Crocetin is a natural
apocarotenoid Apocarotenoids are organic compounds which occur widely in living organisms. They are derived from carotenoids by oxidative cleavage,
catalyzed by carotenoid oxygenases. Examples include the vitamin A retinoids retinal, retinoic acid, and retinol; a ...
dicarboxylic acid
In organic chemistry, a dicarboxylic acid is an organic compound containing two carboxyl groups (). The general molecular formula for dicarboxylic acids can be written as , where R can be aliphatic or aromatic. In general, dicarboxylic acids show ...
that is found in the
crocus
''Crocus'' (; plural: crocuses or croci) is a genus of seasonal flowering plants in the family Iridaceae (iris family) comprising about 100 species of perennials growing from corms. They are low growing plants, whose flower stems remain undergro ...
flower together with its
glycoside
In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. ...
,
crocin
Crocin is a carotenoid chemical compound that is found in the flowers of crocus and gardenia. Crocin is the chemical primarily responsible for the color of saffron.
Chemically, crocin is the diester formed from the disaccharide gentiobiose and ...
, and ''
Gardenia jasminoides'' fruits. It forms brick red crystals with a melting point of 285°C.
The chemical structure of crocetin forms the central core of
crocin
Crocin is a carotenoid chemical compound that is found in the flowers of crocus and gardenia. Crocin is the chemical primarily responsible for the color of saffron.
Chemically, crocin is the diester formed from the disaccharide gentiobiose and ...
, the compound responsible for the color of
saffron
Saffron () is a spice derived from the flower of ''Crocus sativus'', commonly known as the "saffron crocus". The vivid crimson stigma and styles, called threads, are collected and dried for use mainly as a seasoning and colouring agent i ...
.
Cell studies
Crocin and crocetin may provide
neuroprotection
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal lo ...
in rats by reducing the production of various neurotoxic molecules, based on an in-vitro cell study.
Physiological effects
A 2009 study involving 14 individuals indicated that oral administration of crocetin may decrease the effects of physical fatigue in healthy men.
A 2010 pilot study investigated the effect of crocetin on sleep. The clinical trial comprised a double-blind, placebo-controlled, crossover trial of 21 healthy adult men with a mild sleep complaint. It concluded that crocetin may (p=0.025) contribute to improving the quality of sleep.
In high concentrations, it has protective effects against retinal damage ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' and ''
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
''.
Transcrocetinate sodium
The
sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...
salt
Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...
of crocetin, transcrocetinate sodium (
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
, also known as trans sodium crocetinate or TSC) is an experimental drug that increases the movement of
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
from
red blood cells
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...
into
hypoxic
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the t ...
(oxygen-starved) tissues.
Transcrocetinate sodium belongs to a group of substances known as bipolar trans carotenoid salts, which constitute a subclass of
oxygen diffusion-enhancing compound An oxygen diffusion-enhancing compound is any substance that increases the availability of oxygen in body tissues by influencing the molecular structure of water in blood plasma and thereby promoting the movement (diffusion) of oxygen through plas ...
s.
Transcrocetinate sodium was one of the first such compounds discovered.
![Transcrocetinate sodium](https://upload.wikimedia.org/wikipedia/commons/c/cd/Transcrocetinate_sodium.svg)
Transcrocetinate sodium can be prepared by reacting
saffron
Saffron () is a spice derived from the flower of ''Crocus sativus'', commonly known as the "saffron crocus". The vivid crimson stigma and styles, called threads, are collected and dried for use mainly as a seasoning and colouring agent i ...
with
sodium hydroxide
Sodium hydroxide, also known as lye and caustic soda, is an inorganic compound with the formula NaOH. It is a white solid ionic compound consisting of sodium cations and hydroxide anions .
Sodium hydroxide is a highly caustic base and alkali ...
and extracting the
salt
Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...
of the trans crocetin
isomer
In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers.
