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The Journal of Neuroscience, July 15, 2002, 22(14):5833-5839
Limbic Seizures Induce P-Glycoprotein in Rodent Brain: Functional
Implications for Pharmacoresistance
Massimo
Rizzi1,
Silvio
Caccia1,
Giovanna
Guiso1,
Cristina
Richichi1,
Jan A.
Gorter4,
Eleonora
Aronica5,
Marisa
Aliprandi1,
Renzo
Bagnati2,
Roberto
Fanelli2,
Maurizio
D'Incalci3,
Rosario
Samanin1,  , and
Annamaria
Vezzani1
Departments of 1 Neuroscience,
2 Environmental Health Sciences, and
3 Oncology, Istituto di Ricerche Farmacologiche "Mario
Negri," 20157 Milano, Italy, 4 Swammerdam Institute for
Life Sciences, University of Amsterdam, 1098 SM, Amsterdam, The
Netherlands, and 5 Department of (Neuro)Pathology, Academic
Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The
Netherlands
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.
Key words:
anticonvulsant drugs; epilepsy; mdr; P-glycoprotein; rat; seizures
Deceased, June 5, 2001.
Copyright © 2002 Society for Neuroscience 0270-6474/02/22145833-07$05.00/0
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