Skip to main content
SpringerLink
Log in

Neuronal and Glial Expression of the Multidrug Resistance Gene Product in an Experimental Epilepsy Model

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

1. Failure of anticonvulsive drugs to prevent seizures is a common complication of epilepsy treatment known as drug-refractory epilepsy but their causes are not well understood. It is hypothesized that the multidrug resistance P-glycoprotein (Pgp-170), the product of the MDR-1 gene that is normally expressed in several excretory tissues including the blood brain barrier, may be participating in the refractory epilepsy.

2. Using two monoclonal antibodies against Pgp-170, we investigated the expression and cellular distribution of this protein in the rat brain during experimentally induced epilepsy. Repeated seizures were induced in male Wistar rats by daily administration of 3-mercaptopropionic acid (MP) 45 mg/kg i.p. for either 4 days (MP-4) or 7 days (MP-7). Control rats received an equivalent volume of vehicle. One day after the last injection, rats were sacrificed and brains were processed for immunohistochemistry for Pgp-170. As it was previously described, Pgp-170 immunostaining was observed in some brain capillary endothelial cells of animals from control group.

3. Increased Pgp-170 immunoreactivity was detected in MP-treated animals. Besides the Pgp-170 expressed in blood vessels, neuronal, and glial immunostaining was detected in hippocampus, striatum, and cerebral cortex of MP-treated rats. Pgp-170 immunolabeled neurons and glial cells were observed in a nonhomogeneous distribution. MP-4 animals presented a very prominent Pgp-170 immunostaining in the capillary endothelium, surrounding astrocytes and some neighboring neurons while MP-7 group showed increased neuronal labeling.

4. Our results demonstrate a selective increase in Pgp-170 immunoreactivity in the brain capillary endothelial cells, astrocytes, and neurons during repetitive MP-induced seizures.

5. The role for this Pgp-170 overexpression in endothelium and astrocytes as a clearance mechanism in the refractory epilepsy, and the consequences of neuronal Pgp-170 expression remain to be disclosed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Abbot, M. J., and Romero, I. A. (1996). Transporting therapeutics across the blood brain barrier. Mol. Med. Today 2:1106-113.

    Google Scholar 

  • Biedler, N., and Riehm, W. (1990). Cellular resistance to actinomycin D hamster cells in vitro. Cross resistance, radioautographic, and cytogenetics studies. Cancer Res. 30:1174-1184.

    Google Scholar 

  • Campbell, L., Abulrob, A. N., Kandalaf, L., Pumer, S., Hollins, A., Gibbs, A., and Gumbleton, M. (2003). Constitutive expression of P-glycoprotein in normal lung alveolar epithelium and functionally in primary alveolar epithelial cultures. J. Pharmed. Exp. Ther. 304:441-452.

    Google Scholar 

  • Comerford, K. M., Wallace, T. J., Karhausen, J., Louis, N. A., Montalto, M. C., and Colgan, S. P. (2002). Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 62:3387-94.

    Google Scholar 

  • De Sarro, G., Ferreri, G., Gareri, P., Russo, E., De Sarro, A., Gitto, R., and Chimirri, A. (2003). Comparative anticonvulsant activity of some 2,3-benzodiazepine derivates in rodents. Pharmacol. Biochem. Behav. 74:595-602.

    Google Scholar 

  • D'Giano, C., Sevlever, G., Lazarowski, A., Taratuto, A. L., Leiguarda, R., Pomata, H., and Rabinowicz, A. (1997). Expression of P-glycoprotein and related proteins in brain of patients with refractory temporal lobe epilepsy. Epilepsia 38 (Suppl.):7-41.

    Google Scholar 

  • Dombrowski, S., Desai, S., Marroni, M., Cucullo, L., Goodrich, K., Bingaman, W., Myberg, M., Bengez, L., and Janigro, D. (2001). Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia 42:1501-1506.