Iso ...
from the solution.
John L. Gainer and colleagues have investigated the effects of transcrocetinate sodium in animal models.
They discovered that the drug could reverse the potentially fatal decrease in blood pressure produced by the loss of large volumes of blood in severe
hemorrhage
Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
, and thereby improve survival.
Early investigations of transcrocetinate sodium suggested that it had potential applications in
battlefield medicine
Battlefield medicine, also called field surgery and later combat casualty care, is the treatment of wounded combatants and non-combatants in or near an area of combat. Civilian medicine has been greatly advanced by procedures that were first ...
, specifically in treatment of the many combat casualties with
hemorrhagic shock
Hypovolemic shock is a form of shock caused by severe hypovolemia (insufficient blood volume or extracellular fluid in the body). It could be the result of severe dehydration through a variety of mechanisms or blood loss. Hypovolemic shock is a ...
.
Additional studies, carried out in animal models and in clinical trials in humans, indicated that transcrocetinate sodium might prove beneficial in the treatment of a variety of conditions associated with
hypoxia and
ischemia
Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
(a lack of oxygen reaching the tissues, usually due to a disruption in the circulatory system), including
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
,
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
(heart attack), and
stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
.
Transcrocetinate sodium has shown promise of effectiveness in restoring tissue oxygen levels and improving the ability to walk in a clinical trial of patients with
peripheral artery disease
Peripheral artery disease (PAD) is an abnormal narrowing of arteries other than those that supply the heart or brain. When narrowing occurs in the heart, it is called coronary artery disease, and in the brain, it is called cerebrovascular diseas ...
(PAD)
in which reduced delivery of oxygen-rich blood to tissues can cause severe leg pain and impair mobility. The drug has also been under investigation in a clinical trial sponsored by drug developer
Diffusion Pharmaceuticals
Diffusion Pharmaceuticals Inc ( NASDAQ:DFFN) is a publicly traded biotechnology and drug development company based in Charlottesville, Virginia, U.S. It was co-founded in 2001 by American life sciences entrepreneur David Kalergis and University ...
for potential use as a
radiosensitizer
A radiosensitizer is an agent that makes tumor cells more sensitive to radiation therapy. It is sometimes also known as a radiation sensitizer or radio-enhancer.
Mechanism of action
Conventional chemotherapeutics are currently being used in con ...
, increasing the susceptibility of
hypoxic cancer cells to
radiation therapy
Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radia ...
, in patients with a form of brain cancer known as
glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...
.
The drug is currently under investigation for its possible use in enhancing the oxygenation status of COVID-19 patients at risk for developing multiple organ failure due to severe respiratory distress.
Mechanism of action
Similar to other
oxygen diffusion-enhancing compound An oxygen diffusion-enhancing compound is any substance that increases the availability of oxygen in body tissues by influencing the molecular structure of water in blood plasma and thereby promoting the movement (diffusion) of oxygen through plas ...
s, transcrocetinate sodium appears to improve oxygenation in hypoxic tissues by exerting
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, th ...
effects on water molecules in
blood plasma
Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intra ...
and thereby increasing the
hydrogen bonding
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
between the water molecules.
This in turn causes the overall organization of water molecules in plasma to become more structured, which facilitates the diffusion of oxygen through plasma and promotes the movement of oxygen into tissues.
Trans-crocetin has been found to act as an
NMDA receptor antagonist
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...
with high
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
, and has been implicated in the
psychoactivity of saffron.
See also
*
Crocetane
Crocetane, or 2,6,11,15-tetramethylhexadecane, is an isoprenoid hydrocarbon compound. Unlike its isomer phytane, crocetane has a tail-to-tail linked isoprenoid skeleton. Crocetane has been detected in modern sediments and geological records as a ...
References
{{Ionotropic glutamate receptor modulators
Apocarotenoids
Dicarboxylic acids
NMDA receptor antagonists
Saffron