Adsorptive Mediated Endocytosis

Utilization of the transcytosis mechanism for enhancement of the brain delivery of peptides seems promising because of its applicability to a wide range of peptides, including synthetic ones. AME is triggered by an electrostatic interaction between a positively charged moiety of the peptide and a negatively charged plasma membrane surface region. AME has lower affinity and higher capacity than RME, and these properties should be favorable for delivery of peptides to the brain (7, 59-61)....

Nonenzymatic Oxidation of Drugs

The nonenzymatic autoxidation of catecholamines also plays an important role in the physiology and aging of the CNS. Dopamine, like most catecholamines, can be easily oxidized by molecular oxygen in physiological solutions (i.e., at neutral pH and in the presence of transition metal traces) (104). During autoxidation, both semiquinones and quinones are formed, and they react with molecular oxygen to produce reactive oxygen species. Numerous data suggest that the cytotoxicity of levodopa, a...

Pharmacokinetic Aspects of Intracerebroventricular and Intracerebral Drug Administration

Invasive approaches to drug local delivery require (neuro)surgical intervention. This includes methods that physically bypass the BBB by direct delivery into the cerebrospinal fluid or brain parenchyma. Intrathecal and intracerebral drug administration differs fundamentally from systemic drug administration in terms of pharmacokinetic characteristics determining brain tissue concentrations in that case the available dose reaching the target organ is 100 . How ever, there are large gradients...

Formation of Reactive Metabolites

Drug metabolites are not always safe. Xenobiotic metabolism frequently produces reactive metabolites that could directly or indirectly alter brain function and neuron survival. 1. Monoamine Oxidase Inhibitors The metabolism of neurotransmitter amines by cerebral MAO-A and -B produces equivalent amounts of the corresponding aldehydes, and ammonia. Both products are considered to be neurotoxic and could participate in the progressive neuronal death that occurs during senescence. Moreover,...

Drug Delivery by Chimeric Peptides

The opportunity for drug delivery arises from the possibility to synthesize ''chimeric peptides'' (60). These are generated by linking a drug that lacks transport at the BBB to a vector. Binding of the vector at the luminal membrane of brain capillary endothelial cells initiates receptor-mediated or adsorp-tive-mediated transcytosis. The mode of delivery was schematically visualized in Fig. 1. Size and structure of the cargo may vary as long as the drug moiety does not inhibit binding and...

Active Secretion Of Brain Extracellular Fluid

A fundamental process that will affect the concentration of all solutes in brain ECF and CSF is the continuous turnover of these compartments as the result of secretion, bulk flow, and drainage of fluid. Extracellular fluid is secreted continuously across the epithelial cells of the choroid plexuses and the endo-thelial cells of the brain microvasculature into the CSF and extracellular spaces of the brain, respectively. Both cell layers possess tight cell junctions and thus form a barrier to...

Info

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Physiological Transport Mechanisms for Peptides and Proteins at the Blood Brain Barrier

As opposed to the delivery strategies discussed above, which are primarily aimed at short-term application in the treatment regimens of malignant brain tumors, drug treatments of chronic degenerative disorders will require long- term application of the therapeutic agent. This implies the need to develop a noninvasive approach for brain delivery via the systemic route. To this end, utilization of endothelial transport mechanisms is being explored in preclinical studies. For macromolecules, the...