Anti-inflammatory and analgesic activity based on polymorphism of cedrol in mice

Alternate forms of drug crystals display different physicochemical properties. These include stability, dissolution rate, bioavailability and solubility, which can affect pharmacokinetics and pharmacodynamics. It is therefore important to compare the crystal forms of cedrol to obtain optimal anti-inflammatory and analgesic effects. This study, for the first time, obtained and reports three novel forms (I-III) of cedrol polymorphs. The three forms of cedrol were recrystallized from seven organic solvents by slow cooling or volatilization and identified by thermal analysis, fourier transform infrared spectroscopy, scanning electron microscopy and powder X-ray diffraction analysis. Form I originated from acetone and cyclohexane. Form II was obtained from ethanol, ethyl acetate, acetonitrile and n-hexane. Form III was recrystallized from methanol. The anti-inflammatory and analgesic activities of the three crystalline forms were evaluated by acetic acid induced writhing in mice, the hot plate method, carrageenan induced mouse paw edema models, Xylene-induced mouse ear edema models and cotton pellet-induced mouse granuloma models. Experimental results revealed that the highest performance was achieved from Form I. These findings are of great significance during the early research study of cedrol polymorphs.     

Cedrol restricts the growth of colorectal cancer in vitro and in vivo by inducing cell cycle arrest and caspase-dependent apoptotic cell death

Background: Cedrol is a natural sesquiterpene alcohol found in Cedrus atlantica, which has been proven to have a broad spectrum of biological activities, such as antimicrobial, anti-inflammatory, analgesic, anxiolytic, and anti-cancer effects. However, the underlying anticancer mechanisms and in vivo inhibitory effects of cedrol on colorectal cancer (CRC) have not been elucidated. In the present study, we investigated the anti-CRC potential of cedrol using in vitro and in vivo models.Methods: The effects of cedrol on cell viability, cell cycle progression, and apoptosis of HT-29 and CT-26 cells were detected by MTT, flow cytometry, and TUNEL assays. Western blotting was used to measure protein expression for molecular signaling analyses.Results: Cedrol inhibited HT-29 and CT-26 cell proliferation in a time- and dose-dependent manner, with IC₅₀ values of 138.91 and 92.46 µM, respectively. Furthermore, cedrol induced cell cycle arrest at the G0/G1 phase by regulating the expression of cell cycle regulators, such as CDK4 and cyclin D1, and triggered apoptosis through extrinsic (FasL/caspase-8) and intrinsic (Bax/caspase-9) pathways. In addition, cedrol in combination with the clinical drug 5-fluorouracil exhibited synergistic inhibitory effects on CRC cell growth. Importantly, cedrol treatment suppressed the progression of CRC and improved the survival rate of animals at a well-tolerated dose.Conclusion: These results suggest that cedrol has an anti-cancer potential via induction of cell cycle arrest and apoptosis, and it could be considered as an effective agent for CRC therapy.     

Involvement of the dopamine D1 receptor system in the anxiolytic effect of cedrol in the elevated plus maze and light–dark box tests

Cedrol, mainly derived from Juniperus virginiana L. essential oil, has been demonstrated the anxiolytic effect, although its mechanism of action is still not fully established. In the present study, male ICR mice were submitted to the elevated plus maze (EPM) and light–dark box (LDB) tests to investigate the putative mechanism of anxiolytic effect. WAY100635 (5-HT_1A receptor antagonist), flumazenil (benzodiazepine receptor antagonist), SCH23390 (dopamine D₁ receptor antagonist) or sulpiride (dopamine D₂/D₃ receptor antagonist) were used in the behavioral experiment to determine the mechanism of action of cedrol. Subsequently, the monoamine neurotransmitter levels were evaluated after behavioral tests. The data suggest that no significant effect in behavioral parameters were observed after sole intraperitoneal (i.p.) injection of antagonists compared to saline group. The anxiolytic effect of cedrol in behavioral procedures was blocked by either WAY100635 or flumazenil. The anxiolytic effect of cedrol (1200 mg/kg) was effectively antagonized by SCH23390 (0.125 mg/kg). Furthermore, cedrol decreased the DA and NE levels in hippocampus, striatum and hypothalamus. The present findings suggest that the dopaminergic system (D₁ receptor) rather than serotoninergic or GABAergic system may potentially be involved in the modulation of cedrol-induced anxiolytic-like behaviors in mice.     

