title: P-gp Protein Expression and Transport Activity in Rodent Seizure Models and Human Epilepsy.
abstract: A cure for epilepsy is currently not available, and seizure genesis, seizure recurrence, and resistance to antiseizure drugs remain serious clinical problems. Studies show that the blood-brain barrier is altered in animal models of epilepsy and in epileptic patients. In this regard, seizures increase expression of blood-brain barrier efflux transporters such as P-glycoprotein (P-gp), which is thought to reduce brain uptake of antiseizure drugs, and thus, contribute to antiseizure drug resistance. The goal of the current study was to assess the viability of combining in vivo and ex vivo preparations of isolated brain capillaries from animal models of seizures and epilepsy as well as from patients with epilepsy to study P-gp at the blood-brain barrier. Exposing isolated rat brain capillaries to glutamate ex vivo upregulated P-gp expression to levels that were similar to those in capillaries isolated from rats that had status epilepticus or chronic epilepsy. Moreover, the fold-increase in P-gp protein expression seen in animal models is consistent with the fold-increase in P-gp observed in human brain capillaries isolated from patients with epilepsy compared to age-matched control individuals. Overall, the in vivo/ex vivo approach presented here allows detailed analysis of the mechanisms underlying seizure-induced changes of P-gp expression and transport activity at the blood-brain barrier. This approach can be extended to other blood-brain barrier proteins that might contribute to drug-resistant epilepsy or other CNS disorders as well.
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky 40536, United States.|Department of Pharmacology and Nutritional Sciences, University of Kentucky , Lexington, Kentucky 40536, United States.
authors.forename: Anika M S
authors.initials: AM
authors.lastname: Hartz
authors.affiliation: Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota , Duluth, Minnesota 55812, United States.
authors.forename: Anton
authors.initials: A
authors.lastname: Pekcec
authors.affiliation: Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota , Duluth, Minnesota 55812, United States.
authors.forename: Emma L B
authors.initials: EL
authors.lastname: Soldner
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky 40536, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota , Duluth, Minnesota 55812, United States.
authors.forename: Juli
authors.initials: J
authors.lastname: Schlichtiger
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.|Epilepsy Center, University of Kentucky , Lexington, Kentucky 40536, United States.
authors.forename: Bjoern
authors.identifier: 0000-0003-3867-2251
authors.initials: B
authors.lastname: Bauer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D018698:Glutamic Acid
keywords: P-glycoprotein; blood−brain barrier; efflux transporter; epilepsy; pilocarpine; status epilepticus