Control of Drug Delivery to the CNS: Modulating P-glycoprotein Activity

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DESCRIPTION (provided by applicant): SUMMARY DESCRIPTION OF PROGRAM SUMMARY DESCRIPTION OF PROJECT RESEARCH AND DEVELOPMENT PROGRAM PRINCIPAL INVESTIGATOR(S) Banks, William A TITLE OF PROGRAM PROJECT (Not to exceed 72 character spaces) Control of Drug Delivery to the CNS: Modulating P-glycoprotein Activity KEYWORDS (MeSH terms only; minimum three) Drug, blood-brain barrier, Brain, CNS, p-glycoprotein, innate immune system, cytokines, tumor necrosis factor-alpha, nitric oxide BRIEF STATEMENT OF RESEARCH OBJECTIVES (Do not use continuation sheets) A major problem in developing effective therapeutics for the brain is the blood-brain barrier (BBB), which excludes many drugs from the central nervous system (CNS). One major mechanism by which the BBB excludes drugs is through P- glycorprotein (P-gp). P-gp is a brain-to-blood (efflux) pump located in the luminal side of the BBB that prevents its ligands from entering the CNS. P-gp has an affinity for an incredibly large number of clinically used drugs. Increasing P- gp activity further limits the access of its ligands to the CNS, thus making many CNS drugs ineffective, whereas decreasing P-gp activity allows more drug into the CNS, thus increasing effects. Our long-term goal is to learn how to control P-gp activity and so control the delivery of its ligands to the CNS. Recent in vitro work with brain endothelial cells has demonstrated a cascade of events that regulate P-gp activity. P-gp at the brain endothelial cell is inhibited by lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNF). These sequentially stimulate endothelin-1 (ET-1), which acts through its B receptor (ETRB) to increase nitric oxide synthase (NOS) activity that acts within minutes to decrease P- gp activity for min-h: LPS -> TNF -> ET-1 (ETRB) ->NOS -> decreased P-gp activity. This pathway also stimulates NFkB through the ET-1 receptors ETRA and ETRB to increase expression of P-gp, producing within hours a long-term stimulation of P-gp: TNF -> ET-1 (ETRA/ETRB) -> NOS -> NFkB -> mRNA (P-gp) -> increased P-gp activity. Our goal is to determine whether these mechanisms are operational in vivo. Our working hypothesis is: P-gp activity is regulated in vivo by the sequential activation of TNF, ET-1, and NOS. Our specific aims are: SA 1: To determine in vivo in mice the short- and long-term effects of TNF on P-gp. SA2 : To determine in vivo in mice the role of ET-1 on LPS-induced change in P-gp. SA 3: To determine in vivo in mice the short- and long-term effects of NOS on P-gp. Potential Impact on Veteran's Health Care: If all or part of this cascade is active in vivo, then P-gp activity is likely modified in a host of diseases that would result in altered CNS drug activities. These diseases would include not only bacterial sepsis, but diseases such as rheumatoid arthritis, diabetes, stroke, CNS cancers, and even obesity and Alzheimer's disease in which proinflammatory and neuroinflammatory conditions exist. The proposed work will have 3 major impacts on health care: 1) it will help to identify drugs and diseases in which a modified P-gp activity results in altered CNS drug profiles; 2) it will identify stategies and agents which can reverse those altered CNS drug profiles in those disease states; 3) it will lead to a new strategy, that of manipulation of P-gp activity, in the development of drugs both for targeting CNS diseases and for developing drugs with fewer CNS side effects. VA FORM 10-1313-2 Page 2 of VA Form 10-1313 package JUN 1990(R)