# Effects Of Circulating Inflammatory Mediators on Brain and Blood Brain Barrier



## Mike NoLomotil (Jun 6, 2000)

A very interesting tutorial on the current understanding of the effects of various mediators released by circulating immunocytes upon blood brain barrier function, and specific brain functions and their actions/responses to systemic stimuli.The subject is of particular interest when considering the observation of neurologic (central and peripheral) events such as those observed in specific IBS subjects.Several of the specific proinflammatory mediators confirmed to be released in cell mediated reactions in patients presenting with what would be normally diagnosed, based on symptoms, as "IBS" with a diarrheic component are known to cross the BBB, and/or cause specific reactions within the structures of the BBB which lead to secondary mediator release into the CSF which then acts upon specific brain tissue, and many mediators have direct access to certain important brain centers where there is no "effective" BBB.It will be much more enlightening when the observations of brain activity in response to peripheral stimuli such as pressure/volume changes within the distal gut, are combined with the knowledge and study of the mechanisms and provocation of the confirmed inflammatory reactions seen in the upper GI, and systemically, in the same IBS patients, as well as with concurrent assays for cytokines and other mediators which may in the end specifcally account for the observed events which at this time are observed but the mechanisms which can account for them are not yet explored at the same time.The abstract summarizes some of the key points of the paper which is in total a good tutorial on the subject and can shed light on the possible mechanisms, when they are taken in the context of other physiologic events known to occur in specific IBS patients. ___________________________________________Cell Mol Neurobiol. 2000 Apr;20(2):131-47. RInflammatory Mediators and Modulation of Blood-Brain Barrier Permeability.Abbott NJ.Division of Physiology, GKT School of Biomedical Sciences, King's College London, UK. 1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed. 2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved. 3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions. 4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling). 5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized. 6. Bradykinin (Bk) increases blood-brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with evidence that IL-1 beta potentiates the actions of Bk in ischemia. 7. Serotonin (5HT) has been reported to increase blood-brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase. 8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H2 receptors and elevation of [Ca2+]i and an H1 receptor-mediated reduction in permeability coupled to an elevation of cAMP. 9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood-brain barrier permeability. The effects are mediated predominantly via a P2U (P2Y2) G-protein-coupled receptor causing an elevation of [Ca2+]i; a P2Y1 receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations. 10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood-brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways. 11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood-brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood-brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.Publication Types:  Review  Review, Academic __________________________________MNL


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