One limitation of current HIV AIDS drug regimens continues to be the development of pharmacological re sistance selleckchem to currently available Inhibitors,Modulators,Libraries AR drugs. That is, high levels of energy dependent efflux drug transporters such as P glycoprotein and multidrug resistance associated proteins in target cells prevent accumulation of Inhibitors,Modulators,Libraries drugs to levels sufficient to provide a therapeutic effect. Clinically, lower amounts of protease inhibitors such as saquinavir and ritonavir accumulate in peripheral viral compartments such as blood mononuclear cells in HIV infected patients who demonstrate greater P glycopro tein and MRP1 expression. Using P glycoprotein knock out mice, multiple laboratories have confirmed that P glycoprotein significantly limits brain accumula tion of saquinavir, and other protease inhibitors inclu ding indinavir and amprenavir at the level of the blood brain barrier.

Previously, we have demonstrated that cultured Inhibitors,Modulators,Libraries rat microglia also express multiple drug transporters including P glycoprotein, Mrp1, and Mrp4 5. These transporters are not only present in significant quantities but are also func tionally active, able to transport a variety of known anti HIV medications including zidovudine, saquinavir, ritonavir, indinavir and atazanavir. In addition to HIV, AIDS patients frequently suffer multiple bacterial and viral co infections and are under a constant state of generalized brain inflammation. This leads to deregulation of microglial cell function and release of pro inflammatory media tors, reactive oxygen spe cies, and viral proteins, all shown to alter transporter expression and or function in multiple cell types via complex, and often redundant, signaling pathways.

In brain endothelial cells, TNF induces Mdr1b promoter activity via nuclear Inhibitors,Modulators,Libraries trans location of the transcription factor NF ��B. Simi larly, changes in P glycoprotein transport activity and expression in isolated rat brain capillaries occurs following activation of the toll like receptor 4, which in turn triggers a cascade of molecular signal ing events involving TNF, endothelin 1, nitric oxide synthase and protein kinase C. More recently, Mrp1 expression in primary rat astrocytes was also shown to be regulated by TNF, via NF ��B and c Jun N terminal kinase signal ing. How then, a self propelling cycle of inflam mation and consequent cellular dysfunction affects expression and function of microglial drug trans porters, and how this might ultimately affect brain AR drug exposure is unknown.

To begin to answer these questions we have examined how drug trans port is altered in microglial cells following Inhibitors,Modulators,Libraries treatment with the prototypical inflammatory mediator lipopo lysacharride. We show that LPS exposure re duces cellular accumulation of the protease inhibitor saquinavir and examine possible mechanisms under sellekchem lying this effect.