    Google Scholar 

  • Dragunow, M., Young, D., Huges, P., McGibbon, G., Lawlor, P., Singleton, K., Sirimanne, E., and Gluckman, P. (1993). Is Jun-C involved in nerve cells death following status epilepticus and hypoxia-ischemia brain injury? Mol. Brain Res. 18:347-352.

    Google Scholar 

  • Girardi, E., Perez Raffo, G., and Rodríguez de Lores Arnaiz, G. (1989). A study of 5′-nucleotidase activity in subcellular fractions of rat cerebellum fractions after the administration of the convulsant 3-mercaptopropionic acid. Mol. Chem. Neuropathol. 11:65-75.

    Google Scholar 

  • Girardi, E., Schneider, P., and Rodríguez de Lores Arnaiz, G. (1994). Area-specific modification of acetylcholinesterase activity following 3-mercapto propionic acid-induced seizures. Mol. Chem. Neuropathol. 21:13-22.

    Google Scholar 

  • Girardi, E., Ramos, A. J., Vanore, G., and Brusco, A. (in press). Astrocytic response in hippocampus and cerebral cortex in an experimental epilepsy model. Neurochem. Res. Feb. 2004.

  • Giraldez, L., and Girardi, E. (2000). Effect of an adenosine analogue administration on the striatal NMDA receptors in an experimental model of epilepsy. Neurochem. Int. 36:243-247.

    Google Scholar 

  • Giraldez, L., Zanetti, F., and Girardi, E. (1999). Striatum adenosine A2 receptors are modified during seizure: Effect of cyclopentyladenosine administration. Neurochem. Res. 24:1217-1223.

    Google Scholar 

  • Gottesman, M. M., and Pastan, I. (1988). The multidrug transporter, a double-edge sword. J. Biol. Chem. 263:12163-12166.

    Google Scholar 

  • Johnstone, R. W., Cretney, E., and Smyth, A. (1999). P-glycoprotein protects leukemia cells to the agonist caspase-dependent but not caspase-independent cell death. Blood 93:1075-1085.

    Google Scholar 

  • Kwan, P., and Brodie, M. J. (2000). Early identification of refractory epilepsy. N. Engl. J. Med. 342:314-319.

    Google Scholar 

  • Labielle, S., Gayet, L., Marthinet, E., Rigal, D., and Baggetto, L. (2002). Transcriptional regulators of human multidrug resistance 1 gene: Recent views. Biochem. Pharmacol. 64:943-948.

    Google Scholar 

  • Lazarowski, A., Lubiniecki, F., Camarero, S., Pomata, H., Bartoluchi, M., Sevlever, G., and Taratuto, A. (in press). Multidrug Resistance Proteins in tuberousous sclerosis and refractory epilepsy. Ped. Neurol. 2004.

  • Lazarowski, A., Sevlever, G., Taratuto, A., Massaro, M., and Rabinowicz, A. (1999). Tuberousous sclerosis associated with MDR-1 expression and drug-resistant epilepsy. Pediatr. Neurol. 21:731-734.

    Google Scholar 

  • Ling, V. (1989). Does P-glycoprotein predicts response to chemotherapy? J. Natl. Cancer Inst. 81:84-85.

    Google Scholar 

  • Löscher, W., and Potschka, H. (2002). Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J. Pharmacol. Exp. Ther. 301:7-14.

    Google Scholar 

  • Löscher, W., Resissmuller, E., and Ebert, U. (2000). Kindling alters the anticonvulsant efficacy of phenytoin in Wistar rats. Epilepsy Res. 39:211-220.

    Google Scholar 

  • National Institute of Health (1990). Consensus conference. Surgery for epilepsy. JAMA 264:729-733.

    Google Scholar 

  • Pennypacker, K. (1998). AP-1 transcription factor: short and long-term modulation of gene expression in brain. Int. Rev. Neurobiol. 42:169-197.

