Abstracts

Rationale:
Considering that transcranial focal stimulation (TFS) applied via tripolar concentric ring electrodes lessens the high glutamate release during seizure activity, we hypothesized that this neuromodulatory strategy might reduce the P-glycoprotein (Pgp) overexpression and/or function in an experimental model of drug-resistant seizures. We investigated whether this effect was evident after the first convulsive seizure.
Method:
TFS is a non-invasive neuromodulation strategy that reduces the seizure activity in different experimental models. Nevertheless, there is no information about the effects of TFS in the drug-resistant phenotype associated with P-glycoprotein (Pgp) overexpression. The present study focused to determine the effects of TFS on Pgp expression after a single seizure. We also investigated if TFS augments the effects of phenytoin in an experimental model of drug-resistant seizures. Pgp expression was analyzed by western blot in the cerebral cortex and hippocampus of rats receiving 5 min of TFS (300 Hz, 50 mA, 200 μs, biphasic charge-balanced square pulses using a tripolar concentric ring electrode on the scalp prior to administration of 3-mercaptopropionic acid (MPA).  Experiments were also designed to evaluate the seizure activity of animals with drug-resistant seizures receiving TFS alone or associated with phenytoin (75 mg/kg, i.p.).  
Results:
Results: A single administration of MPA induced Pgp overexpression in cortex (68 ± 13.4%, p< 0.05 vs the control group) and hippocampus (48.5 ± 14%, p< 0.05, vs the control group). This effect was avoided when TFS was applied prior to MPA. In animals with drug-resistant seizures, TFS alone did not modify the expression of the convulsive seizures. However, TFS combined with phenytoin reduced the seizure intensity, an effect associated with a lower prevalence of major seizures (50%, p=0.03 vs phenytoin alone). Our experiments demonstrated that TFS avoids the Pgp overexpression induced after a single convulsive seizure. In addition, TFS augments the phenytoin effects in an experimental model of drug-resistant seizures.
Conclusion:
In conclusion, TFS avoids the Pgp overexpression induced by a single seizure and augments the effects of phenytoin in an experimental model of drug-resistant seizures. Therefore, TFS is potentially a new neuromodulatory strategy to revert the drug-resistant phenotype.
Funding:
:National Council of Science and Technology of Mexico (CONACYT) through Scholarship No. 622940 given to DPP