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GEN reports on strategies to overcome blood-brain barrier
February 06, 2009The blood-brain barrier (BBB) remains a major obstacle to the successful delivery of drugs to treat central nervous system (CNS) disorders, reports Genetic Engineering and Biotechnology News (GEN). Researchers are exploring a variety of approaches to preserve the ability of the BBB to block harmful and toxic substances from entering the brain and to permit the passage of effective medicines for the treatment of CNS diseases, according to the February 1 issue of GEN (http://www.genengnews.com/articles/chitem.aspx?aid=2778).
"The blood-brain barrier issue probably serves as the most significant roadblock to the treatment of central nervous system diseases," says John Sterling, Editor in Chief of GEN. "The key challenge is to treat people suffering from CNS disorders while trying to stay true to the physician's oath, 'First do no harm'."
One technology for enabling active transport of small molecule drugs across the BBB involves targeting endogenous nutrient transporters. These transporters are members of the solute carrier (SLC) transporter superfamily. Transport of small molecules across the BBB by these membrane proteins is known as carrier-mediated transport (CMT).
In order to design drugs that utilize CMT to cross the BBB, researchers modify their chemical structures so that they resemble nutrients that are transported across the BBB by specific SLCs. The prototypical drug that uses this strategy (which was developed long before mechanisms of CMT were known) is L-DOPA, the major current drug for Parkinson's disease. L-DOPA is used to replace dopamine that is lost due to degeneration of dopaminergic neurons in the substantia nigra of the brain.
Another major system that is used in normal mammalian physiology to enable needed molecules to cross the BBB is receptor-mediated transport (RMT). The brain uses RMT to transport proteins, peptides, and lipoproteins that are needed for brain function across the BBB. Examples of biomolecules that are transported into the brain via RMT include insulin, insulin-like growth factor (IGF), leptin, transferrin, and low-density lipoprotein (LDL).
In RMT, molecules in the circulation may bind to specific receptors on the luminal surface of brain capillaries (i.e., the surface that interfaces with the bloodstream). Upon binding, the receptor-ligand complex is internalized into the endothelial cell by a process called receptor-mediated endocytosis. The ligand may then be transported across the abluminal membrane of the endothelial cell (i.e., the membrane that interfaces with brain tissue) into the brain. This whole process is called receptor-mediated transcytosis.
Mary Ann Liebert, Inc./Genetic Engineering News
In order to design drugs that utilize CMT to cross the BBB, researchers modify their chemical structures so that they resemble nutrients that are transported across the BBB by specific SLCs. The prototypical drug that uses this strategy (which was developed long before mechanisms of CMT were known) is L-DOPA, the major current drug for Parkinson's disease. L-DOPA is used to replace dopamine that is lost due to degeneration of dopaminergic neurons in the substantia nigra of the brain.
Another major system that is used in normal mammalian physiology to enable needed molecules to cross the BBB is receptor-mediated transport (RMT). The brain uses RMT to transport proteins, peptides, and lipoproteins that are needed for brain function across the BBB. Examples of biomolecules that are transported into the brain via RMT include insulin, insulin-like growth factor (IGF), leptin, transferrin, and low-density lipoprotein (LDL).
In RMT, molecules in the circulation may bind to specific receptors on the luminal surface of brain capillaries (i.e., the surface that interfaces with the bloodstream). Upon binding, the receptor-ligand complex is internalized into the endothelial cell by a process called receptor-mediated endocytosis. The ligand may then be transported across the abluminal membrane of the endothelial cell (i.e., the membrane that interfaces with brain tissue) into the brain. This whole process is called receptor-mediated transcytosis.
Mary Ann Liebert, Inc./Genetic Engineering News
Blood-brain Barrier Current Events and Blood-brain Barrier News RSSScripps research scientists find new link between insulin and core body temperature
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Angiochem crosses BBB, shows safety, efficacy in phase 1/2 brain cancer studies
Angiochem, Inc. a clinical-stage biotechnology company developing drugs that are uniquely capable of crossing the blood-brain barrier to treat brain diseases, announced today that its lead drug candidate, ANG1005, has demonstrated a favorable safety and efficacy profile in more than 100 patients with brain cancer from two separate Phase 1 /2 clinical studies in patients with progressive gliomas, including recurrent glioblastoma, and in patients with progressive brain metastases.
How meningitis bacteria attack the brain
A specific protein on the surface of a common bacterial pathogen allows the bacteria to leave the bloodstream and enter the brain, initiating the deadly infection known as meningitis.
August 10, 2009 New Class of Compounds Discovered for Potential Alzheimer's Disease Drug, Penn Study Finds
A new class of molecules capable of blocking the formation of specific protein clumps that are believed to contribute to the dementia of Alzheimer's disease (AD) patients has been discovered by researchers at the University of Pennsylvania School of Medicine.
Nanoparticles cross blood-brain barrier to enable 'brain tumor painting'
Brain cancer is among the deadliest of cancers. It's also one of the hardest to treat.
Holding Breath for Several Minutes Elevates Marker for Brain Damage
Divers who held their breath for several minutes had elevated levels of a protein that can signal brain damage, according to a new study from the Journal of Applied Physiology.
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The Blood Brain Barrier by Tomas R. Helio (Editor) The blood-brain barrier (BBB) is a membranic structure that acts primarily to protect the brain from chemicals in the blood, while still allowing essential metabolic function. It is composed of endothelial cells, which are packed very tightly in brain capillaries. This higher density restricts passage of substances from the bloodstream much more than endothelial cells in capillaries elsewhere in the body. Astrocyte cell projections called astrocytic feet (also known as 'glia limitans') surround the endothelial cells of the BBB, providing biochemical support to those cells. The BBB is distinct from the similar blood-cerebrospinal fluid barrier, a function of the choroidal cells of the choroid plexus, and from the Blood-retinal barrier, which can be considered a part of the whole (the... |
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Introduction to the Blood-Brain Barrier: Methodology, Biology and Pathology by William M. Pardridge MD (Editor) Knowledge of the blood-brain barrier forms an essential component in the understanding of a large proportion of medical disciplines. Nevertheless, ignorance in this field still impedes progress in many areas, including cerebrovascular disease, Alzheimer's disease, cerebral AIDS, brain tumors, and the development of effective new neuropharmaceuticals. This introduction for both researchers and clinicians across the medical sciences is intended to aid both those beginning work directly in this area and those wishing simply to be better informed when interpreting information where the blood-brain barrier may be involved. Recent advances in both methodology and biology are detailed in fifty state-of-the-art chapters written by international authorities. |
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The Blood-Brain Barrier and Its Microenvironment: Basic Physiology to Neurological Disease by Elga de Vries (Editor), Alexandre Prat (Editor) This reference analyzes the cellular and molecular biology and mechanisms of the blood-brain barrier (BBB) and presents the most recent studies on the role of the BBB in the development and initiation of a wide range of physiological and pathological conditions affecting the central nervous system. |
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The Blood-Brain Barrier and Drug Delivery to the CNS by Michael Bradbury (Editor), David Begley (Editor), Jorg Kreuter (Editor) King's College, London, UK. Addresses how to determine drug permeability across the blood-brain barrier more effectively. Focuses on physiological mechanisms influencing the passage of agents into the brain and covers the latest research, problems and solutions, existing strategies, and prospects for future research. For researchers. Expanded-outline format. |
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