Epilepsia 46 Suppl. 8 :110 (Abst. 2.056 ), 2005
SEIZURE BLOCKADE WITH ETHOSUXIMIDE NORMALIZES Nav1.1, Nav1.6, AND HCN1 CHANNEL EXPRESSION IN EPILEPTIC WAG/Rij RATS
Authors: 1,2,3Joshua P. Klein, 1Ulrich Schridde, 1Hrachya Nersesyan, 1Ravi K. Agarwal, 1April R. Levin, 1-4Stephen G. Waxman, and 1,4Hal Blumenfeld
Abnormal rhythmic oscillatory burst firing between cortical and thalamic neurons underlies the spike wave discharges (SWDs) seen in absence epilepsy. Prior studies in the WAG/Rij rat model of absence epilepsy have shown changes in ion channel expression that may contribute to enhanced cortical excitability. Sodium channels Nav1.1 and Nav1.6 are upregulated, and the hyperpolarization-activated cation channel HCN1 is downregulated, within neurons of the somatosensory cortex in untreated epileptic WAG/Rij rats. It is not known whether these changes are a primary cause, or rather an effect, of chronic epilepsy. We therefore studied expression of Na channels and HCN1 after chronic seizure blockade with ethosuximide (ETX).
24 WAG/Rij rats were compared to 24 age-matched non-epileptic Wistar control rats. Half (12 animals) from each group were treated with 300 mg/kg/d ETX PO for three months beginning at P21. Continous EEG data was recorded from skull electrodes to quantify total seizure time. ETX levels were measured at the time of perfusion and brains were analyzed by immunocytochemistry to identify changes in protein expression of Nav1.1, Nav1.6, and HCN1.
Therapeutic ETX levels were achieved and resulted in blockade of SWDs in all WAG/Rij rats. Protein levels of Nav1.1 and Nav1.6 were up-regulated in layer II-IV neurons of the somatosensory cortex in the untreated WAG/Rij rats, and were decreased to control levels in ETX-treated WAG/Rij rats. Protein expression of HCN1 was decreased in untreated WAG/Rij animals and increased to control levels in ETX-treated WAG/Rij rats in this brain region. Wistar rats treated with ETX showed no change in expression of Nav1.1, Nav1.6, or HCN1 compared to untreated Wistar rats or ETX-treated WAG/Rij rats.
The neuronal expression of Nav1.1, Nav1.6, and HCN1 is altered in WAG/Rij rats. Blocking seizure activity by treatment with ETX results in a normalization of expression of these channels to levels seen in non-epileptic Wistar rats. These results suggest that abnormal changes in ion channel expression associated with chronic epilepsy may be blocked under certain conditions by long-term use of anticonvulsant medications. (Supported by The Medical Research Service and Rehabilitation Research Service, Department of Veterans Affairs, and by grants from the Paralyzed Veterans of America and the United Spinal Association (to S.G.W.); and by NIH NS 049307 and the Blattmachr Fund (to H.B.). J.P.K. is supported by the NIH Medical Scientist Training Program.)
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