Major vault protein, a marker of drug resistance, is upregulated in refractory epilepsy.
OBJECTIVE
The molecular basis of drug resistance in epilepsy is being explored. Two proteins associated with drug resistance in cancer, P-glycoprotein and multidrug resistance-associated protein 1, are upregulated in human epileptogenic pathologies. Other proteins associated with resistance in cancer include major vault protein (MVP) and breast cancer resistance protein (BCRP). We hypothesized that these proteins would also be upregulated in human epileptogenic pathologies.


METHODS
Hippocampal sclerosis (HS), focal cortical dysplasia (FCD), and dysembryoplastic neuroepithelial tumor (DNT) were studied by using immunohistochemistry for MVP and BCRP. Nonepileptogenic control and histologically normal brain adjacent to epileptogenic tissue were used for comparison.


RESULTS
MVP and BCRP were expressed ubiquitously in brain capillary endothelium. Ectopic upregulation of MVP was seen in hilar neurons in HS, dysplastic neurons in FCD, and lesional neurons in DNT. Only in HS cases were rare extralesional neurons immunoreactive. Glial upregulation was not seen. There was no qualitative upregulation of BCRP.


CONCLUSIONS
These results show that more than one resistance protein may be upregulated in a given epileptogenic pathology and may contribute to drug resistance. Determination of the types, amounts, and distribution of such proteins will be necessary for rational treatment for drug resistance in epilepsy.
Sisodiya
Sanjay M
SM
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, England. sisodiya@ion.ucl.ac.uk
Martinian
Lillian
L
Scheffer
George L
GL
van der Valk
Paul
P
Cross
J Helen
JH
Scheper
Rik J
RJ
Harding
Brian N
BN
Thom
Maria
M
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology; D002196:Capillaries / Q000473:pathology; D002540:Cerebral Cortex / Q000002:abnormalities / Q000473:pathology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004730:Endothelium, Vascular / Q000473:pathology; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D009363:Neoplasm Proteins / Q000235:genetics; D018302:Neoplasms, Neuroepithelial / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010641:Phenotype; D012016:Reference Values; D012598:Sclerosis; D015854:Up-Regulation / Q000235:genetics; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics*; D000099187:Major Vault Protein
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000927:Anticonvulsants; D009363:Neoplasm Proteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C116614:ABCG2 protein, human