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The Role Of Extracellular Adenosine In Regulation Of Paracellular And Transcellular Permeability Of Blood Brain Barrier
The brain is the center of cognitive function and also regulates the physiology of the body. Due to its importance, it requires special vascular structure which separates itself from the peripheral circulation to maintain its electrical physiology and protect from insult from circulation. The vasculature of the brain is lined with a single layer of endothelial cells which is sealed with adherent and tight junction molecules. The endothelial cell lining is further insulated with pericytes and astrocytic endfeet. Also endothelial cells express varieties of transporters which selectively allow the entrance of molecules into the brain. This physicochemical vascular entity is called the blood brain barrier. This structural barrier is, however, detrimental in the delivery of molecules to the brain. Many of drugs are dropped out from the pipelines because they cannot show the expected effect in the brain. To overcome this, many approaches were devised to increase the drug delivery to the brain, they were either invasive or ineffective. In previous study, we have shown that adenosine receptor signaling can increase the permeability of large molecules to the brain. Adenosine receptor is the G-protein coupled receptor which is involved in numerous physiological reactions. Activation of adenosine receptor showed potent and reversible increased permeability to the large molecules. In this dissertation, we aimed to reveal if activation of adenosine receptor signaling can increase the permeability in the human primary brain endothelial cell monolayer. Indeed we observed robust and reversible permeability increase in human brain endothelial cells. This was mediated by increased Rho-GTPase activity and following stress fiber formation which subsequently disrupted the tight and adherens junctional molecules. Activation of AR also increased the permeability to chemotherapeutics Gemcitabine. Also, we studied if adenosine receptor signaling can increase transcellular pathway which is mainly mediated by transporters highly expressed on the brain endothelial cells, especially P-glycoprotein. Indeed we observed that AR activation can increase the accumulation of the P-glycoprotein substrate in human primary brain endothelial cells by down regulating the expression and function of P-glycoprotein. Also, we could observe that it down-regulates the P-glycoprotein and thereby increase the accumulation of epirubicin, a P-glycoprotein substrate, in the brain of the mouse. Collectively, we showed that AR activation can increase the permeability paracellular permeability of the human primary brain endothelial cells and also down regulate the P-glycoprotein function and enhance the transcellular permeability. These dual mechanism of regulating the permeability of the blood brain barrier might be beneficial in drug delivery in the brain which will benefit millions of patients suffering from the neurodegenerative disease or brain cancers.
Clark,Theodore G.; August,Avery
Ph.D. of Veterinary Medicine
Doctor of Philosophy
dissertation or thesis