Environmental Factor, June 2010, National Institute of Environmental Health Sciences
P-glycoprotein - 800-lb Gorilla of the Blood-Brain Barrier
By Thaddeus Schug
Our attempts to treat diseases of the central nervous system are often complicated by inadequate transport of drugs and proteins to and from blood and neuronal tissue. That problem has inspired several recent investigations with potential translational impact from the lab of NIEHS Senior Investigator David Miller, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/ltp/intrareg/index.cfm), who has explored the role of transport mechanisms in drug delivery efficacy, as well as the clearance of proteins implicated in Alzheimer's disease.
Addressing the National Advisory Environmental Health Sciences Council (NAEHSC), and a crowded audience in Rodbell Auditorium May 13 as the meeting's featured scientific lecturer, Miller explained, "Delivery of therapeutic drugs to the central nervous system is the major challenge of pharmacotherapy. This is due to the inability of many drugs to cross through a network of endothelium-lined capillaries that permeate the brain."
In this context, Miller has focused on P-glycoprotein (P-gp), a protein responsible for limiting drug trafficking to the brain. Miller considers this transport protein the 800-lb gorilla of the blood-brain barrier (BBB).
Miller added that P-gp - an ATP-driven efflux pump - acts like a gatekeeper for the BBB by restricting numerous xenobiotics from entering the brain. "The problem is the protein does not distinguish well between neurotoxicants and therapeutic drugs, so it is an obstacle to the treatment of a number of diseases, including brain cancer, epilepsy, and neuroAIDS," Miller said.
Xenobiotic exposures alter expression of transporters
Miller's group has identified several ligand-activated intracellular receptors that increase expression of P-gp. "When activated, receptors such as the aryl hydrocarbon receptor (AhR), pregnane-X receptor (PXR), and constitutive androstane receptor (CAR), all of which are considered to be a major part of the first line of defense against toxicants, increase transport activity and protein expression for P-glycoprotein in brain capillaries."
Miller used an in vivo brain-perfusion technique in rats to demonstrate that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which activates the AhR, increases expression of P-gp. TCDD-exposed rats became resistant to drug uptake in the brain due to the elevated transporter levels. "Exposure to toxins and xenobiotics tends to activate p-glycoprotein, making drug delivery to the brain even more problematic," added Miller.
P-gp defective in Alzheimer's disease
Miller then shifted gears to explain that P-gp also plays an important role in Alzheimer's disease (AD). He hypothesized that buildup of the neurotoxic protein amyloid beta (A-beta) in AD patients may be due to defects in BBB transporter function. A-beta plaque formation is a contributing factor to the neural degeneration observed in AD patients. "In the normal situation, P-glycoprotein helps clear A-beta from the brain, so maintenance of transporter function is important," added Miller.
Miller and colleagues found that BBB p-glycoprotein levels were reduced in an AD mouse model, the hAPP mouse. To determine whether they could rescue P-gp levels in these mice, they used PXR activation. Miller noted that treating the 12-week-old AD mice once a day for seven days with a PXR ligand restored P-gp levels in brain capillaries to those found in control mice. Importantly, brain A-beta accumulation in PXR-activated, hAPP mice was reduced by up to 60 percent.
Miller concluded that it is critical to determine whether long-term P-glycoprotein induction by oral dosing reduces brain A-beta levels, angiopathy, neurodegeneration, and cognitive impairment in the AD mice.
AD is the most common form of dementia in older people. It currently affects nearly 4.5 million people in the U.S. The risk of AD doubles for every five-year age interval beyond age 65, and as the U.S. population ages, a higher percentage of the population is likely to suffer from this debilitating disease. Miller's work could eventually provide a better understanding of the etiology of AD (see related story(http://www.niehs.nih.gov/news/newsletter/2010/april/science-are.cfm)).
(Thaddeus Schug, Ph.D., is a postdoctoral research fellow in the NIEHS Laboratory of Signal Transduction.)