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. 2017 Feb 16;12(2):e0172508.
doi: 10.1371/journal.pone.0172508. eCollection 2017.

Triethylene Glycol, an Active Component of Ashwagandha (Withania Somnifera) Leaves, Is Responsible for Sleep Induction

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Free PMC article

Triethylene Glycol, an Active Component of Ashwagandha (Withania Somnifera) Leaves, Is Responsible for Sleep Induction

Mahesh K Kaushik et al. PLoS One. .
Free PMC article

Abstract

Insomnia is the most common sleep complaint which occurs due to difficulty in falling asleep or maintaining it. Most of currently available drugs for insomnia develop dependency and/or adverse effects. Hence natural therapies could be an alternative choice of treatment for insomnia. The root or whole plant extract of Ashwagandha (Withania somnifera) has been used to induce sleep in Indian system of traditional home medicine, Ayurveda. However, its active somnogenic components remain unidentified. We investigated the effect of various components of Ashwagandha leaf on sleep regulation by oral administration in mice. We found that the alcoholic extract that contained high amount of active withanolides was ineffective to induce sleep in mice. However, the water extract which contain triethylene glycol as a major component induced significant amount of non-rapid eye movement sleep with slight change in rapid eye movement sleep. Commercially available triethylene glycol also increased non-rapid eye movement sleep in mice in a dose-dependent (10-30 mg/mouse) manner. These results clearly demonstrated that triethylene glycol is an active sleep-inducing component of Ashwagandha leaves and could potentially be useful for insomnia therapy.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Oral administration of various extracts from Ashwagandha leaves in mice and their effect on sleep-wakefulness.
(A) Hourly plots of NREM and REM sleep after p.o. administration of vehicle (black circles) or alcoholic extract of Ashwagandha leaves (orange circles; n = 5). (B) Hourly plots of NREM and REM sleep after p.o. administration of vehicle (black circles) or water extracts of Ashwagandha leaves; cyclodextrin extract (blue circle) and water extract (magenta circles; n = 6). Arrows indicate time of p.o. administration. Black and white horizontal bars indicate 12 h dark and 12 h light period. (C) Changes in total amount of NREM (left graph) and REM sleep (right graph) during dark phase after p.o. administration of vehicle (black bars) and various Ashwagandha leaf extracts (colored bars). All administrations were done at the onset of dark period (17:00 h). Data presented as mean ± SEM; *p≤0.05, **p≤0.01 vs vehicle by using paired t-test.
Fig 2
Fig 2. Dose-dependent increase in NREM sleep and decrease in wakefulness by p.o. administration of TEG in mice.
(A, B) Typical examples of EEG delta power (0.5–4 Hz), EMG integral, and hypnograms of a mouse after p.o. administration of vehicle (A) or TEG (B). Hypnograms represent concatenated 10-sec epochs of EEG/EMG activity, scored as wake, REM, and NREM sleep. Three hours after p.o. administration are shown. Wake, REM are shown in gray while NREM sleep shown in black. (C, D and E) Hourly plots of NREM, (C), REM sleep (D) and wake (E) in mice after p.o. administration of vehicle (black circles) and TEG (30 mg/mouse; magenta circles). Significant increase in NREM sleep and decrease in wake are apparent in the graphs at least up to 4 h after TEG administration. Black and white horizontal bars indicate 12 h dark and 12 h light period. (F) Total amount of wake, REM, and NREM sleep over 12 h dark period after vehicle (black bars) and various doses of TEG (colored bars) administration. There was a dose-dependent increase in NREM sleep with concomitant decrease in wake. (G) Graph shows total amount of sleep during dark phase (12 h) following vehicle (black bar) and various doses of TEG (color bars) administration. All administrations were done at the onset of dark period (17:00 h). Data presented as mean ± SEM; n = 6; *p≤0.05, **p≤0.01 vs vehicle by using paired t-test for time course data (C, D and E), and one-way ANOVA followed by least square difference (LSD) post-hoc test for dose-response data (F and G). # #p≤0.01 vs TEG (10 mg/head).
Fig 3
Fig 3. TEG decreased NREM sleep onset latency and induces physiological sleep.
(A), Graph shows changes in NREM sleep onset latency after vehicle (black bar) and various doses of TEG (color bars) administration. (B), Graph shows NREM EEG power density over 12 h dark phase following vehicle (black line) and TEG (magenta line) administration in mice. Data presented as mean ± SEM; n = 6; *p≤0.05, **p≤0.01 vs vehicle by one-way ANOVA followed by least square difference (LSD) post-hoc test.
Fig 4
Fig 4. TEG induces sleep by targeting sleep generation mechanism.
Graphs represent changes in number of episodes (A), stage duration (B) of wake, REM and NREM sleep during 12 h dark phase after p.o. administration of vehicle (black bars) and various doses of TEG (colored bars). (C) Stage transition between wake, REM, and NREM sleep in mice after vehicle or TEG treatment. (D) NREM sleep stage distribution was calculated by averaging various NREM episodes within specific time durations, in mice after vehicle and TEG administration. Data presented as mean ± SEM; n = 6; *p≤0.05, **p≤0.01 vs vehicle; +p≤0.05, ++p≤0.01 vs 10 mg/mouse TEG, by using one-way ANOVA followed by least square difference (LSD) post-hoc test. NR: NREM sleep; W: Wake; R: REM sleep.

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Grant support

This study was supported financially by grant from "Japan Society for the Promotion of Science", KAKENHI grant number 16H01881 to Yoshihiro Urade.
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