Widespread upregulation of drug-resistance proteins in fatal human status epilepticus.
OBJECTIVE
Accumulating evidence implicates drug-transporter proteins ABCB1 and ABCC1 in resistance to multiple antiepileptic drugs (AEDs) in refractory epilepsy. These proteins are upregulated in surgically resected human brain tissue containing epileptogenic pathologies, including cortical dysplasia. In surgically resected cases, no upregulation is seen in normal adjacent tissue, suggesting that neither seizures nor prolonged exposure to AEDs need induce ABCB1 or ABCC1 expression. We wished to determine if status epilepticus might cause upregulation of these proteins.


METHODS
Immunohistochemistry was performed for ABCB1 and ABCC1 in postmortem human brain tissue from a patient who died in status epilepticus and was found to have unihemispheric cortical dysplasia.


RESULTS
There was upregulation of both proteins, as expected, in the hemisphere containing dysplasia. There also was widespread upregulation of both proteins in glia from the normal hemisphere. Previous work shows that drug treatment does not cause such upregulation.


CONCLUSIONS
Upregulation of these proteins in histologically normal brain tissue is most likely the result of seizures in status, as seen in animal models. The findings provide a possible explanation for the appearance of AED resistance in prolonged status and emphasise the importance of prompt treatment of status epilepticus.
Sisodiya
Sanjay M
SM
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, England. sisodiya@ion.ucl.ac.uk
Thom
Maria
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002540:Cerebral Cortex / Q000002:abnormalities / Q000473:pathology; D004292:Dominance, Cerebral / Q000502:physiology; D018432:Drug Resistance, Multiple / Q000502:physiology*; D004359:Drug Therapy, Combination; D004830:Epilepsy, Tonic-Clonic / Q000188:drug therapy / Q000473:pathology*; D017809:Fatal Outcome; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000473:pathology; D012016:Reference Values; D013226:Status Epilepticus / Q000188:drug therapy / Q000473:pathology*; D015854:Up-Regulation / Q000502:physiology
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1