Nerolol causes the saprophytic fungus Aspergillus flavus to undergo apoptosis in response to the generation of ROS and Ca2+ overload [1]. Through an apoptosis-like mechanism, nerolidol (NEL)'s antifungal action against the pathogenic fungus Candida albicans, with a minimum inhibitory concentration (MIC) of 4.4 μM, can induce substantial Candida activity [2]. By raising Ca2+ and ROS levels in Candida albicans, nerolidol causes mitochondrial malfunction and destruction [2].

Absorption, Distribution and Excretion
As a part of corresponding study on the effects of test material on the motility of mice (groups of four 4- to 6-week old and 6-month-old female outbred Swiss mice), concentrations of test material in blood samples were determined after inhalation exposure. Air was passed into the cage through a glass tube containing 1.5 mL of test material for a total test material volume of 20-50 mg. Blood samples were taken from the animals after 0, 30, 60 and 90 minutes of inhalation exposure. The concentration of nerol in blood sample 1 hr following inhalation was 5.7 ng/mL.

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Metabolism / Metabolites
Biotransformation of nerol by larvae of the common cutworm (Spodoptera litura) was investigated. The resulting major metabolites were (2Z,6E)-1-hydroxy-3,7-dimethyl-2,6-octadien-8-oic acid and 8-hydroxynerol, and the minor metabolites were 9-hydroxynerol and (2Z,6E)-1-hydroxy-3,7-dimethyl-2,6-octadien-8-al. (2Z,6E)-1-Hydroxy-3,7-dimethyl-2,6-octadien-8-oic acid is a novel compound. The results indicate that biotransformation of nerol by S. litura larvae involved 2 pathways; the main pathway involved oxidation at the methyl group of the geminal dimethyl at C-8 position followed by carboxylation, and the minor pathway involved oxidation at the methyl group of the geminal dimethyl at C-9 position.
The biotransformation of geraniol, nerol and citral by Aspergillus niger was studied. A comparison was made between submerged liquid, sporulated surface cultures and spore suspensions. This bioconversion was also carried out with surface cultures of Penicillium sp. The main bioconversion products obtained from geraniol and nerol by liquid cultures of A. niger were linalool and alpha-terpineol. Linalool, alpha-terpineol and limonene were the main products obtained from nerol and citral by sporulated surface cultures, whereas geraniol was converted predominantly to linalool, also resulting in higher yields. Bioconversion of nerol with Penicillium chrysogenum yielded mainly alpha-terpineol and some unidentified compounds. With P. rugulosum the major bioconversion product from nerol and citral was linalool. The bioconversion of nerol to alpha-terpineol and linalool by spore suspensions of A. niger was also investigated. Finally the biotransformation with sporulated surface cultures was also monitored by solid phase microextraction (SPME). It was found that SPME is a very fast and efficient screening technique for biotransformation experiments.
Allylic alcohols, such as geraniol 1, are easily oxidized by varying mechanisms, including the formation of both 2,3-epoxides and/or aldehydes. These epoxides, aldehydes, and epoxy-aldehydes can be interconverted to each other, and the reactivity of them all must be considered when considering the sensitization potential of the parent allylic alcohol. An in-depth study of the possible metabolites and autoxidation products of allylic alcohols is described, covering the formation, interconversion, reactivity, and sensitizing potential thereof, using a combination of in vivo, in vitro, in chemico, and in silico methods. This multimodal study, using the integration of diverse techniques to investigate the sensitization potential of a molecule, allows the identification of potential candidate(s) for the true culprit(s) in allergic responses to allylic alcohols. Overall, the sensitization potential of the investigated epoxyalcohols and unsaturated alcohols was found to derive from metabolic oxidation to the more potent aldehyde where possible. Where this is less likely, the compound remains weakly or nonsensitizing. Metabolic activation of a double bond to form a nonconjugated, nonterminal epoxide moiety is not enough to turn a nonsensitizing alcohol into a sensitizer, as such epoxides have low reactivity and low sensitizing potency. In addition, even an allylic 2,3-epoxide moiety is not necessarily a potent sensitizer, as shown for 2, where formation of the epoxide weakens the sensitization potential. /Geraniol/

