is an efflux transporter which is abundantly expressed at the blood-brain barrier (BBB) and which has been implicated in the pathophysiology of various brain diseases. The radiolabelled antiemetic drug [11C]metoclopramide is a P-gp substrate for positron emission tomography (PET) imaging of P-gp function at the BBB. To assess whether [11C]metoclopramide can detect increased P-gp function in the human brain, we employed drug-resistant temporal lobe epilepsy (TLE) as a model disease with a well characterised, regional P-gp up-regulation at the BBB.MethodsEight patients with drug-resistant (DRE) TLE, 5 seizure-free patients with drug-sensitive (DSE) focal epilepsy, and 15 healthy subjects underwent brain PET imaging with [11C]metoclopramide on a fully-integrated PET/MRI system. Concurrent with PET, arterial blood sampling was performed to generate a metabolite-corrected arterial plasma input function for kinetic modelling. The choroid plexus was outmasked on the PET images to remove signal contamination from the neighbouring hippocampus. Using a brain atlas, 10 temporal lobe sub-regions were defined and analysed with a 1-tissue-2-rate constant compartmental model to estimate the rate constants for radiotracer transfer from plasma to brain (K1) and from brain to plasma (k2), and the total volume of distribution (VT = K1/k2).ResultsDRE patients but not DSE patients showed significantly higher k2 values and a trend towards lower VT values in several temporal lobe sub-regions located ipsilateral to the epileptic focus as compared to healthy subjects (k2: hippocampus: +34%, anterior temporal lobe, medial part: +28%, superior temporal gyrus, posterior part: +21%).Conclusions[11C]Metoclopramide PET can detect a seizure-induced P-gp up-regulation in the epileptic brain. The efflux rate constant k2 seems to be the most sensitive parameter to measure increased P-gp function with [11C]metoclopramide. Our study provides evidence that disease-induced alterations in P-gp expression at the BBB can lead to changes in the distribution of a central nervous system-active drug to the human brain, which could affect the efficacy and/or safety of drugs. [11C]Metoclopramide PET may be used to assess or predict the contribution of increased P-gp function to drug resistance and disease pathophysiology in various brain diseases.Trial registrationEudraCT 2019-003137-42. Registered 28 February 2020.

Cellular and non-cellular components of the tumor microenvironment (TME) are emerging as key regulators of primary tumor progression, organ-specific metastasis, and therapeutic response. In the era of TME-targeted- and immunotherapies, cancer-associated inflammation has gained increasing attention. In this regard, the brain represents a unique and highly specialized organ. It has long been regarded as an immunological sanctuary site where the presence of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB) restricts the entry of immune cells from the periphery. Consequently, tumor cells that metastasize to the brain were thought to be shielded from systemic immune surveillance and destruction. However, the detailed characterization of the immune landscape within border-associated areas of the central nervous system (CNS), such as the meninges and the choroid plexus, as well as the discovery of lymphatics and channels that connect the CNS with the periphery, have recently challenged the dogma of the immune privileged status of the brain. Moreover, the presence of brain metastases (BrM) disrupts the integrity of the BBB and BCB. Indeed, BrM induce the recruitment of different immune cells from the myeloid and lymphoid lineage to the CNS. Blood-borne immune cells together with brain-resident cell-types, such as astrocytes, microglia, and neurons, form a highly complex and dynamic TME that affects tumor cell survival and modulates the mode of immune responses that are elicited by brain metastatic tumor cells. In this review, we will summarize recent findings on heterotypic interactions within the brain metastatic TME and highlight specific functions of brain-resident and recruited cells at different rate-limiting steps of the metastatic cascade. Based on the insight from recent studies, we will discuss new opportunities and challenges for TME-targeted and immunotherapies for BrM.

Neuropharmacokinetics is an emerging field dedicated to understanding the pharmacokinetics of drugs within the central nervous system (CNS), with a particular emphasis on overcoming the challenges posed by the blood-brain barrier. This paper reviews the latest advancements in drug delivery strategies, including nanoparticle-based systems, receptor-mediated transcytosis, and efflux transporter inhibition, which have been designed to enhance drug penetration into the brain. Additionally, the use of advanced imaging techniques such as positron emission tomography, functional magnetic resonance imaging, and magnetic resonance imaging with contrast agents has provided critical insights into drug distribution, receptor occupancy, and the functional impact of therapeutic agents within the CNS. These innovations not only enhance our understanding of CNS drug action but also pave the way for more effective treatments for neurological and psychiatric disorders.

