Epilepsy is a common chronic neurological disorder that affects more than 50 million people worldwide. 1 Antiseizure drug that serves as the first line of treatment is used to control seizures. However, one-third of patients with epilepsy suffer from drug-resistant epilepsy (DRE) because they fail to achieve control of seizures despite the appropriate treatment schemes used (in monotherapy or various combinations). 2 According to the target hypothesis that explains the drug-resistance phenotype in epilepsy, failure to control epileptic activity by antiseizure medication (ASM) results in losing therapeutic efficacy as a consequence of alterations in the structure and/or function of their targets 3 (Figure 1). In this regard, adopting different therapeutic targets in patients with DRE is crucial, which include alterations in voltage-gated sodium channels (VGSCs) and γ-aminobutyric acid (GABA) receptors.Some studies confirm that resected brain tissue obtained from patients with drug-resistant temporal lobe epilepsy (DR-TLE) who have undergone surgery show reduced sensitivity to carbamazepine, a drug that inhibits VGSC. 4,5 Experimental models have not yet reproduced this condition in DRE. However, studies in models of acute seizures and epilepsy have demonstrated induced alterations in VGSC similar to those detected in brain tissue of patients with the DRE. [6][7][8]

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Recent evidence suggests that P-glycoprotein (P-gp) overexpression mediates hyperexcitability and is associated with epileptogenesis. Transcranial focal electrical stimulation (TFS) delays epileptogenesis and inhibits P-gp overexpression after a generalized seizure. Here, first we measured P-gp expression during epileptogenesis and second, we assessed if TFS antiepileptogenic effect was related with P-gp overexpression avoidance. Male Wistar rats were implanted in right basolateral amygdala and stimulated daily for electrical amygdala kindling (EAK), P-gp expression was assessed during epileptogenesis in relevant brain areas. Stage I group showed 85% increase in P-gp in ipsilateral hippocampus (p < 0.001). Stage III group presented 58% and 57% increase in P-gp in both hippocampi (p < 0.05). Kindled group had 92% and 90% increase in P-gp in both hippocampi (p < 0.01), and 93% and 143% increase in both neocortices (p < 0.01). For the second experiment, TFS was administrated daily after each EAK stimulation for 20 days and P-gp concentration was assessed. No changes were found in the TFS group (p > 0.05). Kindled group showed 132% and 138% increase in P-gp in both hippocampi (p < 0.001) and 51% and 92% increase in both cortices (p < 0.001). Kindled + TFS group presented no changes (p > 0.05). Our experiments revealed that progression of EAK is associated with increased P-gp expression. These changes are structure-specific and dependent on seizure severity. EAK-induced P-gp overexpression would be associated with neuronal hyperexcitability and thus, epileptogenesis. P-gp could be a novel therapeutical target to avoid epileptogenesis. In accordance with this, TFS inhibited P-gp overexpression and interfered with EAK. An important limitation of the present study is that P-gp neuronal expression was not evaluated under the different experimental conditions. Future studies should be carried out to determine P-gp neuronal overexpression in hyperexcitable networks during epileptogenesis. The TFS-induced lessening of P-gp overexpression could be a novel therapeutical strategy to avoid epileptogenesis in high-risk patients.

Transcranial focal stimulation (TFS) is a non-invasive neuromodulation strategy with neuroprotective effects. On the other hand, 6-hidroxidopamine (6-OHDA) induces neurodegeneration of the nigrostriatal system producing modifications in the dopaminergic, serotoninergic, and histaminergic systems. The present study was conducted to test whether repetitive application of TFS avoids the biogenic amines’ changes induced by the intrastriatal injection of 6-OHDA. Experiments were designed to determine the tissue content of dopamine, serotonin, and histamine in the brain of animals injected with 6-OHDA and then receiving daily TFS for 21 days. Tissue content of biogenic amines was evaluated in the cerebral cortex, hippocampus, amygdala, and striatum, ipsi- and contralateral to the side of 6-OHDA injection. Results obtained were compared to animals with 6-OHDA, TFS alone, and a Sham group. The present study revealed that TFS did not avoid the changes in the tissue content of dopamine in striatum. However, TFS was able to avoid several of the changes induced by 6-OHDA in the tissue content of dopamine, serotonin, and histamine in the different brain areas evaluated. Interestingly, TFS alone did not induce significant changes in the different brain areas evaluated. The present study showed that repetitive TFS avoids the biogenic amines’ changes induced by 6-OHDA. TFS can represent a new therapeutic strategy to avoid the neurotoxicity induced by 6-OHDA.