Major vault protein, a marker of drug resistance, is upregulated in refractory epilepsy
Sisodiya SM, Martinian L, Scheffer GL, van der Valk P, Cross JH, Scheper JR, Harding BN and Thom M;
Commented by , 4 Dec 2003
Background
Vaults are huge intracellular ribonucleoprotein particles, so named because their structure resembles cathedral roof vaults (1).
Vaults are fascinating and still largely mysterious entities. In many tumor types, upregulation of major vault protein (MVP), a major component of vaults, is an excellent predictor and marker of multiple drug resistance (MDR) (2).
Whether vaults could play a role in resistance to antiepileptic drugs (AEDs) is unknown.
Aim
To assess whether MVP and BCRP (breast cancer resistance protein, another protein implicated in drug resistance in cancer patients) are abnormally expressed in the brain of patients with refractory epilepsy.
Methods
MVP and BCPR were evaluated by immunohistochemistry in specimens from epilepsy surgery patients with focal cortical dysplasia (FCD, n=5), hippocampal sclerosis (HS, n=10) and dysembryoplastic neuroepithelial tumour (DNT, n=4).
Specimens from patients operated for non-epilepsy conditions as well as histologically normal brain tissue adjacent to the epileptogenic area were used as controls.
Results
MVP and BCRP were expressed in endothelial cells of both normal and pathological brain tissue. For BCRP, there was no evidence of ectopic upregulation.
MVP was over-expressed in dysplastic neurons in FCD, hilar neurons in HS, and lesional neurons in DNT. Glial upregulation was not seen.
Comments
The ABC (adenosine triphosphate-binding cassette) superfamily of proteins, which include P-glycoprotein (MDR1) and multidrug resistance-associated proteins 1 (MRP1) and 2 (MRP2), have been reported to modulate the transport of phenytoin, phenobarbital, topiramate, valproate, lamotrigine, felbamate and, possibly, carbamazepine, across the blood brain barrier.
Upregulation of these transporters has been observed in human epileptogenic tissue and may limit the access of AEDs to the epileptic focus, resulting in drug resistance (3,4,5,6,7).
With explosion of research in this area, the range of proteins upregulated in refractory epilepsy appears to be broader than originally thought. MVP is the latest newcomer to this growing list. The specific association of MVP with epileptogenic tissue compared with adjacent normal tissue is particularly striking.
Many questions concerning these findings remain to be answered:
- What is causing MVP upregulation? Is it genes, epileptogenesis, seizures, or an interaction of any of the former with AED therapy?
- Does MVP upregulation reflect over-expression of vaults?
- Do vaults play a role in epileptogenesis, AED resistance, or both? If they do, what are the mechanisms involved?
Answering those questions will have important implications. In any case, the complex plasticity of epileptogenic tissues cannot be ignored in therapeutic discovery programmes targeted at modulating resistance-associated proteins (8).
References
1. Scheffer GL, Schroeijers AB, Izquierdo MA et al. Lung resistance-related protein/major vault protein and vaults in multidrug resistance cancer. Curr Opin Oncol 2000;12:550-6
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2. Izquierdo MA, Scheffer GL, Flens MJ et al. Broad distribution of the multidrug resistance-related vault lung-resistance protein in normal human tissues and tumors. Am J Pathol 1996;148:877-87
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3. Potschka H, Fedrowitz M, Loscher W. Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J Pharmacol exp Ther 2003; 306:124-131
4. Potschka H, Fedrowitz M, Loscher W. P-Glycoprotein mediated efflux of phenobarbital, lamotrigine, and felbamate at the blood-brain barrier: Evidence from microdialysis experiments in rats. Neurosci Lett 2002;327:173-6
5. Potschka H, Fedrowitz M, Loscher W. P-glycoprotein and multidrug resistance associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. Neuroreport 2001;12:3557-60
6. Sisodiya SM. Mechanisms of antiepileptic drug resistance. Curr Opin Neurol 2003; 16:197-201
7. Sisodiya SM, Thom M. Widespread upregulation of drug resistance proteins in fatal human status epilepticus. Epilepsia 2003;44:261-4
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8. Sisodiya SM. Mechanisms of antiepileptic drug resistance. Curr Opin Neurol 2003; 16:197-201
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