Locomotor-Reducing Activity of Sesquiterpenes Related to <i>Zingiber zerumbet</i> Essential Oil and Hexahydrozerumbone Derivatives

Abstract

Zerumbone derivatives 1-4 are 11-membered cyclic compounds synthesised from a sesquiterpene zerumbone obtained from the rhizomes of Zingiber zerumbet SMITH (Zingiberaceae). In this study, we investigated the locomotor-reducing effects of hexahydrozerumbone derivatives 1-3 and zerumbol 4, and those of β-caryophyllene 5 and caryophyllene oxide 6, which are present in Z. zerumbet essential oil. The absence of the double bond at C6 weakened the locomotor-reducing effects. β-Caryophyllene 5 and caryophyllene oxide 6 showed locomotor-reducing effects in mice at 4.5 10 3 mg/cage. Moreover, locomotor activity increased significantly at 0.45 mg/cage of caryophyllene oxide 6.Key words hexahydrozerumbone; caryophyllene; locomotor-reducing effect; inhalation Zerumbone obtained from Zingiber zerumbet SMITH (Zingiberaceae) and its derivatives are highly volatile compounds with distinct aromas.1,2) They show locomotorreducing effects when inhaled, and their structure-activity relationships have been investigated.3) The synthesis of hexahydrozerumbone derivatives 1-3, which also have distinct aromas, 1) was achieved by hydrogenation of the C6 double bonds of tetrahydrozerumbone (THZ) derivatives.Takemoto et al. 4) reported locomotor-reducing effects when bicyclic and tricyclic terpenoids are inhaled by mice. Thus, the compounds β-caryophyllene 5 and caryophyllene oxide 6 5) contained in the rhizomes, leaves and flowers of Z. zerumbet, whose structures are similar to zerumbone's structure, could also show locomotor-reducing effects. In this study, the locomotor-reducing effects of the new zerumbone derivatives 1-3 and caryophyllene derivatives 5 and 6 were investigated. Furthermore, the effects of 8-hydroxyl-α-humulene (zerumbol) 4, an expected intermediate in the biosynthesis of zerumbone 6) from α-humulene, were also investigated. MATERIALS AND METHODSMaterials Compounds 1-6 (Fig. 1) were prepared as follows. Hexahydrozerumbone (HHZ) derivatives and zerumbol 1-4 were derived from the starting material zerumbone, which was obtained from the rhizomes of Z. zerumbet SMITH. First, zerumbone was hydrogenated under an H 2 atmosphere using Pd/C in hexane to give 2,3,6,7,10,11-hexahydrozerumbone 1. Compound 1 was reduced with NaBH 4 in ethanol to give hexahydrozerumbol 2. Compound 2 was acetylated with acetic anhydride and pyridine to give hexahydrozerumbyl acetate 3. Racemic zerumbol 4 was obtained by reduction of zerumbone with LiAlH 4 in dry tetrahydrofuran. Compounds 1-4 were each refined to more than 99.9% purity, as evaluated by 1 H-NMR.7) β-Caryophyllene 5 was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan), and caryophyllene oxide 6 was purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). The odourless solvent triethyl citrate used to dissolve and dilute the fragrant compounds for inhalation was purchased from Merck KGaA (Darmstadt, Germany). The reagents used in this study were of the highest grade available.Animals The animal studies were approved by the Animal Research Committee of Kyoto Univer...

Essential Oil from the Leaves of Chromolaena odorata, and Sesquiterpene Caryophyllene Oxide Induce Sedative Activity in Mice

“…As presented in Figure 8, mice locomotor activity was reduced by more than 61% in regard to the control group (p = 0.009). In the same way, β-caryophyllene was also reported sedative in a previous study [28] and more, it demonstrated sedative and anxiolytic activities following oral administration to mice [50]. Comparison with the results of caryophyllene oxide revealed the same double U-shaped curve pattern; however, as β-caryophyllene seems to be more effective at lower doses, this indicated that the existence of an epoxy functional group (Figure 9A) could render the activity less effective in caryophyllene oxide.…”

“…Comparison with the results of caryophyllene oxide revealed the same double U-shaped curve pattern; however, as β-caryophyllene seems to be more effective at lower doses, this indicated that the existence of an epoxy functional group (Figure 9A) could render the activity less effective in caryophyllene oxide. Ogawa et al [28] also previously made similar assertions in their study on Zingiber zerumbet (L.) Roscoe ex Sm. related compounds.…”

“…In the present study, caryophyllene oxide significantly decreased locomotor activity at 0.0004 and 0.04 mg/cage by 56% and 57%, respectively, compared to the control group (F [ 7 , 36 ] = 2.436; p = 0.04) ( Figure 4 ). Likewise, caryophyllene oxide previously induced sedative activity in mice when administered via inhalation at 0.45 mg/cage [ 28 ]. In addition, caryophyllene oxide was a major compound of Baccharis uncinella DC.…”

Inhalation Administration of the Bicyclic Ethers 1,8- and 1,4-cineole Prevent Anxiety and Depressive-Like Behaviours in Mice

“…To further investigate the effects of 1,8-and 1,4-cineole on the CNS, we explored the sedative activity of 1,4-cineole in the OFT. The OFT utilises behavioural changes in rodents exposed to a novel environment and has been used to detect sedative activity in mice [3,14,19,[25][26][27]. Mice administered 1,4-cineole at doses ranging from 4 × 10 −6 to 4 × 10 −1 mg per 400 μL of TEC showed a decrease in locomotor activity at all doses.…”

“…Additionally, Gomes et al [9] performed the OFT for 5 min, whereas we performed it for 60 min. It has been reported that the sedative activity is observed generally 20-30 min after drug administration [3,14,19,[25][26][27]. Moreover, Gomes et al [9] concluded that a higher dose of 1,4-cineole could demonstrate sedative activity because their pentobarbital test indicated a possible sedative effect for 1,4-cineole.…”