Toxicity Summary
IDENTIFICATION AND USE: Nerol is a colorless oily fluid. Nerol is reported to be found in neroli oil (with geraniol) and in many essential oils. It used as a base for the manufacture of perfumes and in fragrances. HUMAN EXPOSURE AND TOXICITY: A single sensitization test was carried out on 25 volunteers. The material was tested at a concentration of 4% in petrolatum and produced no sensitization reactions. In other study, nerol was utilized in a closed patch test on the back or forearm of 314 subjects for 24-48 hr. Slight erythema was demonstrated in 10 (3.19%) subjects. In an in vitro chromosome aberration test in cultured human lymphocytes nerol was not clastogenic with and without metabolic activation. ANIMAL STUDIES: Eye irritant effects were observed in rabbits. Slight skin irritation was observed in guinea pigs and rabbits. Respiratory irritation was assessed in mice by recording their respiratory rate when exposed to nerol. Mice were exposed to the test material for 1 min using a nebulizer for aerosolization in a 2600 mL chamber. Mild to moderate decrease in the respiratory rate was observed, and the ED25 (dose at which there is a 25% reduction in the respiratory rate) was calculated to be 591 ug /L. Rats (10 males/dose) were administered the test substance at 2560 - 9800 mg/kg and observed for 14 days. The numbers of deaths per dose were 1, 4, 7 and 10 at 2560, 4000, 6250 and 9800 mg/kg-bw, respectively. All deaths occurred within two days of dose administration. Clinical signs in rats included exophthalmia, hyperflexiveness, restlessness, lethargy and loss of righting reflex. Nerol was not mutagenic in Salmonella typhimurium (TA 1535, TA 1537, TA 98, TA 100 and TA 102) with or without activation. In an in vitro mammalian cell gene mutation test with mouse lymphoma cells nerol was not mutagenic at the hprt locus of L5178Y mouse lymphoma cells, in the presence and absence of metabolic activation.

