The gene encoding P-glycoprotein (P-gp) is mdr1a, which is a key part of the blood-brain barrier (BBB) that prevents the buildup of many substances in the brain. Mdr1a Pgp deficient [mdr1a (-/-)] mice could help explain how the efflux transporter protein P- gp influences brain uptake and selectively facilitate stroke drugs' delivery to the brain.

Role of P-gp in Drug Disposition to the Ischemic Brain

P-gp, also known as multidrug resistance protein 1 (Mdr1) or ATP-binding cassette subfamily B member 1 (ABCB1), is a 170 kDa intact transmembrane protein that is highly expressed in brain microvascular endothelial cells. It selectively transports substrates from the interstitial fluid to the bloodstream, thereby limiting the entry of substances from the blood into the brain parenchyma.

P-gp is encoded by the multidrug resistance (Mdr) gene, which has two isoforms in humans (i.e., Mdr1 and Mdr3) and three isoforms in rodents (i.e., mdr1a, mdr1b, and mdr2). In mouse brain, mdr1a is the predominantly expressed isoform.

The functional expression of P-gp in the BBB is changed by ischemic damage, studies have reported. Ischemia/reperfusion (I/R) damage upregulates several ABC transporters in the brain on an mRNA level, including P-gp and multiple Mrp isoforms (Mrp1, Mrp2, Mrp4, Mrp5). Modified P-gp functional expression alters CNS transmission of drugs used in pharmacological therapy in ischemic stroke. In fact, some neuroprotective agents are P-gp transporter substrates (e.g., tanshinone IIA), suggesting that inhibiting P-gp by drug might be an effective approach to increase drug delivery to ischemic brain tissue. Inhibition of P-gp expression or function may help to enhance drug entry into the target brain region and provide efficacy of stroke medications, according to the study.

Fig.1. Localization of ATP-Binding Cassette (ABC) transporters at the BBB. (Nilles, et al., 2022)

The Mdr1a (-/-) Mouse Model

Scientists have generated and characterized mice homozygous for a disruption of the mdr1a gene, which encodes a drug-transporting P-glycoprotein. These mice are viable and fertile and have a normal phenotype. By comparing mdr1a (+/+) and (-/-) mice, it was found that the mdr1a P glycoprotein is the major P glycoprotein in the blood-brain barrier and that its deletion leads to elevated drug levels in the brain and reduced drug elimination. In addition, these mice are useful for studying brain neuroprotection and neurotoxicity.

1. Nilles, K. L., et al. (2022). Blood–brain barrier transporters: opportunities for therapeutic development in ischemic stroke. International Journal of Molecular Sciences, 23(3), 1898.