MULTIDRUG RESISTANCE PROTEIN-1 (MDR-1) IS ACUTELY ALTERED BY STATUS EPILEPTICUS IN THE DEVELOPING RAT BRAIN
Abstract number :
3.027
Submission category :
Year :
2002
Submission ID :
1595
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Raman Sankar, Ludmila Mazarati, Don Shin, Lucie Suchomelova, Claude Wasterlain, Andrey Mazarati. Pediatrics, UCLA, Los Angeles, CA; Neurology, UCLA, Los Angeles, CA; Research, VA GLAHS, Los Angeles, CA
RATIONALE: MDR-1 has been implicated in antiepileptic drug (AED) resistance. Previous studies have shown the expression of these proteins in the developing rat brain. We examined changes in MDR-1 after status epilepticus (SE) and their possible role on the efficacy of treatment with phenytoin (PHT), administered as fos-phenytoin (FPHT). Our objective is to contribute to a greater understanding of the relationship between MDR and seizures and the potential to alter the expression of these proteins as a new treatment strategy for SE and epilepsy.
METHODS: Two week old Wistar rat pups were pretreated with LiCl (3mEq/kg) followed by pilocarpine (60 mg/kg) the next day to induce SE. Rats were perfused with paraformaldehyde at 1-2 hr, 6 hr and 24 hr after SE. Brains were cut frozen and examined for the presence of the MDR-1 isoform like-immunoreactivity (IR) using routine immunohistochemistry. Another group of rats were injected with FPHT one hr after the start of SE.
RESULTS: Rat pups possessed extensive MDR-1 immunoreactivity in the brain capillaries. In those that underwent SE, however, the labeling seen in the microvasculature of the control animals was almost entirely absent after 1-2 hr and remained so at 6 hr. Immunostaining did not become readily visible in glial-like elements at any time point. Twenty-four hr after SE, MDR-1 expression returned to baseline. Those animals given the MDR-1 dependent drug, PHT, 1 hr after SE showed complete cessation of behavioral seizure activity within 20 min.
CONCLUSIONS: The effectiveness of PHT during the early period of SE provide further evidence that MDR-1 may play a role in resistance to AED therapy. The finding that young animals may be more sensitive, i.e. responsive, to PHT after 1hour of SE may be due to the lack of SE-induced MDR-1 in glia that may serve to act as a drug sink in the mature animal. Since glial MDR-1 expression is not altered by SE in the immature animal that remained responsive to PHT under circumstances when PHT fails in the mature animal, inhibiting expression of this protein may be an area for a new treatment modality to restore responsivity to PHT when SE tends to become refractory to this drug.
[Supported by: The DAPA Foundation, NS13515 from NINDS and the Research Service of the VHA.]