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Interactions
Oral carcinogenesis, a multistep process with multifaceted etiology, arises due to accumulation of heterogeneous genetic changes in the genes involved in the basic cellular functions including cell division, differentiation, and cell death. These genetic changes in the affected cell progressively increase the cell proliferation, angiogenesis, and inhibition of apoptosis. The present study investigated the modulating effect of geraniol on the expression pattern of cell proliferative (PCNA, cyclin D1, c-fos), inflammatory (NF-kappaB, COX-2), apoptotic (p53, Bax, Bcl-2, caspase-3 and -9), and angiogenic (VEGF) markers in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. Topical application of 0.5 % DMBA in liquid paraffin, three times a week, for 14 weeks, developed well-differentiated squamous cell carcinoma (SCC) in the buccal pouch of golden Syrian hamsters. All the hamsters treated with DMBA alone (100 %) developed oral tumors in the buccal pouch after 14 weeks. Over-expression of mutant p53, PCNA, Bcl-2, and VEGF accompanied by decreased expression of Bax were noticed in hamsters treated with DMBA alone. Increased expression of c-fos, COX-2, NF-kappaB, and cyclin D1 and decreased activities of caspase-3 and -9 were also noticed in hamsters treated with DMBA alone. Oral administration of geraniol at a dose of 250 mg/kg bw (body weight) not only completely prevented the formation of oral tumors but also prevented the deregulation in the expression of above mentioned molecular markers in hamsters treated with DMBA. The present results thus suggest that geraniol has potent anti-inflammatory, anti-angiogenic, anti-cell proliferative, and apoptosis-inducing properties in DMBA-induced hamster buccal pouch carcinogenesis. /Geraniol/
Geraniol (GO) potent antitumor and chemopreventive effects are attributed to its antioxidant and anti-inflammatory properties. In the current study, the potential efficacy of GO (250 mg/kg) in ameliorating metabolic syndrome (MetS) induced by fructose in drinking water was elucidated. Moreover, the effect of pioglitazone (5 and 10 mg/kg; PIO) and the possible interaction of the co-treatment of GO with PIO5 were studied in the MetS model. After 4 weeks of treatment, GO and/or PIO reduced the fasting blood glucose and the glycemic excursion in the intraperitoneal glucose tolerance test. GO and PIO5/10 restrained visceral adiposity and partly the body weight gain. The decreased level of peroxisome proliferator activated receptor (PPAR)-gamma transcriptional activity in the visceral adipose tissue of MetS rats was increased by single treatment regimens. Though GO did not affect MetS-induced hyperinsulinemia, PIO5/10 lowered it. Additionally, GO and PIO5/10 suppressed glycated hemoglobin and the receptor for advanced glycated end products (RAGE). These single regimens also ameliorated hyperuricemia, the disrupted lipid profile, and the elevated systolic blood pressure evoked by MetS. The rise in serum transaminases, interleukin-1beta, and tumor necrosis factor-a, as well as hepatic lipid peroxides and nitric oxide (NO) was lowered by the single treatments to different extents. Moreover, hepatic non-protein thiols, as well as serum NO and adiponectin were enhanced by single regimens. Similar effects were reached by the combination of GO with PIO5; however, a potentiative interaction was noted on fasting serum insulin level, while synergistic effects were reflected as improved insulin sensitivity, as well as reduced RAGE and triglycerides. Therefore, GO via the transcriptional activation of PPAR-gamma reduces inflammation and free radical injury produced by MetS. Thereby, these effects provide novel mechanistic insights on GO management of MetS associated critical risk factors. Moreover, the co-administration of GO to PIO5 exalted the antidiabetic drug anti-MetS efficacy. /Geraniol/
In the recent past, several phytoconstituents are being explored for their potential neuromodulatory effects in neurological diseases. Repeated exposure of acrylamide (ACR) leads to varying degree of neuronal damage in experimental animals and humans. In view of this, the present study investigated the efficacy of geraniol (GE, a natural monoterpene) to mitigate acrylamide (ACR)-induced oxidative stress, mitochondrial dysfunction and neurotoxicity in a rat model and compared its efficacy to that of curcumin (CU, a spice active principle with multiple biological activities). ACR administration (50mg/kg bw, i.p. 3times/week) for 4weeks to growing rats caused typical symptoms of neuropathy. ACR rats provided with daily oral supplements of phytoconstituents (GE: 100mg/kg bw/d; CU: 50mg/kg bw/d, 4weeks) exhibited marked improvement in behavioral tests. Both phytoconstituents markedly attenuated ACR-induced oxidative stress as evidenced by the diminished levels of reactive oxygen species, malondialdehyde and nitric oxide and restored the reduced glutathione levels in sciatic nerve (SN) and brain regions (cortex - Ct, cerebellum - Cb). Further, both phytoconstituents effectively diminished ACR-induced elevation in cytosolic calcium levels in SN and Cb. Furthermore, diminution in the levels of oxidative markers in the mitochondria was associated with elevation in the activities of antioxidant enzymes. While ACR mediated elevation in the acetylcholinesterase activity was reduced by both actives, the depletion in dopamine levels was restored only by CU in brain regions. Taken together our findings for the first time demonstrate that the neuromodulatory propensity of GE is indeed comparable to that of CU and may be exploited as a therapeutic adjuvant in the management of varied human neuropathy conditions. /Geraniol/
The present studies were performed to compare the differences between sensitization potency of fragrance mix and its ingredients (oak moss absolute, isoeugenol, eugenol, cinnamal, hydroxycitronellal, geraniol, cinnamic alcohol, alpha amyl cinnamal), by using ex vivo LLNA-BrdU ELISA. The SI and EC3 values were calculated and potency classification was found for the mixture and for each ingredients. TH1 cytokines (IL-2, IFN-?) and TH2 cytokines (IL-4, IL-5) releases from lymph node cell culture were also investigated as contact sensitization endpoints. The EC3 values were calculated and the potency of contact sensitization were classified for fragrance mix, oak moss absolute, isoeugenol, eugenol, cinnamal, hydroxycitronellal, geraniol, cinnamic alcohol, alpha amyl cinnamal respectively: 4.4% (moderate), 3.4% (moderate), 0.88% (strong), 16.6% (weak), 1.91% (moderate), 9.77% (moderate), 13.1% (weak), 17.93% (weak), 7.74% (moderate). According to our results it should be concluded that exposure to fragrance mix does not constitute an evidently increased hazard compared to exposure to each of the eight fragrance ingredients separately. Cytokine analyses results indicate that both TH1 and TH2 cytokines are involved in the regulation of murine contact allergy and can be considered as useful endpoints. /Geraniol/
For more Interactions (Complete) data for Nerol (6 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat Oral 4.5 g/kg
LD50 Rabbit dermal > 5000 mg/kg
LD50 Mouse intramuscular 3000 mg/kg

