Phytohormone abscisic acid boosts pentobarbital-induced sleep through activation of GABA-A, PPARβ and PPARγ receptor signaling

ABSTRACT Background: Sleep disorders induce anxiety and forgetfulness and change habits. The chemical hypnotic drugs currently used have serious side effects and, therefore, people are drawn towards using natural compounds such as plant-based healing agents. Abscisic acid (ABA) is produced in a variety of mammalian tissues and it is involved in many neurophysiological functions. Objective: To investigate the possible effect of ABA on pentobarbital-induced sleep and its possible signaling through GABA-A and PPAR (γ and β) receptors, in male Wistar rats. Methods: The possible effect of ABA (5 and 10 µg/rat, intracerebroventricularly) on sleep onset latency time and duration was evaluated in a V-maze model of sleep. Pentobarbital sodium (40 mg/kg, intraperitoneally) was injected to induce sleep 30 min after administration of ABA. PPARβ (GSK0660, 80 nM/rat), PPARγ (GW9662, 3 nM/rat) or GABA-A receptor (bicuculline, 6 µg/rat) antagonists were given 15 min before ABA injection. Diazepam (2 mg/kg, intraperitoneally) was used as a positive control group. Results: ABA at 5 µg significantly boosted the pentobarbital-induced subhypnotic effects and promoted induction of sleep onset in a manner comparable to diazepam treatment. Furthermore, pretreatment with bicuculline significantly abolished the ABA effects on sleep parameters, while the amplifying effects of ABA on the induction of sleep onset was not significantly affected by PPARβ or PPARγ antagonists. The sleep prolonging effect of ABA was significantly prevented by both PPAR antagonists. Conclusions: The data showed that ABA boosts pentobarbital-induced sleep and that GABA-A, PPARβ and PPARγ receptors are, at least in part, involved in ABA signaling.

摘要
背景：睡眠障碍可引发焦虑、健忘，并改变行为习惯。当前临床使用的化学催眠药物存在严重不良反应，因此人们愈发倾向于使用植物源性治疗剂等天然化合物。脱落酸（Abscisic acid, ABA）可在多种哺乳动物组织中合成，并参与诸多神经生理功能。
目的：探究脱落酸（ABA）对戊巴比妥诱导睡眠的潜在影响，及其通过γ-氨基丁酸A型（GABA-A receptor）受体与过氧化物酶体增殖物激活受体（Peroxisome Proliferator-Activated Receptor, PPAR）β、γ介导的信号通路发挥作用的机制，实验对象为雄性Wistar大鼠。
方法：采用V型迷宫睡眠模型，评估ABA（5与10 μg/只，侧脑室给药）对睡眠潜伏期与睡眠时长的潜在影响。在ABA给药30分钟后，腹腔注射戊巴比妥钠（pentobarbital sodium，40 mg/kg）以诱导睡眠。在ABA注射前15分钟，分别给予PPARβ拮抗剂GSK0660（80 nM/只）、PPARγ拮抗剂GW9662（3 nM/只）或GABA-A受体拮抗剂荷包牡丹碱（bicuculline，6 μg/只）。以地西泮（diazepam，2 mg/kg，腹腔注射）作为阳性对照组。
结果：5 μg剂量的ABA可显著增强戊巴比妥诱导的亚催眠效应，并缩短睡眠潜伏期，其效果与地西泮治疗相当。此外，预先给予荷包牡丹碱可完全抵消ABA对睡眠参数的影响；而PPARβ或PPARγ拮抗剂并不会显著改变ABA对睡眠潜伏期诱导的增强作用。但两种PPAR拮抗剂均可显著阻断ABA的睡眠延长效应。
结论：本研究数据表明，ABA可增强戊巴比妥诱导的睡眠，且GABA-A、PPARβ与PPARγ受体至少部分参与了ABA的信号传导通路。