MiRNA Profiling And The Role Of MiR-146a In Topiramate Therapy For Temporal Lobe Epilepsy

Background:Epilepsy is one of the most common neurological disorders, characterized by the repeated occurrence of spontaneous bursts of neuronal overactivity, mainstream temporal lobe of epilepsy (TLE) treatment involves the use of anti-epileptic drugs, with topiramate (TPM) being one of the most effective, but the mechanism of TPM on TLE still remains unclear. MiRNAs are short, noncoding RNAs, and it is not only involed in the development of neurons, but also in the development of TLE, but the detail mechanism of it is unknown. At present, we haven’t found any studies which are related with the action of miRNAs on the mechanism of TPM action in TLE, and this afford us an opportunity to find out it. Thus, this study therefore aimed to investigate this by examining the expression profile of miRNAs through the establishment of a TLE rat model using lithium-pilocarpine.Materials and Methods:Rats were divided into four groups:1) control,2) TLE group,3) low dose TPM group (40mg/kg), and4) high dose TPM group (80mg/kg). MiRNAs profiling was detected using gene chip microarray analysis, the morphological changes were observed using H&E staining, and the expression level of caspase-8protein was detected by western blot, immunofluorescence (IF), arid immunohistochemistry (IHC).Results:A total of12miRNAs (miR-146a,-183,-204,-210,-339,-34b,351,-429,-455,466b,-503, and-532) were up-regulated and15(miR-34a,-383,-451,-101a,-488,-499,-300,-551b,-380,-592,-598,-741,-7b,-374, and-9) were down-regulated in TLE rat models compared with control rats. Importantly, these12up-regulated miRNAs were down-regulated, and the15down-regulated miRNAs were up-regulated in both low dose and high dose TPM-treated groups. Of these, miR-146a underwent the greatest change in regulation, indicating that TPM could effectively treat TLE through down-regulating miR-146a expression. Caspase-8was significantly up-regulated in the TLE group, but down-regulated in TPM-treated groups, especially in the low dose group, suggesting that TPM could inhibit the apoptosis of cells in the hippocampus of epileptic patients by down-regulating caspase-8expression. Additionally, we also found the expression of caspase-8protein was lower in low dose TPM when compared with high dose TPM, suggesting that low dose TPM had the better effects. The DG region showed severe damage changes, CA3region is the next, and the death of neurons were significantly decreased after the treatment with TPM via H&E staining, IHC and IF analysis on above four groups, indicating that low dose TPM had better effects compared with the high dose TPM. These results are consistant with the western blot.Conclusions:1) TPM could inhibit the apoptosis of cells in the hippocampus of epileptic patients by down-regulating caspase-8expression;2) miRNAs appear to be involved in the progression of TLE, and miR-146a could be a useful therapeutic target for TLE therapy.