P‑gp Protein Expression and Transport Activity in Rodent Seizure Models and Human Epilepsy

• Published in: Molecular pharmaceutics Vol. 14; no. 4; pp. 999 - 1011
• Main Authors: Hartz, Anika M. S, Pekcec, Anton, Soldner, Emma L. B, Zhong, Yu, Schlichtiger, Juli, Bauer, Bjoern
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 03.04.2017
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Blood-Brain Barrier - metabolism; Brain - metabolism; Capillaries - metabolism; Carrier Proteins - metabolism; Disease Models, Animal; Epilepsy - metabolism; Female; Glutamic Acid - metabolism; Humans; Rats; Rats, Wistar; Seizures - metabolism; Up-Regulation - physiology; P-glycoprotein; epilepsy; pilocarpine; blood−brain barrier; status epilepticus; efflux transporter
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.6b00770

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.