The CNS action of saffron is believed to be attributed to crocetin, a metabolite that is obtained from the crocin carotenoid and has been demonstrated to have a significant affinity for NMDA receptors. The activity of Caco-2 cells was measured by the MTT assay after 24 hours of incubation of cellular mitochondrial dehydrogenase with test compounds: hydroalcoholic saffron extract (SE, 0.5-1 mg/mL) and crocin-1 (250-1000 µM) did not show significant changes in cell viability with negative results. This was done to ensure that the viability of Caco-2 cells remained unchanged throughout the transport experiment. Cell viability is unaffected by crocetin at concentrations of 10 µM, but is considerably decreased at 40–160 µM [1].

Interactions
This study used a pentylenetetrazole (PTZ)-induced mouse seizure model to evaluate the anticonvulsant activity of saffron stigma components saffronaldehyde and Crocetin. Saffronaldehyde (0.15 and 0.35 mL/kg, intraperitoneal injection) shortened seizure duration, delayed the onset of tonic-clonic seizures, and protected mice from death. Crocetin (200 mg/kg, intraperitoneal injection) showed no anticonvulsant activity. /Saffronaldehyde and Crocetin/
Gavage administration of 125-250.0 mg/kg body weight of 50% ethanol extract of saffron stigma to mice produced a sedative effect and enhanced the sedative effect of barbiturates. Saffron Stigma Ethanol Extract
Topical application of 100 mg/kg body weight of 95% ethanol extract of saffron stigma inhibited the two-stage initiation and development of skin cancer in mice, delayed papilloma formation, and reduced the average number of papillomas per mouse. Daily gavage administration of the same extract at 100.0 mg/kg body weight for 30 days reduced the incidence of 20-methylcholanthrene-induced soft tissue sarcoma in mice by 10%. Gavage administration of 100.0 mg/kg body weight of saffron stigma ethanol extract inhibited the growth of solid Dalton lymphoma ascites and sarcoma 180 tumors by 87% and 41%, respectively. Weekly subcutaneous injection of 400.0 mg/kg body weight of saffron extract for 13 weeks slowed the growth of colon adenocarcinoma and prolonged the lifespan of female mice (but not male mice). /Saffron stigma ethanol extract/
Intraperitoneal injection of 50 mg/kg body weight of 95% saffron stigma ethanol extract partially prevented cisplatin-induced decreases in body weight, hemoglobin levels, and white blood cell counts in mice. Saffron Ethanol Extract

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Non-human Toxicity Values
LD50 Rats (Male) 5.53 mL/kg /saffronaldehyde/
LD50 Rats (Male) 1.5 mL/kg /saffronaldehyde/
LD50 Mice (Female) Intraperitoneal Injection 1.88 mL/kg /saffronaldehyde/
LD50 Mice (Male) Intraperitoneal Injection 1.48 mL/kg /saffronaldehyde/
For more complete non-human toxicity data for saffron oil (8 types in total), please visit the HSDB record page.

[1]. Intestinal formation of trans-Crocetin from saffron extract (Crocus sativus L.) and in vitro permeation through intestinal and blood brain barrier. Phytomedicine. 2015 Jan 15;22(1):36-44.

[2]. Saffron: An Old Medicinal Plant and a Potential Novel Functional Food. Molecules. 2017 Dec 23;23(1). pii: E30.

Crocetin is a 20-carbon dicarboxylic acid, belonging to the diterpenoid class of compounds, and is also a natural carotenoid. It is found in saffron and has been used as an anti-fatigue dietary supplement. Crocetin has nutritional, health-promoting, metabolic, and antioxidant effects. It is a carotenic acid, a diterpenoid, and a polyunsaturated dicarboxylic acid. It is the conjugate acid of Crocetin (2-). It is a vitamin A analog that increases the diffusion rate of oxygen in aqueous solutions (including plasma). Crocetin has been reported in gardenia, perilla, and other organisms with relevant data. Drug Indications It has been studied for the treatment of cancer/tumors (unspecified), hemorrhage, hypoxia, respiratory failure, and stroke. Mechanism of Action Sodium trans-Crocetin is a novel drug that has been shown to increase systemic oxygen consumption during hemorrhagic shock. Its mechanism of action is by increasing the rate of oxygen diffusion in the plasma, rather than targeting specific symptoms of hemorrhagic shock, and is therefore considered a potential treatment for hypoxemia. Therefore, it may also be beneficial in the treatment of respiratory insufficiency.