[1]. Nerol-induced apoptosis associated with the generation of ROS and Ca2+ overload in saprotrophic fungus Aspergillus flavus. Appl Microbiol Biotechnol. 2018 Aug;102(15):6659-6672.

[2]. Nerol triggers mitochondrial dysfunction and disruption via elevation of Ca2+ and ROS in Candida albicans. Int J Biochem Cell Biol. 2017 Apr;85:114-122.

Nerol is the (2Z)-stereoisomer of 3,7-dimethylocta-2,6-dien-1-ol. It has been isolated from the essential oils from plants like lemon grass. It has a role as a volatile oil component, a plant metabolite and a fragrance.
Nerol has been reported in Camellia sinensis, Cymbopogon martinii, and other organisms with data available.
Nerol is a metabolite found in or produced by Saccharomyces cerevisiae.

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Therapeutic Uses
Vet: Antineoplastic and antiviral properties detected against chick lymphoma and avian leukosis in chicks.
Found to be useful as a sedative and spasmolytic agent in doses of 0.01- 1 g.
Vet: Vasodilator action in dogs, rabbits, and mice.
Pharmacology of Nerol: The search for therapeutic agents that will provide the ground for man and an improvement in their quality of life is ceaseless. The nerol (cis-2,6-dimethyl- 2,6-octadien-8-ol) is a monoterpene which can be found in various medicinal plants as Lippia spp and Melissa officinalis L. The objective of this study was to analyze the acute effect of nerol in the central nervous system (CNS) by performing behavioral tests in mice (open field, elevated plus-maze, light/dark and rota rod tests). We used male albino mice (Mus musculus), Swiss variety, adult with 2 month-old. The animals were divided into five groups (n = 8) for each experimental protocol, and they were administered intraperitoneally (i.p.), respectively, Tween 80 0.05% dissolved in saline solution 0.9%, nerol (30, 60 or 90 mg/kg) or diazepam (2 mg/kg). In the open field test, all groups treated with nerol showed a significant decrease in motor activity (number of crossings, rearings and groomings) when compared with vehicle group. In the elevated plus-maze test, nerol groups significantly increased the number of entries and time of permanence in the open arms when compared with vehicle group. In the light-dark test, nerol groups showed a significant increase the time of permanence in the room clear when compared with vehicle group. In the rota rod test, the groups treated with nerol didn't show modification in time spent and number of falls in the revolving bar when compared with vehicle group. These results indicate a possible anxiolytic effect of nerol in mice.
For more Therapeutic Uses (Complete) data for Nerol (8 total), please visit the HSDB record page.

C10H18O

154.253

154.135

106-25-2

643820

Colorless to light yellow liquid

0.9±0.1 g/cm3

229.5±0.0 °C at 760 mmHg

< -10ºC

76.7±0.0 °C

0.0±1.0 mmHg at 25°C

1.471

3.28

1

1

4

11

150

0

O([H])C([H])([H])/C(/[H])=C(/C([H])([H])[H])\C([H])([H])C([H])([H])/C(/[H])=C(\C([H])([H])[H])/C([H])([H])[H]

GLZPCOQZEFWAFX-YFHOEESVSA-N

InChI=1S/C10H18O/c1-9(2)5-4-6-10(3)7-8-11/h5,7,11H,4,6,8H2,1-3H3/b10-7-

(2Z)-3,7-dimethylocta-2,6-dien-1-ol

cis-Geraniol; (Z)-Geraniol; Nerol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~648.30 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (16.21 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (16.21 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (16.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)