Antioxidant; anti-inflammatory

(+)-nootkatone is a sesquiterpenoid that is 4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one which is substituted by methyl groups at positions 4 and 4a, and by an isopropenyl group at position 6 (the 4R,4aS,6R stereoisomer). It has a role as a plant metabolite, a fragrance and an insect repellent. It is a sesquiterpenoid, an enone and a carbobicyclic compound.

In behavioral tests including the Morris water maze and Y-maze, the Nootkatone (10 mg/kg) group did well. Nootkatone (10 mg/kg) reversed the effects of LPS-induced neuronal degeneration and astrocyte activation, particularly in the hippocampus, according to the results of histological inspection and immunohistochemistry analysis. These inflammatory cytokines' elevated expression was decreased by ELISA (10 mg/kg) [1].

Neuroinflammatory responses play a crucial role in the pathogenesis of Alzheimer's disease (AD). Our previous study demonstrated that petroleum ether extracts from Alpiniae Oxyphyllae Fructus(AOF) could attenuate lipopolysaccharide (LPS)-induced learning and memory impairment in mice, which could be associated with its inhibitory effect on neuroinflammation. Therefore, our present study is to investigate the potential therapeutic neuroprotective effects of nootkatone (NKT) on an AD mouse model induced by intracerebroventricular injection of LPS. We found that NKT (10 mg/kg) group showed good performance in behavior experiments including Y-maze test and Morris water maze test. The results of histopathological examination and immunohistochemical analysis showed that LPS induced degeneration of neurons and activation of microglia particularly in hippocampus and NKT (10 mg/kg) reversed these changes. Enzyme linked immunosorbent assay and western blot analysis also demonstrated that the model group had increased expression of IL-1β, IL-6, TNF-α, NLRP3 and NF-κB p65, especially in hippocampus relative to sham-operated group, and NKT (10 mg/kg) decreased the high expression of these inflammatory cytokines. Collectively, these data indicated that LPS-induced learning and memory impairments in mice could be improved by NKT, which was associated with attenuating neuroinflammatory responses. Our study indicated that NKT could act as a potential therapeutic agent for the treatment of neuroinflammation and AD.[1]

Toxicity Summary
IDENTIFICATION AND USE: Nootkatone forms crystals; however, commercial product is a colorless to yellowish liquid. It is used in beverages to impart grapefruit flavor; in fragrance compositions with other citrus oils. Potential bio-based pesticide to kill ants, termites, mosquitoes, cockroaches, and ticks, including Ixodes scapularis (blacklegged tick), whose bite can transmit bacteria that cause Lyme disease in humans and other animals. HUMAN EXPOSURE AND TOXICITY: No human data were found. ANIMAL STUDIES: In a 28-day study, rats (male and female) were given nootkatone at a dose of 10 mg/kg bw per day by oral gavage. No clinically observable signs of toxicity were reported. Histopathological examination revealed accumulation of globular eosinophilic material in the tubular epithelium of male rats treated with nootkatone at a dose of 10 mg/kg bw per day. This finding is consistent with the presence of hyaline droplet nephropathy, which results from the excessive accumulation of alpha-2u-globulin in renal proximal tubular epithelial cells. Accumulation of alpha-2u-globulin in the proximal tubular epithelium is considered to be of no relevance to humans. ECOTOXICITY STUDIES: Encapsulation of nootkatone improved toxicity for tick control, reduced nootkatone volatility, and reduced plant phytotoxicity.

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Antidote and Emergency Treatment
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

[1]. Nootkatone, a neuroprotective agent from Alpiniae Oxyphyllae Fructus, improves cognitive impairment in lipopolysaccharide-induced mouse model of Alzheimer's disease. Int Immunopharmacol. 2018 Sep;62:77-85.

(+)-nootkatone is a sesquiterpenoid that is 4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one which is substituted by methyl groups at positions 4 and 4a, and by an isopropenyl group at position 6 (the 4R,4aS,6R stereoisomer). It has a role as a plant metabolite, a fragrance and an insect repellent. It is a sesquiterpenoid, an enone and a carbobicyclic compound.
Nootkatone has been reported in Mandragora autumnalis, Citrus reticulata, and other organisms with data available.

C15H22O

218.3346

218.167

4674-50-4

1268142

White to yellow solid

1.0±0.1 g/cm3

318.6±42.0 °C at 760 mmHg

35-39ºC

142.1±18.7 °C

0.0±0.7 mmHg at 25°C

1.503

3.84

0

1

1

16

364

3

O=C1C([H])=C2C([H])([H])C([H])([H])[C@@]([H])(C(=C([H])[H])C([H])([H])[H])C([H])([H])[C@@]2(C([H])([H])[H])[C@]([H])(C([H])([H])[H])C1([H])[H]

WTOYNNBCKUYIKC-JMSVASOKSA-N

InChI=1S/C15H22O/c1-10(2)12-5-6-13-8-14(16)7-11(3)15(13,4)9-12/h8,11-12H,1,5-7,9H2,2-4H3/t11-,12-,15+/m1/s1

(4R,4aS,6R)-4,4a-dimethyl-6-prop-1-en-2-yl-3,4,5,6,7,8-hexahydronaphthalen-2-one

NOOTKATONE; (+)-Nootkatone; 4674-50-4; Nootkanone; (+/-)-Nootkatone; Nootkatone, (+/-)-; Nootkatone (+/-)-form [MI]; UNII-3K3OKV2A5A;

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 (~458.02 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (11.45 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 (11.45 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 (11.45 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.)