CD163, a Marker of Perivascular Macrophages, Is Up-Regulated by Microglia in Simian Immunodeficiency Virus Encephalitis after Haptoglobin-Hemoglobin Complex Stimulation and Is Suggestive of Breakdown of the Blood-Brain Barrier

An Analysis Of Mechanisms Of Central Nervous System Infiltration In Acute Lymphoblastic Leukaemia Using Primary Cells Xenografted Into Immunodeficient Mice

The exchanges between blood, on the one hand, and the cerebrospinal fluid (CSF) and brain-tissue on the other, are governed by so-called “barriers”, which may be assessed quantitatively by measuring rate of uptake of a given solute from blood into the CSF — the blood-CSF barrier — and into the brain tissue — the blood-brain barrier. From these uptakes a simple unidirectional transfer coefficient, Kin, can usually be derived. The two barriers are not independent since the uptake into one component of the central nervous system may include a contribution from, or to, the other because of the free diffusional communication between brain-tissue and CSF across the ependymal and pia-glial membranes. Typically, this interchange is seen with relatively lipid-soluble substances, such as the thioureas or ethyl alcohol; simultaneous measurement of uptake into brain and CSF indicates that the brain comes much more rapidly into equilibrium with blood than does the CSF. This is due, essentially, to the different geometries of the systems. As Figure 1 illustrates, direct penetration from blood into CSF takes place almost exclusively within the ventricles across the choroidal epithelium; once outside the ventricles, the fluid is no longer exposed directly to the blood, so that further gains from this can only be achieved by diffusion from the brain tissue. The volume of the subarachnoid fluid is several times greater than that of the ventricular fluid, and this geometrical arrangement means that the final equilibration with blood is delayed by the requirement that CSF should flow from ventricles to subarachnoid spaces. If there were no additions to the CSF after if had left the ventricles, the maximum value of Kin would be given by the turnover-constant of the CSF; on average this represents a renewal-rate of some 0.045% per minute to give a constant of 4.5×10−3min−1. In practice we find, with lipid-soluble solutes such as the thioureas or ethyl alcohol, much larger values of Kin (Figure 2); thus with ethyl alcohol the rate of equilibration in rabbit has a half-life of one or two minutes, giving a Kin of 7 to 3.5×10−1min−1.

The blood-brain barrier (BBB) actually consists of several relatively distinct barriers, operating in parallel to one another in different anatomical regions. These barriers restrict and regulate the passage of materials between the peripheral and cerebrospinal compartments. The best studied and most important of the barriers are the vascular barrier and the choroid plexus. Barrier functions arises through mechanisms associated primarily with endothelial cells (tight junctions, infrequent fenestrations, reduced pinocytosis) but also involve the capillary basement membrane, pericytes, and astrocytes. BBB function responds dynamically to the needs of the central nervous system (CNS) and for this reason the BBB is sometimes described as a "slave" of the CNS. The BBB communicates with microglia, neurons, and other cells, and it responds to a wide range of soluble factors released by these cells. Multiple transport processes, both passive and active, carry materials into and out of (efflux) the cerebrospinal fluid. Efflux mechanisms help explain why some drugs fail to reach therapeutic concentrations in the CNS; and inter-individual variations in efflux mechanisms can explain why some people are more or less sensitive to the therapeutic effects or side effects of particular CNS medications. Immune cells, once thought to be excluded from the CNS except under conditions of brain infection, are now recognized to patrol the normal CNS; and a major type of brain cell, the microglia, is derived from peripheral macrophages and may exist in some (as-yet poorly defined) equilibrium with the peripheral macrophage pool. This chapter presents these varied aspects of BBB structure and function in some detail, then builds on that fundamental understanding to discuss the BBB's role in neuroimmune interactions in both health and disease, including in HIV-1 disease.

Effect of estrogen on the expression of occludin in ovariectomized mouse brain