Tropoflavin, also known as 7,8-dihydroxyflavone, is a

naturally occurring A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical sy ...

flavone Flavone is an organic compound with the formula . A white solid, flavone is a derivative of chromone with a phenyl (Ph) substituent adjacent to the ether group. The compound is of little direct practical importance, but susbstituted derivatives, ...

found in ''

Godmania aesculifolia ''Godmania aesculifolia'' is a species of flowering plant in the family Bignoniaceae Bignoniaceae is a family of flowering plants in the order Lamiales commonly known as the bignonias or trumpetvines.Vernon H. Heywood, Richard K. Brummitt, Ol ...

'', ''

Tridax procumbens ''Tridax procumbens'', commonly known as coatbuttons or tridax daisy, is a species of flowering plant in the family Asteraceae. It is best known as a widespread weed and pest plant. It is native to the tropical Americas including Mexico, but it ...

'', and primula tree leaves. It has been found to act as a potent and selective

small-molecule Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

of the

tropomyosin receptor kinase B Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the ''NTRK2'' gene. TrkB is a recep ...

(TrkB) (K_d ≈ 320 nM), the main signaling receptor of the

neurotrophin Neurotrophins are a family of proteins that induce the survival, development, and function of neurons. They belong to a class of growth factors, secreted proteins that can signal particular cells to survive, differentiate, or grow. Growth fact ...

brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canon ...

(BDNF). Tropoflavin is both orally

bioavailable In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

and able to penetrate the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of the central nervous system where ne ...

. A

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...

of tropoflavin with greatly improved potency and

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

, R13 (and, formerly, R7), is under development for the treatment of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

. Tropoflavin has demonstrated therapeutic efficacy in

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

s of a variety of

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

disorders, including depression,

cognitive deficit Cognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to the cognition process. The term may describe * deficits in overall intelligence (as with intellectual disabilities), * specific and restricted defic ...

s in

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most commo ...

traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury TBI/concussionto severe traumatic br ...

cerebral ischemia Brain ischemia is a condition in which there is insufficient bloodflow to the brain to meet metabolic demand. This leads to poor oxygen supply or cerebral hypoxia and thus leads to the death of brain tissue or cerebral infarction/ischemic stroke. ...

fragile X syndrome Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features ma ...

, and Rett syndrome. Tropoflavin also shows efficacy in animal models of age-associated

cognitive impairment Cognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to the cognition process. The term may describe * deficits in overall intelligence (as with intellectual disabilities), * specific and restricted defici ...

and enhances memory consolidation and emotional learning in healthy rodents. In addition, tropoflavin possesses powerful

antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubrica ...

activity independent of its actions on the TrkB receptor, and protects against

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

-induced

excitotoxicity In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate ...

6-hydroxydopamine Oxidopamine, also known as 6-hydroxydopamine (6-OHDA) or 2,4,5-trihydroxyphenethylamine, is a neurotoxic synthetic organic compound used by researchers to selectively destroy dopaminergic and noradrenergic neurons in the brain. The main use for o ...

-induced

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate do ...

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...

, and

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

-induced

genotoxicity Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, but some genotoxic ...

. It was also found to block

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamp ...

-induced

, an effect which, in contrast to the preceding, ''was'' found to be TrkB-dependent. In 2017, evidence was published suggesting that tropoflavin and various other reported small-molecule TrkB agonists might not actually be direct agonists of the TrkB and might be mediating their observed effects by other means. Tropoflavin has been found to act as a weak

aromatase inhibitor Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone ex ...

''in vitro'' (K_i = 10 μM), though there is evidence to suggest that this might not be the case ''in vivo''. In addition, it has been found to inhibit

aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have b ...

and

estrogen sulfotransferase Estrone sulfotransferase (EST) (), also known as estrogen sulfotransferase, is an enzyme that catalyzes the transformation of an unconjugated estrogen like estrone into a sulfated estrogen like estrone sulfate. It is a steroid sulfotransferase an ...

''in vitro'' (K_i = 35 μM and 1–3 μM, respectively), though similarly to the case of aromatase, these activities have not yet been confirmed ''in vivo''. Unlike many other

flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...

s, tropoflavin does not show any inhibitory activity on

17β-hydroxysteroid dehydrogenase A hydroxysteroid is a molecule derived from a steroid with a hydrogen replaced with a hydroxy group. When the hydroxy group is specifically at the C3 position, hydroxysteroids are referred to as sterols, with an example being cholesterol. See ...

. Tropoflavin has also been observed to possess ''in vitro''

antiestrogen Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or ...

ic effects at very high concentrations (K_i = 50 μM). A variety of close structural analogues of tropoflavin have also been found to act as TrkB agonists ''in vitro'', including

diosmetin Diosmetin, also known as 5,7,3′-trihydroxy-4′-methoxyflavone, is an ''O''-methylated flavone, a chemical compound that can be found in the Caucasian vetch. It has been found to act as a weak TrkB receptor agonist. Glycosides Diosmetin is t ...

(5,7,3'-trihydroxy-4'-methoxyflavone),

norwogonin Norwogonin, also known as 5,7,8-trihydroxyflavone (5,7,8-THF), is a flavone, a naturally occurring flavonoid-like chemical compound which is found in '' Scutellaria baicalensis'' (Baikal skullcap). It has been found to act as an agonist of the Trk ...

(5,7,8-trihydroxyflavone), eutropoflavin (4'-dimethylamino-7,8-dihydroxyflavone), 7,8,3'-trihydroxyflavone, 7,3'-dihydroxyflavone, 7,8,2'-trihydroxyflavone, 3,7,8,2'-tetrahydroxyflavone, and 3,7-dihydroxyflavone. The highly hydroxylated analogue

gossypetin Gossypetin, also known as 3,5,7,8,3',4'-hexahydroxyflavone, is a flavonol, a type of flavonoid. It has been isolated from the flowers and the calyx of ''Hibiscus sabdariffa'' (roselle) and exhibits a strong antibacterial activity. The compound ha ...

(3,5,7,8,3',4'-hexahydroxyflavone), conversely, appears to be an

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...

of TrkB ''in vitro''. Tropoflavin was also found to decrease mouse sleep in dark phase and reduce hypothalamus level of orexin A but not orexin B in mice.

References

{{Estrogen receptor modulators Antidepressants Antioxidants Aromatase inhibitors Flavones Neuroprotective agents Nootropics Phytoestrogens Steroid sulfotransferase inhibitors TrkB agonists

See also

References