Bioconversion of Mono- and Sesquiterpenoids by Recombinant Human Cytochrome P450 Monooxygenases

Cytochrome P450 monooxygenases play an important role in the biosynthesis and metabolism of terpenoids. We explored the potential of recombinant human liver cytochrome P450 monooxygenases CYP1A2, CYP2C9, and CYP3A4, heterologously expressed in Escherichia coli, to convert mono- and sesquiterpenoids to human metabolites. This natural product group is a diverse class of secondary metabolites and includes several industrially and pharmaceutically interesting compounds. Incubation of cedrol with CYP3A4 resulted in a bioconversion of 74% (±8.9%) after 1 h of the unknown metabolites 2-hydroxycedrol and 4-hydroxycedrol, which have been structurally elucidated by ¹H and ¹³C NMR and GC-MS. We conclude that recombinant human cytochrome P450 enzymes can be useful tools in a combinatorial biosynthesis strategy for the production of new natural products and for in vitro metabolization studies.     

Hair growth promoting activity of cedrol isolated from the leaves of Platycladus orientalis

Platycladus orientalis (L.) Franco is traditionally known to potentiate hair growth promotion. However, there has been no report on its main active ingredient responsible for the hair growth activity. In the current work, cedrol as a major constituent from P. orientalis was evaluated for its potential on hair growth in vivo. Different concentrations of cedrol (10, 20 and 30 mg/mL) were applied topically over the shaved skin of C57BL/6 mice and monitored for 21 days. Results indicated that cedrol significantly promoted hair growth in a dose-dependent manner, particularly for the female mice. Both male and female mice groups treated with 30 mg/mL cedrol required shorter time than the blank control and 2% minoxidil groups at different growth stages. Compared with the blank control (8.87 mm) and 2% minoxidil (9.94 mm) groups at 21 days, the hair length of female mice treated with 30 mg/mL cedrol showed a remarkable increase with the value of 11.07 mm. Hair in male and female mice groups treated with 30 mg/mL cedrol was heavier than the 2% minoxidil (38.2 and 35.9 mg, respectively) groups with the weight of 42.6 and 45.2 mg, respectively. Further observation of the hair follicle demonstrated that cedrol exerted a remarkable effect on the hair follicle length. These findings suggested that cedrol may be the main active ingredient of P. orientalis and have the potential of becoming a new hair growth promoter.     

Preventive effects of cedrol against alopecia in cyclophosphamide-treated mice

Although numerous hypotheses have been proposed to prevent chemotherapy-induced alopecia (CIA), effective pharmaceuticals have yet to be developed. In our study, the back hairs of C57BL/6 mice were factitiously removed. These mice were then treated with cedrol or minoxidil daily. Mice with early-stage anagen VI hair follicles were treated with cyclophosphamide (CYP, 125 mg/kg) to induce alopecia. The CYP-damaged hair follicles were observed and quantified by using a digital photomicrograph. The results demonstrated that the minoxidil-treated mice suffered from complete alopecia similar to the model 6 days after CYP administration. Simultaneously, the cedrol-treated (200 mg/kg) mice manifested mild alopecia with 40% suppression. Histological observation revealed that anagen hair follicles of the cedrol-pretreated mice (82.5%) likely provided from damage compared with the sparse and dystrophic hair follicles of the model mice (37.0%). Therefore, the use of topical cedrol can prevent hair follicle dystrophy and provide local protection against CIA.