If granted passage, take one of these routes to the destination
It is a known fact that highly lipid soluble compounds like barbiturates easily cross the BBB. Also certain non-lipophillic micro molecules as well as macromolecules cross the BBB. The transport of such molecules takes place by one of the three processes:
* Bulk-phase endocytosis
* Absorptive endocytosis &
* Receptor-mediated endocytosis.
Absorptive endocytosis takes place by the alteration of charges and development of opposite charges on the substance and the cell membrane molecules. An example of such transport is the Wheat Germ Agglutinin (WGA).
Receptor mediated endocytosis takes place in two steps. First the ligand (drug/compound) binds to the receptors like Insulin receptor, transferring receptor etc. Then the ligand-receptor complex is internalized, i.e. taken up into the cell by dissociation of the cell membrane molecules. It then results in the formation of endosomes which release the drug or ligand onto the opposite of receptor.
Bulk phase endocytosis, also termed pinocytosis or simply "cell drinking", a very common transport mechanism in various other tissues of the body like epithelium etc but is very rare in the brain tissue. It becomes significant in the brain tissue affected by pathological conditions like tumours or infections etc.
The transport systems operating across the BBB may be summarized as:
1. Carrier mediated transport system
2. Receptor-mediated transport system (RMT)
3. Absorptive mediated transcytosis (AMT)
Carrier mediated transport systems comprise of a very limited number of selective peptide transport systems (PTS) which selectively transport a limited number of structurally related peptides e.g.: PTS Tyr-Pro-Leu-Gly-amide transports methionine, encephalon, vasopressin and arginine. As explained earlier, there is a bidirectional variation in the transport of substances transported by carrier mediated systems i.e. the transport from blood to brain varies from transport from brain to blood. This may be used for our advantage, for example we can inhibit certain transport systems transporting from the brain to blood thereby leading to accumulation of certain peptides for beneficial effects. Similarly we may also increase peptide transport from brain to blood thereby decreasing drug accumulation in the brain and reduced toxicity.
Receptor mediated transport (RMT) occurs with specific receptors like insulin, transferring, insulin like growth factor (IGF) I and IGF II. The transport occurs in three steps. First, the ligand binds to the receptor on the luminal or blood side. Then the ligand-receptor complex is internalized and forms the endosomes. Third, the endosomes is released at the abluminal or brain side. The transport mechanism varies slightly for the different receptors. For example, the transferrin receptor transports iron by first forming the ligand-receptor complex and after internalization, in the endosomes, the iron and receptor protein is separated and the receptor protein molecules are transported back or recycled to the cell membrane surface or they may be degraded and the iron alone reaches the abluminal surface by excytosis. Research suggests that the iron may be transported through the various cell components like golgi complex, lysosomes etc. It has been found that certain viruses express antigens which are transported by interacting with the receptors.
Absorptive mediated transport (AMT) occurs in a functionally similar manner as receptor mediated transport (RMT) and it does not require a receptor. This transport is applicable to ploycationized compounds like cationized albumin, cationized IgG, histone, avidin etc. Lectins and cationized molecules are transported by this system. This system has been extensively studied using the WGA-HRP (Wheat Germ Agglutinin-Horse Radish Peroxidase) conjugate system. This conjugate is taken up into the cell, endocytosed and mainly transported with the enzymatic action of golgi complex which packs this conjugate into vesicles and transports across the endothelial cell to the abluminal side. The main advantage of using this system is that it operates independent of the molecular size of peptides, not restricted to specific peptides and does not depend on the structure of the peptide.
Factors affecting the transport across BBB include:
* Route of administration: intracerebral, intraventricular or intracarotid arterial administration
* The plasma concentration-time profile of the compound.
* Binding of drugs to the plasma proteins and plasma clearance rates.
* Local cerebral blood flow.
* Diffusion from ISF and enzymatic stability in the interstitial fluid (ISF) (in case of transport into CSF)
1. Targeted & Controlled Drug Delivery (Drug Delivery to Brain); pgs: 494-499, S. P. Vyas & R. K. Khar. C. B. S. Publishers. [access date: 12th June, 2010]
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