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Therapeutic Use
EXPL THER: This study evaluated the antitussive activity of saffron stigma and petal extracts and their components Crocetin and Crocetinin in guinea pigs using a 20% citric acid nebulized solution. Both extracts and drugs were administered intraperitoneally. Saffron ethanol extracts (100-800 mg/kg) and Crocetin (0.25-0.75 mL/kg) reduced the frequency of coughing. Neither the ethanol nor the aqueous extracts of petals and Crocetin showed antitussive activity. /Saffron Stigma Extract/
EXPL THER: Saffron (Crocus sativus L.) is widely used in folk medicine, for example as an anti-edema agent. The authors aimed to evaluate the analgesic and anti-inflammatory activities of saffron extracts in mice. They used aqueous and ethanolic extracts of saffron (Crocus sativus L.) stigmas and petals. The analgesic activity of the extracts was assessed using the hot plate test and writhing test. The effects of the extracts on acute inflammation were studied using a xylene-induced mouse ear edema model. The effects of the extracts on chronic inflammation were assessed using a formalin-induced rat paw edema model. In the hot plate test, intraperitoneal injection of either extract showed no significant analgesic activity in mice. The extracts showed analgesic activity in the acetic acid-induced writhing test. Naloxone only partially blocked the analgesic activity of the stigma aqueous extract. Only the stigma extract showed weak to moderate analgesic activity in acute inflammation. In chronic inflammation, the stigma aqueous extract, ethanol extract, and petal ethanol extract all showed anti-inflammatory effects. The authors conclude that the aqueous and ethanol extracts of saffron stigmas and petals possess analgesic effects, as well as acute and/or chronic anti-inflammatory activity. Stigma Extract
Experimental Treatment: Monthly intramuscular injection of Crocetin (dosage not specified) into rabbits fed an atherosclerosis-inducing diet reduced serum cholesterol concentration by 50% and the severity of atherosclerosis by approximately 30%. Crocetin
Experimental Treatment: A clinical trial evaluating the antioxidant effects of saffron stigmas enrolled 30 participants in three groups: 10 healthy volunteers, 10 patients with coronary artery disease, and 10 healthy controls. Both experimental groups received 50 mg of saffron stigmas twice daily for 6 weeks, added to 100 ml of milk, while the control group consumed only milk. Compared to the control group, lipoprotein oxidation in blood samples was reduced by 42.3% (P < 0.001) in healthy volunteers and by 37.9% (P < 0.01) in patients with coronary artery disease. /Saffron/
For more complete data on the therapeutic uses of saffron oil (7 types), please visit the HSDB record page.

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Drug Warnings
Saffron doses of 5.0 g or more may cause serious adverse reactions. Overdose of saffron (12.0–20.0 g/day) may be fatal. /Saffron/
Saffron may induce uterine contractions, therefore it is contraindicated in pregnant women. Due to a lack of safety data, children and breastfeeding women should limit their saffron consumption to normal ranges. Saffron is contraindicated in patients with bleeding disorders. Stigma croci inhibits platelet aggregation, therefore patients taking anticoagulants or antiplatelet drugs should use it with caution.

C20H24O4

328.4022

328.167

27876-94-4

Crocetin disodium;591230-99-8;Crocetin meglumine

5281232

Yellow to orange solid powder

1.1±0.1 g/cm3

585.1±23.0 °C at 760 mmHg

285°

321.7±19.1 °C

0.0±3.5 mmHg at 25°C

1.559

4.72

2

4

8

24

608

0

C/C(=C\C=C\C=C(\C=C\C=C(\C(=O)O)/C)/C)/C=C/C=C(/C(=O)O)\C

PANKHBYNKQNAHN-MQQNZMFNSA-N

InChI=1S/C20H24O4/c1-15(11-7-13-17(3)19(21)22)9-5-6-10-16(2)12-8-14-18(4)20(23)24/h5-14H,1-4H3,(H,21,22)(H,23,24)/b6-5+,11-7+,12-8+,15-9+,16-10+,17-13+,18-14+

(2E,4E,6E,8E,10E,12E,14E)-2,6,11,15-tetramethylhexadeca-2,4,6,8,10,12,14-heptaenedioic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product is not stable in solution, please use freshly prepared working solution for optimal results.

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

DMSO : ~1 mg/mL (~3.05 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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