Blood-brain barrier system

HPLC studies on the brain of mature rainbow trout revealed essentially four metabolites, including the dihydrodiol and 1-naphthol (12). No evidence was found for the presence of conjugated derivatives. It was concluded that the conjugated derivatives of naphthalene were excluded by blood-brain barrier systems that develop in mature organisms. 

Yasutake A, Adachi T, Hirayama K, et al. 1991a. Integrity of the blood-brain barrier system against methylmercury acute toxicity. Eisei Kagaku 37(5) 355-362. 

Dhopeshwarkar, G.A. and Mead, J.F. (1973) Uptake and transport of fatty acids into the brain and the role of the blood-brain barrier system. Adv. Lipid Res. 11 109-142. 

Brain Blood-brain barrier system, drug testing/ permeability studies Neurons Axon-glia interaction... 

In liver failure the plasma concentrations of the aromatic amino acids (AAAs) tyrosine, phenylalanine, and tryptophan increase, probably because they are predominantly broken down in the liver, whereas the plasma levels of BCAAs decrease while they are degraded in excess in muscle as a consequence of hepatic failure-induced catabolism. As AAAs and BCAAs are all neutral amino acids and share a common transporter across the blood-brain barrier (system L carrier), changes in their plasma ratio are reflected in the brain, subsequently disrupting the neurotransmitter profile of the catecholamines and indoleamines (see sections on tyrosine and tryptophan). It has been hypothesized that this disturbance contributes to the multifactorial pathogenesis of hepatic encephalopathy. In line with this hypothesis it has been suggested that normalization of the amino acid pattern by supplementing extra BCAAs counteracts hepatic encephalopathy. 

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. 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

Alternate ways to interfere with the orexin system may be via inhibition of dipeptidyl peptidases or proteolysis-resistant peptide analogs as shown for other peptides. This could prolong and boost orexinergic signaling. OX-A but not OX-B can enters the brain by simple diffusion via the blood-brain barrier. Abundance of orexins and their receptors in the olfactory bulb and throughout all parts of the central olfactory system may offer transnasal routes for drug application. 

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... 

Early studies indicate that combined GP Ilb/IIIa inhibition with rt-PA thrombolysis may improve clinical and MRI outcomes after acute ischemic stroke, with an acceptable safety prohle. The dual targeting of platelets and hbrin by combination therapy may provide synergistic benefits, including increased arterial recanalization, reduced microvascular thrombosis, reduced arterial reocclusion, and less rt-PA-mediated blood-brain barrier injury and secondary activation of the coagulation system. 

In parallel with the identification of distinct transporters for GABA there has been continued interest in the development of selective blockers of these transporters and the therapeutic potential that could result from prolonging the action of synaptically released GABA. It has been known for a long time that certain pro-drugs of nipecotic add (e.g. nipecotic acid ethyl ester) are able to cross the blood-brain barrier and are effective anticonvulsants in experimental models of epilepsy. More recently, several different systemically active lipophillic compounds have been described that act selectively on GAT-1, GAT-2 or GAT-3 (Fig. 11.4). Of these, tiagabine (gabitiil), a derivative of nipecotic acid that acts preferentially on GAT -1, has proved clinically useful in cases of refractory epilepsy. 

However, more recently, a functionally selective inhibitor of nNOS has been described — 7-nitroindazole (7-NI). It is puzzling that in vitro this compound has no selectivity for nNOS over eNOS but after systemic administration, fails to change blood pressure yet alters neuronal responses that are thought to result from production of NO. A suggested resolution of this action is that 7-NI is metabolised in the periphery but not the CNS, so that once it has crossed the blood-brain barrier, it can only act on nNOS. 

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