    Google Scholar 

  • Potschka, H., and Löscher, W. (2001). In vivo evidence for P-glycoprotein-mediated transport of Phenytoin at the blood-brain barrier in rats. Epilepsia 42:1231-1240.

    Google Scholar 

  • Rizzi, M., Caccia, S., Guisso, G., Richichi, C., Gorter, J., Aronica, E., Aliprandi, M., Begnati, R., Fanelli, R., D'Incalci, M., Samanin, R., and Vezzani, A. (2002). Limbic seizures induce P-glycoprotein in rodent brain: Functional implications for pharmacoresistance. J. Neurosci. 22:5833-5839.

    Google Scholar 

  • Seegers, U., Potschka, H., and Löscher, W. (2002a). Expression of the multidrug transporter P-glycoprotein in brain capillary endothelial cells and brain parenchyma of amygdala-kindled rats. Epilepsia 43:675-684.

    Google Scholar 

  • Seegers, U., Potschka, H., and Löscher, W. (2002b). Transient increase of P-glycoprotein expression in endothelium and parenchyma of limbic brain regions in the kainate model of temporal lobe epilepsy. Epilepsia Res. 52:257-268.

    Google Scholar 

  • Seegers, U., Potschka, H., and Löscher, W. (2002c). Lack of effects of prolonged treatment with phenobarbital or phenytoin on the expression of P-glycoprotein in various rat brain regions. Eur. J. Pharmachol. 45:149-155.

    Google Scholar 

  • Sisodiya, S. M., Lin, W. R., Squier, M. V., and Thom, M. (2001). Multidrug-resistance protein I in focal cortical dysplasia. Lancet 357:42-43.

    Google Scholar 

  • Sisodiya, S. M., Lin, W. R., Harding, B. N., Squier, M. V., and Thom, M. (2002). Drug resistance in epilepsy: Expression of drug resistance proteins in common causes of refractory epilepsy. Brain 125:22-31.

    Google Scholar 

  • Sprince, H., Parker, C. M., Josephs, J. A., Jr., and Magazino J. (1969). Convulsant activity of homocysteine and other short-chain mercaptoacids: Protection therefrom. Ann. N. Y. Acad. Sci. 166:323-325.

    Google Scholar 

  • Sukhai, M., and Piquette-Miller, M. (2000). Regulation of the multidrug resistance genes by stress signals. J. Pharm. Pharm. Sci. 3:268-280.

    Google Scholar 

  • Tishler, D., Weinberg, K., Hinton, D., Barbaro, N., Geralyn, A., and Corey, R. (1995). MDR1 Gene expression in brain of patient with medically intractable epilepsy. Epilepsia 36:1-6.

    Google Scholar 

  • Zhang, L., Ong, W., and Lee, T. (1999). Induction of P-glycoprotein expression in astrocytes following intracerebroventricular kainate injection. Exp. Brain Res. 126:509-16.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Instituto de Biología Celular y Neurociencia, Universidad de Buenos Aires, Buenos Aires, Argentina

    Alberto Lazarowski (Prof. Eduardo De Robertis,” Facultad de Medicina), Alberto Javier Ramos, Alicia Brusco & Elena Girardi

  2. Departamento de Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina

    Alberto Lazarowski (Prof. Eduardo De Robertis,” Facultad de Medicina)

  3. Laboratorio de Anatomía Patológica, Hospital Italiano de Buenos Aires, Argentina

    Hernán García-Rivello

Authors
  1. Alberto Lazarowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alberto Javier Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hernán García-Rivello
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alicia Brusco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elena Girardi
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lazarowski, A., Ramos, A.J., García-Rivello, H. et al. Neuronal and Glial Expression of the Multidrug Resistance Gene Product in an Experimental Epilepsy Model. Cell Mol Neurobiol 24, 77–85 (2004). https://doi.org/10.1023/B:CEMN.0000012726.43842.d2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:CEMN.0000012726.43842.d2

Search

Navigation