The Therapeutic Effects of Low-Frequency Electrical Stimulations Adjunct to Sodium Valproate on Seizure and Behaviors

Introduction: Consuming antidepressant medications induce several problems leading to the need for alternative agents for emotional disturbances. Antidepressant medications increase the seizure risk; thus, alternative treatments, like Antiepileptic Drugs (AED), might be useful for patients with epilepsy comorbid with a psychiatric disorder. The present study evaluated the behavioral effects of sodium valproate, a none effective dose in seizure treatment [100 mg/kg; Intraperitoneal (IP)] along with the application of Low-Frequency Stimulations (LFS) during CA1 hippocampal kindling. Methods: In total, 42 male rats were randomly divided into 6 groups, including control group with intact animals handled daily (I); sham group which was subjected to the surgical process, but received no real stimulation (II); saline-kindled Kindled group (S.kindled) which were stimulated daily with the following protocol: 3 strain of 50Hz monophasic pulses of 1ms duration applied 12 times a day with the threshold intensity at intervals of 10 minutes where saline was administrated 15 min before kindling stimulations (III); saline-kindled-LFS group (K4LFS) in which saline was injected 15 min before kindling stimulations and LFS was applied daily after the termination of kindling stimulation (IV ); drug-kindle group (Drug100.kindled) that underwent rapid kindling procedure daily where sodium valproate (100 mg/kg) was administrated 15 min before kindling stimulations(V), and drug-kindled-LFS (Drug100.kindled.4LFS) group in which drug and LFS were administrated respectively before and after kindling stimulations (VI). The behavioral tests were assessed using elevated plus maze, open field, and forced swim tests.  Results: The combination of sodium valproate (100 mg/kg) and LFS significantly decreased cumulative seizure severity compared with the kindle group. Thus, it provided a strong seizure suppressing effect. Additionally, sodium valproate and LFS increased the percentage of Open Arms (OAs) entries and the OAs exploration; they also decreased jumping from elevated plus maze test and rearing in open field test. Furthermore, there was no significant change in the OAs entries and OAs exploration percentages, jumping from apparatus, and rearing in open field in Drug100. Kindled, K4LFS, and Drug100.kindled.LFS groups, compared with the sham group. There was no significant difference in the latency to first immobility and the duration of immobility in K4LFS groups compared with the S. kindled group. In the drug-kindled group, the latency to first immobility significantly increased, and the duration of immobility decreased, compared with the S. kindled group. Besides, the latency to first immobility significantly increased, and the duration of immobility decreased in drug-kindled-LFS, compared to S. kindled group; however, the latency to first immobility was not significantly changed, compared to drug-kindled groups. Conclusion: Sodium valproate and LFS can modulate the function of the brain regions involved in emotional processing in epilepsy, as well as anxiety- and depressive-like behaviors. Such a combination could also decrease emotional disturbances induced by the kindling process.