title: Glutamate is critically involved in seizure-induced overexpression of P-glycoprotein in the brain.
abstract: About 30% of patients with epilepsy do not respond adequately to drug therapy, making pharmacoresistance a major problem in the treatment of this common brain disorder. Mechanisms of intractability are not well understood, but may include limitation of antiepileptic drug access to the seizure focus by overexpression of the drug efflux transporter P-glycoprotein (Pgp) at the blood-brain barrier. Increased expression of Pgp has been determined both in epileptogenic brain tissue of patients with intractable epilepsy and in rodent models of temporal lobe epilepsy, including the pilocarpine model. The mechanisms underlying the increase of Pgp after seizures are unclear. We have recently suggested that the excitatory neurotransmitter glutamate, which is excessively released by seizures, is involved in the seizure-induced overexpression of Pgp in the brain. This hypothesis was evaluated in the present study in the pilocarpine model in rats. After 90 min of status epilepticus (SE), diazepam was administered, followed by either vehicle or the glutamate receptor antagonist MK-801 (dizocilpine). Following SE in vehicle treated rats, Pgp expression in brain capillary endothelial cells increased about twofold in the hippocampus, which was completely prevented by MK-801. Furthermore, neurodegeneration developing in the hippocampus and parahippocampal regions was reduced by the glutamate antagonist. In contrast, the Pgp inhibitor tariquidar did not affect the SE-induced overexpression of Pgp or neurodegeneration in most regions examined. The data indicate that seizure-induced glutamate release is involved in the regulation of Pgp expression, which can be blocked by MK-801. The finding that MK-801 counteracts both Pgp overexpression and neuronal damage when administered after SE may offer a clinically useful therapeutic option in patients with refractory SE.
authors.affiliation: Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Hannover, Germany.
authors.forename: Jens P
authors.initials: JP
authors.lastname: Bankstahl
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bethmann
authors.forename: W
authors.initials: W
authors.lastname: Löscher
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001923:Brain Chemistry / Q000502:physiology*; D002196:Capillaries / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000502:physiology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D018721:Muscarinic Agonists; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D010862:Pilocarpine; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018691:Excitatory Amino Acid Antagonists; D018721:Muscarinic Agonists; D011804:Quinolines; D010862:Pilocarpine; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; C402343:tariquidar