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 Overview
Identification and Uses: Nocacolone is crystalline; however, commercially available products are colorless to pale yellow liquids. It is used in beverages to impart a grapefruit flavor; it is also used in flavor formulations blended with other citrus essential oils. It is a potential bio-based insecticide used to kill ants, termites, mosquitoes, cockroaches, and ticks, including the hard tick (Black-legged Tick), whose bites can transmit bacteria that causes Lyme disease in humans and other animals. Human Exposure and Toxicity: No human data were found. Animal Studies: In a 28-day study, male and female rats were administered nocacolone by gavage at a dose of 10 mg/kg body weight/day. No clinically observable toxicities were reported. Histopathological examination revealed the accumulation of globular eosinophilic material in the renal tubular epithelial cells of male rats administered nocacolone at a dose of 10 mg/kg body weight/day. This finding is consistent with hyaline drop nephropathy, caused by the excessive accumulation of α-2u-globulin in the proximal tubular epithelial cells of the kidney. Accumulation of α-2u-globulin in proximal tubule epithelial cells is considered irrelevant to humans. Ecotoxicity studies: Encapsulation of nocaconone improves its control toxicity against ticks, reduces its volatility, and decreases its phytotoxicity.

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Antidote and First Aid Measures
/SRP:/Immediate First Aid Measures: Ensure adequate decontamination has been performed. If the patient stops breathing, begin artificial respiration immediately, preferably using a machine on demand, bag-valve-mask respirator, or simple breathing mask, following the training instructions. Perform cardiopulmonary resuscitation if necessary. Immediately flush contaminated eyes with running water. Do not induce vomiting. If vomiting occurs, tilt the patient forward or place them in the left lateral decubitus position (head down if possible) to maintain an open airway and prevent aspiration. Keep the patient calm and maintain normal body temperature. Seek medical attention. /Class A and Class B Poisoning/
/SRP:/Basic Treatment: Establish an open airway (using an oropharyngeal or nasopharyngeal airway if necessary). Suction if necessary. Observe for signs of respiratory failure and provide assisted ventilation if necessary. Administer oxygen via a non-invasive ventilation mask at a flow rate of 10 to 15 liters per minute. Monitor for pulmonary edema and treat as necessary… Monitor for shock and treat as necessary… Anticipate seizures and treat as necessary… If eyes are contaminated, flush immediately with water. During transport, continuously flush each eye with 0.9% saline… Do not use emetics. If the patient has ingested the substance, rinse mouth, and if the patient is able to swallow, has a strong gag reflex, and does not drool, dilute with 5 mL/kg to 200 mL of water… After decontamination, cover skin burns with a dry, sterile dressing… /Class A and Class B Poisons/
/SRP:/ Advanced Treatment: For patients with impaired consciousness, severe pulmonary edema, or severe respiratory distress, consider oropharyngeal or nasopharyngeal endotracheal intubation to control the airway. Positive pressure ventilation via bag-valve-mask may be effective. Consider medical treatment for pulmonary edema… Consider using a beta-agonist (e.g., salbutamol) to treat severe bronchospasm… Monitor heart rhythm and treat any arrhythmias as needed… Start intravenous infusion of 5% glucose solution (D5W TKO)/SRP: “Keep patent,” minimum flow rate/. If signs of hypovolemia appear, use 0.9% normal saline (NS) or lactated Ringer's solution (LR). Use caution with fluid administration for hypotension accompanied by signs of hypovolemia. Watch for signs of fluid overdose… Treat seizures with diazepam or lorazepam… Use promecaine hydrochloride to assist eye irrigation… /Toxins 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.

(+)-Nocacolone is a sesquiterpene compound with the structure 4,4a,5,6,7,8-hexahydronaphthyl-2(3H)-one, substituted with methyl groups at positions 4 and 4a, and with an isopropenyl group at position 6 (4R,4aS,6R stereoisomers). It is a plant metabolite, fragrance, and insect repellent. It is a sesquiterpene compound, an enone, and a carbon-bicyclic compound. Nocacolone has been reported in Mandragora autumnalis, Citrus reticulata, and several other organisms with relevant data.

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.)