Inhalation Administration of Valerena-4,7(11)-diene from <i>Nardostachys chinensis</i> Roots Ameliorates Restraint Stress-Induced Changes in Murine Behavior and Stress-Related Factors

Abstract

Dried Nardostachys chinensis roots contain sesquiterpenoids that are widely used as herbal tranquilizers. We previously identified the highly sedative sesquiterpenoid valerena-4,7(11)-diene (VLD) from this plant. In the present study, we investigated stress reducing effects of VLD and the associated mechanisms of action. Application of 15-min restraint stresses induced excitatory behaviors in mice. Immobility times in the forced swim test and sleeping times in the pentobarbital sleep test were shortened in the stressed group by 47% and 43%, respectively, compared with the control group. Furthermore, restraint stress increased serum corticosterone levels by 75%, and cerebral serotonin (5-HT) and dopamine (DA) levels. Inhaled VLD (300 µg/cage) suppressed stress-induced excitatory behaviors and significantly reduced stress-induced blood corticosterone, cerebral 5-HT, and DA levels. These results suggest that VLD interacts with the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenomedullary system. These interactions appear to involve GABAergic and D 2 antagonist activities. Moreover, tests in anosmic and intravenously treated mice showed that the sedative effect of inhaled VLD was expressed via olfactory stimulation and pulmonary absorption. Although more studies are required to further elucidate the properties of this compound, our studies suggest that VLD may be an effective anti-stress aromatherapy for humans. Key words Nardostachys chinensis; valerena-4,7(11)-diene; anti-stress effect; inhalationVarious daily stress significantly influence health and may evoke physical disorders such as insomnia and dyspepsia. 1)Anxiolytic or psycholeptic agents are widely used as sedative drugs, but they are associated with problematic side effects such as drug dependence.2) Therefore, as one of the complementary and alternative medicines, aromatherapy has recently attracted significant attention for its ability to ameliorate stress. In our previous study, we identified natural tranquilizing vapors from spikenard extracts, and showed marked sedative effects after inhalation in mice.3) Spikenard, the dried root of Nardostachys chinensis BATAL. (Valerianaceae), which is abundant in sesquiterpenoids, has a long history as an essential ingredient in scented sachets and has been used as a traditional herbal tranquilizer in Asia.4) The hydrocarbon sesquiterpenoids in spikenard, such as tricyclic aristolane type compounds and bicyclic valerena-4,7(11)-diene (VLD), were identified as the active sedative ingredients.5) Among these compounds, VLD showed a particularly profound sedative effect (Fig. 1). Currently, the presence of this compound has only been reported in plants of the Valerianaceae Valeriana species 6) and Nardostachys families. 7)Stressful events give rise to several neurochemical changes that promote emotional and behavioral responses, including sympathetic activities that might facilitate an organism's ability to deal with the stressors and ameliorate adverse consequences.8) Sabban et al. reported that restr...

Ephedrine Alkaloids-Free Ephedra Herb Extract, EFE, Has No Adverse Effects Such as Excitation, Insomnia, and Arrhythmias

“…20) The sleep time of mice administered EHE (700 mg/kg) was significantly shortened, and was much shorter than that of mice administered 20 mg/kg caffeine. The action mechanisms of caffeine and EHE on sleep may be different.…”

“…18) A delay of pentobarbitalinduced sleep onset implies stimulation of the central nervous system, 19) and excessive excitation of the central nervous system causes insomnia. 20) In the electrocardiogram test, we studied the influence of EHE and EFE on cardiac electrophysiology using a radiotelemetry system in mice.…”

Nardostachys chinensis Batalin: A review of traditional uses, phytochemistry, and pharmacology

“…69 is a diterpene; and 70-71 are pentacyclictriterpenoids isolated from roots and rhizomes of N. chinensis (Hwang et al, 2012;Zhang et al, 2007). Valerena-4,7(11)-diene (72) is a sesquiterpinoid reported to possess strong anxiolytic activity (Takemoto et al, 2014). After 12 weeks, LVPWs 2.55 mm and standard drug atorvastatin at 2.68 mg/kg/day for 6 weeks showed LVPWs 1.68 mm After 12 weeks, LVIDd 5.97 mm and standard drug atorvastatin at 16.5 mg/kg/day for 6 weeks showed LVIDd 5.81 mm After 12 weeks, LVIDs 3.86 mm and standard drug atorvastatin at 16.5 mg/kg/day for 6 weeks showed LVIDs 3.82 mm After 12 weeks, IVSd 1.56 mm and standard drug atorvastatin at 16.5 mg/kg/day for 6 weeks showed IVSd 1.52 mm After 12 weeks, IVSs 2.63 mm and standard drug atorvastatin at 16.5 mg/kg/day for 6 weeks showed IVSs 2.83 mm After 12 weeks, LVEF 1.57% and standard drug atorvastatin at 16.5 mg/kg/day for 6 weeks showed LVEF 62.65% After 12 weeks, LVFS 35.19% and standard drug atorvastatin at 16.5 mg/kg/day for 6 weeks showed LVFS 33.98% After 12 weeks, LVW/BW 2.46 mg/g and standard drug atorvastatin at 16.5 mg/kg/day for 6 weeks showed LVW/BW 2.49 mg/g Increased serum NO level to 72 μmol/L from 35 μmol/L and standard drug atorvastatin at (Continues) (Li et al, 1999; 70% increase in NG when administered with 0.3 mM dbcAMP and 20 μM PD980 59.90% increase in NG when administered with 10 nm staurosporine 45% increase in NG when administered with 0.3 mM dbcAMP and 20 μM PD98059 85% increase in NG when administered with 2 ng/ml NGF 25% increase in NG when administered with 2 ng/ml NGF and 20 μM PD98059.12.5% increase in NG when administered with 2 ng/ml NGF and 100 nm GF109203X (PKC inhibitor) Enhanced NGF-induced NG factor from PC12 cells that was blocked by PD98059, a MAPK inhibitor N. chinensis glycoside 100 mg/L In vitro 60% increase in the NG growth in rat pheochromocytoma PC12 cells and 7s NGF showed 65% increase at 100 μg/L (Liu et al, 2005) 200% (% of control) increase in the GAP-43 levels in PC12 cells and 7s NGF showed 250% increase at 100 μg/L…”

Inhibitory Effects of Methanol Extract from Nardostachys chinensis on 27-hydroxycholesterol-induced Differentiation of Monocytic Cells

“…7 Inhalation of dried Nard roots reduced the level of serum corticosterone, a stressrelated hormone, increased by restraint stress causing stress cage. 8 Methanol extract of Nard roots also inhibited lipopolysaccharides (LPS)-stimulated production of nitric oxide (NO) in RAW 264.7 macrophages. 9 These studies suggest that Nard acts as an anti-oxidant and antiinflammatory reagent.…”

“…We think that the Nard extract is composed of various compounds, including sesquiterpenes, as analyzed by previous studies. 6,8 Therefore, it is necessary to determine the active ingredients responsible for the inhibitory effects through further investigations.…”