| Epilepsy is a common chronic neurological disorder characterized by unprovoked and recurrent seizures. In some cases, epilepsy can damage patient’s cognitive function and even lead to personal accidents. Because the complex pathogenesis of epilepsy still remains unclear, clinical antiepileptic drug treatment can not completely control the seizures so that approximately30%cases eventually develop refractory epilepsy (drug-resistant epilepsy). The applications of surgery are limited by its irreversible brain injury and few appropriate candidates. Therefore, treatment of refractory epilepsy remains one of the major problems in epilepsy research.Low frequency stimulation (LFS,1-3Hz) is emerging as a new strategy in recent years with the advantages of adjustability, reversibility and less adverse reactions. Evidences from clinical and animal studies show that LFS at epileptic foci or related structures outside foci can inhibit seizures. However, along with unclear mechanisms of LFS, there are many unresolved important problems worthy of further investigation, such as selection of stimulation targets and optimization of stimulation parameters. Our previous studies found that LFS delieved to the fastigial nucleus, the amygdala and the entorhinal cortex exhibites a very narrow therapeutic time window, which lasts from seconds to tens of seconds, thus restricting its clinical application. Therefore, it is important to determine whether there exists a target without such a time window or with a wider therapeutic window for LFS treatment.The subiculum is the major input and output gateway of the hippocampal CA1-subiculum-entorhinal cortex pathways. Endogenous1Hz interictal discharges also originate from the subiculum, which is considered against seizures. Thus, the subiculum may be an ideal potential target without a therapeutic time window or with a wider therapeutic time window owing to its special interictal firing properties. So we firstly investigate whether LFS at the subiculum has an antiepileptic effect with a wider therapeutic time window in temporal lobe epilepsy model in rats.On the other hand, most studies on LFS were concentrated in assessing its effect on temporal lobe epilepsy rather than refractory epilepsy. Refractory epilepsy differs from other epilepsy in pathological changes and epilepsy network composition, mainly including:1, some histological changes caused by recurrent seizures (such as P-glycoprotein overexpression) weaken the ability of drugs to cross the blood-brain barrier;2, several intracerebral receptors generate tolerance to antiepileptic drugs;3, the sensitivity of some ion channels (especially sodium channels) as targets of antiepileptic drugs is changed;4, the epilepsy network composition and involved loop may change.Therefore, the present study further investigated the EEG features in a refractory epilepsy model induced by phenytoin sodium (PHT) in rats, then we assessed the antiepileptic effect of LFS at the subiculum on refractory epilepsy and whether LFS at the subiculum improves the effect of antiepileptic drugs.1. Wide therapeutic time-window of low-frequency stimulation at the subiculum for temporal lobe epilepsy treatment in rats1Hz LFS delivered to the subiculum before and immediately after the kindling stimulation, or after the cessation of afterdischarge (afterdischarge duration, ADD) decreased the seizure stages and shortened the ADD both in seizure acquisition and expression in amygdaloid-kindled seizures. In addition, even LFS delivered after double ADD duration prolonged the kindling progression. LFS delivered at0.5,3or130Hz, immediately after the cessation of kindling stimulations did not retard the progression of kindling seizures. Pilocarpine-induced spontaneous recurrent seizures were markedly inhibited by1Hz LFS. Thus, these results demonstrate that LFS of the subiculum has a wide therapeutic time-window for temporal lobe epilepsy treatment in rats, suggesting that the subiculum may be a promising and suitable target for clinical application.2. Effect of low frequency electrical stimulation at the subiculum on refractory epilepsy in ratIn a model of drug-resistant epilepsy induced by PHT in rats, the EEG power in normal state was retrospectively analyzed. We found that the1Hz EEG power of animals in non-response group is higher compared with that in response group, suggesting people with higher1Hz EEG power may be more susceptible to develop refractory epilepsy. We found that after the induction of the model of drug-resistant epilepsy was completed, LFS at the subiculum significantly inhibited the incidence of generalized seizures, suppressed the average seizure stage and extended the lantency of generalized seizures in the PHT-resistant animals as well as animals in other groups. These data directly demonstrated that LFS at the subiculum had a significant therapeutic effect on refractory epilepsy. Meanwhile, we also found that both1Hz and3Hz LFS at the subiculum significantly suppressed generalized seizures in PHT-resistant animals, suggesting that3Hz may also be effective and centain changes may happen in the epilepsy network following refractory epilepsy. After LFS treatment, the response to PHT showed a transient improvement in PHT-resistant animals, indicating that LFS at the subiculum may transiently reverse the resistance to PHT in animals with refractory epilepsy.In conclusion, we found that LFS at the subiculum has therapeutic effects on epileptogenesis, generalized seizures and pilocarpine-induced spontaneous epilepsy with a wider therapeutic time window compared with other stimulation targets;1Hz may be the optimal frequency of LFS at the subiculum and the stability of1Hz EEG background activity may be one of the mechanisms of LFS; LFS at the subiculum also suppresses refractory epilepsy and even can transiently reverse drug resistance. In addition to providing a reference for LFS clinical research, our results suggest that the subiculum may be a suitable target for LFS treatment of temporal lobe epilepsy and even refractory epilepsy. |
