Nervous system blood-brain barrier

Continuous capillaries are found in the skin, all types of muscle, mesenteries, and the central nervous system (blood-brain barrier). These capillaries are characterized by tight junctions between the endothelial cells and an uninterrupted basement membrane. The restrictive capacity of the capillary walls barely allows extravasation of macromolecules into the parenchyma of these tissues. 

Barriers in the Central Nervous System Blood Brain... 

Concerning the distribution of a drug, models have been published for log BB blood/brain partition coefficient) for CNS-active drugs (CNS, central nervous system) crossing the blood-brain barrier (BBB) [38-45] and binding to human serum albumin (HSA) [46]. 

The blood-brain barrier (BBB) forms a physiological barrier between the central nervous system and the blood circulation. It consists of glial cells and a special species of endothelial cells, which form tight junctions between each other thereby inhibiting paracellular transport. In addition, the endothelial cells of the BBB express a variety of ABC-transporters to protect the brain tissue against toxic metabolites and xenobiotics. The BBB is permeable to water, glucose, sodium chloride and non-ionised lipid-soluble molecules but large molecules such as peptides as well as many polar substances do not readily permeate the battier. 

As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. The most important mechanism involves feedback inhibition by the catecholamines, which compete with the enzyme for the pteridine cofactor. Catecholamines cannot cross the blood-brain barrier hence, in the brain they must be synthesized locally. In certain central nervous system diseases (eg, Parkinson s disease), there is a local deficiency of dopamine synthesis. L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier and so is an important agent in the treatment of Parkinson s disease. 

In all higher species, locomotion is controlled by a central nervous system and, therefore, it might be argued that this system would provide an "ideal" target for toxins. However, when the nervous system is centrally located there is often in-built protection from blood-borne toxins and this "blood-brain" barrier offers protection, especially against large molecular weight toxins. 

McCandless EE, Budde M, Lees JR, Dorsey D, Lyng E, Klein RS (2009) IL-IR signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyehtis. J Immunol 183(l) 613-620 McEarland HE, Martin R (2007) Multiple sclerosis a complicated picture of autoimmunity. Nat Immunol 8 913-919... 

Proteases are crucial enzymes induced by HIV to alter the physiology of the central nervous system. Indeed, proteases participate in brain infection, helping infected peripheral cells to cross the blood-brain barrier, as well as in the viral neuropathogenesis as will be later discussed. We will first describe examples of... 

Endogenous estrogens are known to be active in a number of areas of the brain. There are indications that estrogens may play a role in mood, locomotor activity, pain sensitivity, vulnerability to neurodegenerative diseases and cognition (McEwan, 1999). In humans, the blood brain barrier is not fiilly developed at birth and, for this reason, the central nervous system (CNS) may be more sensitive to phytoestrogens in utero or at birth. As ERs are expressed in the CNS, phytoestrogens may also be active in this area. 

Tso and Lam suggested that astaxanthin could be useful for prevention and treatment of neuronal damage associated with age-related macular degeneration and may also be effective in treating ischemic reperfusion injury, Alzheimer s disease, Parkinson s disease, spinal cord injuries, and other types of central nervous system injuries. Astaxanthin was found to easily cross the blood-brain barrier and did not form crystals in the eye. 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Another very important site for drug delivery is the central nervous system (CNS). The blood-brain barrier presents a formidable barrier to the effective delivery of most agents to the brain. Interesting work is now advancing in such areas as direct convective delivery of macromolecules (and presumably in the future macromolecular drug carriers) to the spinal cord [238] and even to peripheral nerves [239]. For the interested reader, the delivery of therapeutic molecules into the CNS has also been recently comprehensively reviewed... 

The ability of the anesthetic agent to function is related to the partial pressure of the drug in the brain. Two major factors dictate the concentration of anesthetic agent in the neural tissue (1) the pressure gradients from lung alveoli to the brain (i.e., inhaled gas —> alveoli — bloodstream —> brain) and (2) the lipid solubility of the drug that enables it to pass between the blood-brain barrier to the central nervous system. 

L-dopa is effective in the treatment of Parkinson s disease, a disorder characterised by low levels of dopamine, since L-dopa is metabolised into dopamine. However, this biosynthesis normally occurs in both the peripheral nervous system (PNS) and the central nervous system CNS. The related drug carbidopa inhibits aromatic L-amino acid decarboxylase only in the periphery, since it does not cross the blood-brain barrier. So, when carbidopa is given with L-dopa, it reduces the biosynthesis of L-dopa to dopamine in the periphery and, thus, increases the bioavailability of L-dopa for the dopaminergic neurons in the brain. Hence, carbidopa increases the clinical efficacy of L-dopa for Parkinsonian patients. 

Initial safety tests were carried out in beagle dogs and subsequently in cynomolgus monkeys. Single bolus i.v. doses of up to 100 mg kg-1 were used and were found to exert no negative effect upon general condition, blood pressure, heart or cardiovascular parameters, respiration rate or body temperature. No safety tests evaluating potential product effects upon the central nervous system were undertaken, as the protein is considered unlikely to cross the blood-brain barrier. 

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