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 inmdr1a/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.

[1]  W. Löscher,et al.  P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain , 2001, Neuroreport.

[2]  M. Pirmohamed,et al.  Carbamazepine is not a substrate for P-glycoprotein. , 2001, British journal of clinical pharmacology.

[3]  E. Aronica,et al.  Progression of spontaneous seizures after status epilepticus is associated with mossy fibre sprouting and extensive bilateral loss of hilar parvalbumin and somatostatin‐immunoreactive neurons , 2001, The European journal of neuroscience.

[4]  M. Thom,et al.  Multidrug-resistance protein 1 in focal cortical dysplasia , 2001, The Lancet.

[5]  C. Higgins,et al.  Communication between multiple drug binding sites on P-glycoprotein. , 2000, Molecular pharmacology.

[6]  U. Brinkmann,et al.  Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  S. Sisodiya,et al.  Over-expression of P-glycoprotein in malformations of cortical development. , 1999, Neuroreport.

[8]  A. Rabinowicz,et al.  Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy. , 1999, Pediatric neurology.

[9]  W. Ong,et al.  Induction of P-glycoprotein expression in astrocytes following intracerebroventricular kainate injections , 1999, Experimental Brain Research.

[10]  W. Pardridge,et al.  P-glycoprotein on astrocyte foot processes of unfixed isolated human brain capillaries , 1999, Brain Research.

[11]  N. Fountain,et al.  Responses of deep entorhinal cortex are epileptiform in an electrogenic rat model of chronic temporal lobe epilepsy. , 1998, Journal of Neurophysiology.

[12]  D. Breimer,et al.  Effect of the Mdr1a P-glycoprotein gene disruption on the tissue distribution of SDZ PSC 833, a multidrug resistance-reversing agent, in mice. , 1998, The Journal of pharmacology and experimental therapeutics.

[13]  F Andermann,et al.  Cortical dysplasia , 1998, Neurology.

[14]  E. Schönau.  The Development of the Skeletal System in Children and the Influence of Muscular Strength , 1997, Hormone Research in Paediatrics.

[15]  Wolfgang Löscher,et al.  Animal models of intractable epilepsy , 1997, Progress in Neurobiology.

[16]  A. Schinkel,et al.  P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. , 1996, The Journal of clinical investigation.

[17]  Y. M. Hart,et al.  Remission of epilepsy: results from the National General Practice Study of Epilepsy , 1995, The Lancet.

[18]  N. Barbaro,et al.  MDR1 Gene Expression in Brain of Patients with Medically Intractable Epilepsy , 1995, Epilepsia.

[19]  F. Baas,et al.  The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[20]  J. H. Beijnen,et al.  Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs , 1994, Cell.

[21]  C. Munari,et al.  Stereo‐electroencephalography methodology: advantages and limits , 1994, Acta neurologica Scandinavica. Supplementum.

[22]  L. Forman,et al.  Simultaneous determination of carbamazepine, phenytoin, phenobarbital, primidone and their principal metabolites by high-performance liquid chromatography with photodiode-array detection. , 1993, Journal of chromatography.

[23]  H. Kobayashi,et al.  Overproduction of voltage-dependent Na+ channels in the developing brain of genetically seizure-susceptible El mice , 1992, Neuroscience.

[24]  L. Bongiovanni,et al.  Prognosis of Epilepsy in Newly Referred Patients: A Multicenter Prospective Study of the Effects of Monotherapy on the Long‐Term Course of Epilepsy , 1992, Epilepsia.

[25]  A. Vezzani,et al.  Increased preproneuropeptide Y mRNA in the rat hippocampus during the development of hippocampal kindling: Comparison with the expression of preprosomatostatin mRNA , 1991, Neuroscience Letters.

[26]  O. Haas,et al.  MDR1 gene expression and treatment outcome in acute myeloid leukemia. , 1991, Journal of the National Cancer Institute.

[27]  T. Tsuruo,et al.  Modulation of multidrug resistance by verapamil or mdr1 anti‐sense oligodeoxynucleotide does not change the high susceptibility to lymphokine‐activated killers in mdr‐resistant human carcinoma (LoVo) line , 1990, International journal of cancer.

[28]  W. Hauser,et al.  Epilepsy: Frequency Causes and Consequences , 1990 .

[29]  D. Housman,et al.  The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues , 1989, Molecular and cellular biology.

[30]  I. Pastan,et al.  Expression of Multidrug Resistance Gene in Human Cancers , 1989 .

[31]  K. Cowan,et al.  Mechanisms and clinical significance of multidrug resistance. , 1988, Oncology.

[32]  M C Willingham,et al.  Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[33]  E. Reynolds.  Early Treatment and Prognosis of Epilepsy , 1987, Epilepsia.

[34]  R L Juliano,et al.  A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. , 1976, Biochimica et biophysica acta.

[35]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. II. Motor seizure. , 1972, Electroencephalography and clinical neurophysiology.

[36]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. 3. Mechanisms. , 1972, Electroencephalography and clinical neurophysiology.

[37]  A. Dantzig,et al.  Reversal of multidrug resistance by the P-glycoprotein modulator, LY335979, from the bench to the clinic. , 2001, Current medicinal chemistry.

[38]  Hitoshi Sato,et al.  Dose-dependent brain penetration of SDZ PSC 833, a novel multidrug resistance-reversing cyclosporin, in rats , 1996, Cancer Chemotherapy and Pharmacology.

[39]  R. Kuzniecky,et al.  Altered brain sodium channel transcript levels in human epilepsy. , 1996, Brain research. Molecular brain research.

[40]  I. Pastan,et al.  Biochemistry of multidrug resistance mediated by the multidrug transporter. , 1993, Annual review of biochemistry.

[41]  J. Endicott,et al.  The biochemistry of P-glycoprotein-mediated multidrug resistance. , 1989, Annual review of biochemistry.

[42]  M. Melamed,et al.  Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[43]  C. Nitsch,et al.  Pathophysiological aspects of blood-brain barrier permeability in epileptic seizures. , 1986, Advances in experimental medicine and biology.