Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance.
The causes and mechanisms underlying multidrug resistance (MDR) in epilepsy are still elusive and may depend on inadequate drug concentration in crucial brain areas. We studied whether limbic seizures or anticonvulsant drug treatments in rodents enhance the brain expression of the MDR gene (mdr) encoding a permeability glycoprotein (P-gp) involved in MDR to various cancer chemotherapeutic agents. We also investigated whether changes in P-gp levels affect anticonvulsant drug concentrations in the brain. Mdr mRNA measured by RT-PCR increased by 85% on average in the mouse hippocampus 3-24 hr after kainic acid-induced limbic seizures, returning to control levels by 72 hr. Treatment with therapeutic doses of phenytoin or carbamazepine for 7 d did not change mdr mRNA expression in the mouse hippocampus 1-72 hr after the last drug administration. Six hours after seizures, the brain/plasma ratio of phenytoin was reduced by 30% and its extracellular concentration estimated by microdialysis was increased by twofold compared with control mice. Knock-out mice (mdr1a/b -/-) lacking P-gp protein showed a 46% increase in phenytoin concentrations in the hippocampus 1 and 4 hr after injection compared with wild-type mice. A significant 23% increase was found in the cerebellum at 1 hr and in the cortex at 4 hr. Carbamazepine concentrations were measurable in the hippocampus at 3 hr in mdr1a/b -/- mice, whereas they were undetectable at the same time interval in wild-type mice. In rats having spontaneous seizures 3 months after electrically induced status epilepticus, mdr1 mRNA levels were enhanced by 1.8-fold and fivefold on average in the hippocampus and entorhinal cortex, respectively. Thus, changes in P-gp mRNA levels occur in limbic areas after both acute and chronic epileptic activity. P-gp alterations significantly affect antiepileptic drugs concentrations in the brain, suggesting that seizure-induced mdr mRNA expression contributes to MDR in epilepsy.
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milano, Italy.
Massimo
M
Rizzi
Silvio
S
Caccia
Giovanna
G
Guiso
Cristina
C
Richichi
Jan A
JA
Gorter
Eleonora
E
Aronica
Marisa
M
Aliprandi
Renzo
R
Bagnati
Roberto
R
Fanelli
Maurizio
M
D'Incalci
Rosario
R
Samanin
Annamaria
A
Vezzani
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000502:physiology; D004558:Electric Stimulation; D004569:Electroencephalography; D018728:Entorhinal Cortex / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006720:Homozygote; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000503:physiopathology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D012333:RNA, Messenger