| Epilepsy is a common chronic neurological disorder. Despite treated by a variety of antiepileptic drugs, approximately 30% of patients continue to have seizures. They become intractable epilepsy, which is very common in temporal lobe epilepsy (TLE). However, the pathogenesis of epilepsy is still unclear, and the results of drug treatment and surgical treatment for TLE are far from satisfactory. Therefore, investigating the pathogenesis and effective treatment of epilepsy are urgently needed.Neuroplasticity plays an important role in epileptogenesis. Epilepsy is currently considered to be the development of abnormal neural networks inducing by interaction between normal neural plasticity and risk factors. Early development period is crucial for the formation of neural networks. Thus the event happened during early developmental period may play a very important role in the formation of epileptic networks. Complex febrile seizures (FSs) are common during early developmental period, and it closely related with TLE. Clinical retrospective studies have found that a considerable portion of temporal lobe epilepsy patients experienced FSs. In addition, animal studies showed that although FSs cause only 35-45% of TLE in rats, subdose (5 mg/kg) kainic acid (KA, a agonist of KA receptors, used as an epileptic agents) can lead to seizures in all rats that experienced FSs, indicating that FSs may cause increased susceptibility to seizures. However, it is still unknown that whether the increase of seizure susceptibility induced by FSs is a common phenomenon, and whether this phenomenon can maintain for long duration. Furthermore, the relationship between this phenomenon and non-familial epilepsy is unknown. These all suggest that the pathogenesis of epilepsy is very complex.The complexity of the pathogenesis determines that current drug therapy and surgical treatment is not satisfactory. Therefore, we investigated the effect of low-frequency stimulation (LFS) as a new strategy for the treatment of epilepsy. LFS, because of its advantages of reversibility and adjustability, is emerging as a new option for the treatment of intractable epilepsy. The effect of LFS treatment for intractable epilepsy is still unclear. Research has focused on the choice of targets and the improvement of parameters. In addition, the importance of stimulation pattern has been found recently. Among which, our previous studies have found that:LFS delivered to the cerebellar fastigial nucleus achieve therapeutic effect when given immediately after electrical stimulation, whereas there is no treatment effect when given after the cessation of afterdischarge, suggesting the existence of time-dependent effect. However, it is still unknown whether it is a general phenomenon, especially for the LFS of epileptic focus. If this phenomenon does generally exist, it is potentially important for designing the LFS protocol in the clinic.Therefore, this study investigated the long-lasting effect of FSs and the influence of FSs to the future offspring, and using amygdaloid-kindling seizure as a temporal lobe epilepsy model to investigate the time-dependent effect of LFS in kindling focus.1. Enhanced susceptibility and its transgenerational transmission after complex febrile seizure in ratsExposure of rat pups to a hyperthermic environment (44±2?) induced FSs and the ictal EEGs were recorded. One-year-old rats (FO) that had experienced showed higher scores to maximum electric shock seizures (MES,65mA,0.2 s,50 Hz), suggesting that FSs increased susceptibility to seizures maintained for at least a year in rats. Offspring (F1) were raised in a conventional environment for about 90 days and then the susceptibility to MES seizures was compared with that of F1 rats whose parents had not experienced FSs. Offspring of FSs rats also displayed higher susceptibility to MES(40 mA,0.2 s,50 Hz) although they did not experience FSs, indicating that FSs induced enhancement of susceptibility to seizures can be passed to the naive offspring; in the same way the third generation (F2) animals were also test by MES (40 mA,0.2 s,50 Hz), and results showed that the susceptibility of F2 rats to MES were not statistically different from F2 rats whose grandparents did not experienced FSs, indicating that the effect of FSs was almost completely lost by the third generation. Different intensity of FSs in F0 rats resulted in positively correlating effects on F1 rats, indicating that the transmission of enhanced susceptibility caused by FSs had the characteristics of severity-dependent. FSs mothers were mated with non-FSs fathers and vice versa, to reveal which parent contributes to the transmissional phenomenon. Results showed that the transmission was through the mother because only when she experienced FSs did her offspring display higher MES scores. We then investigated whether the transgenerationl effect existed in other seizures models or not. Result showed that the susceptibility to kainate-induced seizures was higher in the offspring of FSs group than offspring of control rats, whereas offspring of FSs rats did not show significant difference in PTZ seizures compared with offspring of control rats. Therefore, the transgenerational transmission showed model-dependent characteristics. Our results show that FSs in immature not only lead to increased susceptibility to seizures in F0 generation but also cause increased susceptibility in the next generation.2. Time-dependent effect of low-frequency stimulation on amygdaloid-kindling seizures in ratsIn kindling animals, LFS (15 min train of 0.1 ms per pulses,100 A) delivered immediately after cessation of the kindling stimulus (1 s train of 1 ms pulses at 60 Hz and 100-300 A) inhibited the seizure stage during kindling acquisition, whereas LFS delivered after the cessation of afterdischarge accelerated the kindling progression to stages 1 and 2, indicating that whether LFS prolonged the progression of epileptogenesis depend on when to deliver LFS. In fully kindled animals, when using the generalized seizure threshold current as the kindling stimulus, immediate LFS decreased the incidence of generalized seizures and the average seizure stage as well as shortened the cumulative generalized seizure duration (GSD), whereas delayed LFS prolonged the cumulative GSD and afterdischarge duration, indicating that whether LFS inhibited the generalized seizures also depend on when to deliver LFS. Thus, our study indicates that there is a time-dependent aspect of LFS treatment, and immediate LFS has anti-epileptogenic action. We show that the effect of LFS on seizures can be significantly changed if stimulation is delivered at a different time point.In conclusion, our study demonstrates the complexity of the pathogenesis:the enhanced susceptibility of seizures after acquired FSs can transmitted to their offspring through the mother and the transgenerational transmission shows severity-dependent and model-dependent characteristics, suggesting epigenetic effect on the epileptogenesis. For therapeutic strategy, the effects of LFS delivered to a kindling site depend on when the stimulation is administered, suggesting the existence of "time window" for LFS treatment. It is important for designing the LFS protocol in the clinic. |
PDF Full Text Request