Valproate Exhibits Both Hypnotic, Antiepileptic Properties During Sleep

Valproate, a common drug for treating epilepsy, may help improve sleep quality and quality of life for patients with nocturnal epilepsy, according to an animal study published in Physiology & Behavior.

Nocturnal epilepsy can have a significant impact on sleep, and many antiepileptic drugs can alter the structure of sleep. Pentylenetetrazol (PTZ) is an inducting agent for generalized epileptic seizures in animal studies and serves as a way to evaluate the efficacy of antiepilieptic drugs in basic research. Generalized convulsions produced using PTZ administration impacts sleep structure by reducing the amount of rapid eye movement (REM) sleep and non-REM sleep (NREM).

Valproate is a second-generation antiepileptic medication that facilitates the syntesis and release of gamma-aminobutyric acid. In other animal analyses, valproate has shown to inhibit effects again convulsions induced by electric shock, kindling, or PTZ administration. Although the drug is widely used in the treatment of human patients with epilepsy, it is unclear whether it has an effect on sleep alterations produced by PTZ-induced convulsions.

The researchers evaluated 18 male adult Wistar strain rates weighting between 350 g and 400 g.The animals were placed in a soundproof chamber with a temperature range between 21℃ and 25℃. Water and food were available 24 hours a day. The rates were assessed over 3 consecutive days and were separated into 2 groups. Day 1 was a control day.

On day 2, one group received 50 mg/kg of PTZ alone and the other group was administered 60 mg/kg valproate prior to PTZ. The researchers recorded the results for 10 hours during a Grass model 7 polygraph at a paper speed of 2.5 mm/s. The statistical analysis was conducted using the Shapiro-Wilk test, with nonparametric tests used for when variables did not have a normal distribution. The vigilance states of the 3 days were compared using the Freidman test for mean ranks.

In the valproate treated group, the latency of epileptic episodes (SD) was significantly higher than the PTZ alone group, 1095.71 (49.56) vs 55.00 (1.80) sec, respectively. The valproate group also had both fewer and shorter epileptic episodes than the PTZ alone group.

Compared to the control day, NREM sleep latency was lengthened in the PTZ alone group and shortened in the valproate group. In addition, REM sleep latency was prolonged in the PTZ alone group and shortened in the valproate group. The number of REM sleep episodes (SD) was decreased from 43.00 (8.90) episodes to 4.00 (3.50) episodes in the PTZ alone group and increased to 38.00 (11.00) episodes in the valproate group.

The amount of time the rats experienced wakefulness was significantly higher in the PTZ alone group (Z = 3.60; P < .001). REM sleep was significantly higher in the valproate and PTZ cohort (Z = 3.6; P < .001).

The study authors noted that changes in the vigilance states triggered by PTZ-induced epilepsy were less intense in the rats treated by valproate compared to the other group, suggesting that valproate may have a protective effect on sleep when administered 2 hours prior to PTZ administration.

Additionally, the plasmatic concentration of valproate reaches a maximum of 1 to 4 hours after administration, with a half-life of 9 to 15 hours and therapeutic effects lasting for several more hours. The authors said that this could explain valproate’s inhibitory action on the intensity of epilepsy observed on day 2 of the study as well as the hypnotic effect that reduced wakefulness and increased NREM and REM sleep.

“The results obtained in this study indicate that valproate has an inhibitory action on epileptic activity, in addition to favoring the activation of the regulatory mechanisms of sleep…. In accordance with other authors, the inhibition of epilepsy by valproate could be due to its action on the pontis oralis nucleus, and thus, it could facilitate the activation of sleep mechanisms,” the authors wrote.

Reference

Ayala-Guerrero F, Castro-Domíngues D, Mateos-Salgado EL, Maxicano-Medina G, Gutiérrez-Chávez CA. Effect of valproate on sleep patterns disturbed by epilepsy. Physiol. Behav. Published online December 9, 2022. Accessed January 20, 2023. doi: 10.1016/j.physbeh.2022.114054