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Epilepsy is a chronic neurological disorder that affects more than 50 million people worldwide. Despite a recent introduction of antiseizure drugs for the treatment of epileptic seizures, one-third of these patients suffer from drug-resistant epilepsy (DRE). The therapeutic target hypothesis is a cited theory to explain DRE. According to the target hypothesis, the failure to achieve seizure freedom leads to alteration of the structure and/or function of the antiseizure medication (ASM) target. However, this hypothesis fails to explain why patients with DRE do not respond to antiseizure medications of different targets. This review presents different conditions, such as epigenetic mechanisms and protein-protein interactions that may result in alterations of diverse drug targets using different mechanisms. These novel conditions represent new targets to control DRE.

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.