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In recent years, there have been several important advancements in the development of neuropeptide therapeutics. Nevertheless, the targeting of peptide drugs to the CNS remains a formidable obstacle. Delivery of peptide drugs is limited by their poor bioavailability to the brain due to low metabolic stability, high clearance by the liver, and the presence of the blood brain barrier (BBB). Multiple...
The blood-brain barrier (BBB) is formed by the brain capillary endothelium and excludes from the brain ∼100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. Despite the importance of the BBB to the neurotherapeutics mission, the BBB receives insufficient attention in either academic neuroscience or industry programs. The combination of so little effort in developing...
More than 30 neurotrophins have been identified, and many of them have neuroprotective effects in brain ischemia or injury. However, all the clinical trials with several neurotrophins for the treatment of acute ischemic stroke or neurodegenerative diseases have failed so far, primarily because of their poor blood-brain barrier (BBB) permeability. This article is an overview of recent progress in the...
Immunogold electron microscopy has identified a variety of blood-brain barrier (BBB) proteins with transporter and regulatory functions. For example, isoforms of the glucose transporter, protein kinase C (PKC), and caveolin-1 are BBB specific. Isoform 1 of the facilitative glucose transporter family (GLUT1) is expressed solely in endothelial (and pericyte) domains, and ∼75% of the protein is membrane-localized...
Antibody-conjugated liposomes or immunoliposomes are particulate drug carriers that can be used to direct encapsulated drug molecules to diseased tissues or organs. The present review discusses examples of successful applications of this technology to achieve drug transport across the blood-brain barrier. In addition, information will be provided on practical aspects such as phospholipid compositions...
The brain uptake of xenobiotics is restricted by the blood-brain brain barrier formed by brain capillary endothelial cells. Active efflux transport systems in the blood-brain barrier work as a detoxification system in the brain by facilitating removal of xenobiotic compounds from the brain. Drugs, acting in the brain, have to overcome such efflux mechanisms to achieve clinically significant concentration...
The extent to which a substance in the circulation gains access to the CNS needs to be determined for potential neuropharmaceuticals as well as for drug candidates with primary targets in the periphery. Characteristics of the in vivo methods, ranging from classical pharmacokinetic techniques (intravenous administration and tissue sampling) over brain perfusions to microdialysis and imaging techniques,...
Transvascular gene therapy of Parkinson's disease (PD) is a new approach to the gene therapy of PD and involves the global distribution of a therapeutic gene to brain after an intravenous administration and transport across the blood-brain barrier (BBB). This is enabled with the development of a nonviral gene transfer technology that encapsulates plasmid DNA inside pegylated immunoliposomes or PILs...
The blood-brain barrier (BBB) is an impermeable cellular interface that physically separates the blood from the interstices of the brain. The endothelial cells lining the brain blood vessels form the principle barrier, and their unique phenotype is a consequence of dynamic interactions with several perivascular cell types present in the brain parenchyma. In addition, BBB dysfunction has been observed...
The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated...
Because of the physiological nature of the blood-brain barrier (BBB), transport of chemical compounds between blood and brain has been widely believed to occur by means of passive diffusion, depending upon the lipophilicity of the compounds. However, discrepancies exist between the lipophilicity and apparent BBB permeation properties in many cases, and these discrepancies can be ascribed to the existence...
The human epidermal growth factor receptor (EGFR) plays an oncogenic role in solid cancer, including brain primary and metastatic cancers. Transvascular nonviral gene therapy in combination with EGFR-RNA interference (RNAi) represents a new therapeutic approach to silencing oncogenic genes in solid cancers. This is achieved with pegylated immunoliposomes (PIL) carrying short hairpin RNA expression...
In the past decade, research into P-glycoprotein involving the blood-brain barrier (BBB) has seen a shift in the concept of the BBB as a structural barrier to that of a functional barrier for xenobiotics and changed simultaneously the strategy for the discovery and development of drugs acting in the CNS. As far as making advances in neurotherapeutics are concerned, the brain-to-blood transport function...
Nanoparticle drug carriers consist of solid biodegradable particles in size ranging from 10 to 1000 nm (50–300 nm generally). They cannot freely diffuse through the blood-brain barrier (BBB) and require receptor-mediated transport through brain capillary endothelium to deliver their content into the brain parenchyma. Polysorbate 80-coated polybutylcyanoacrylate nanoparticles can deliver drugs to the...
During the past decade, major breakthroughs in magnetic resonance imaging (MRI) quality were made by means of quantum leaps in scanner hardware and pulse sequences. Some advanced MRI techniques have truly revolutionized the detection of disease states and MRI can now—within a few minutes—acquire important quantitative information noninvasively from an individual in any plane or volume at comparatively...
Neuroimaging has important applications in the diagnosis and treatment of patients with seizures and epilepsy. Having replaced computed tomography (CT) in many situations, MRI is the preferred imaging technique for patients with epilepsy. Advances in radionuclide-based techniques such as single-photon emission CT/positron emission tomography and electromagnetic source imaging with magnetoencephalography...
Imaging in patients with brain tumors aims toward the determination of the localization, extend, type, and malignancy of the tumor. Imaging is being used for primary diagnosis, planning of treatment including placement of stereotaxic biopsy, resection, radiation, guided application of experimental therapeutics, and delineation of tumor from functionally important neuronal tissue. After treatment,...
Anatomic and functional neuroimaging with magnetic resonance imaging (MRI) includes the technology more widely known as magnetic resonance spectroscopy (MRS). Now a routine automated “add-on” to all clinical magnetic resonance scanners, MRS, which assays regional neurochemical health and disease, is therefore the most accessible diagnostic tool for clinical management of neurometabolic disorders....
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