Tropoflavin, also known as 7,8-dihydroxyflavone (DHF), 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 ...

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 substituted derivatives, ...

found in ''

Godmania aesculifolia ''Godmania aesculifolia'' is a species of flowering plant in the family Bignoniaceae Bignoniaceae () is a Family (biology), family of flowering plants in the Order (biology), order Lamiales commonly known as the bignonias or trumpet vines.Ver ...

'', ''

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 noxious weed, weed and pest plant. It is native to the tropical Americas including M ...

'', and

primula ''Primula'' () is a genus of herbaceous plant, herbaceous flowering plants in the family (biology), family Primulaceae. They include the primrose (''Primula vulgaris, P. vulgaris''), a familiar wildflower of banks and verges. Other common specie ...

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

small-molecule In 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 are small molecules; t ...

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

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 recept ...

(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 facto ...

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 can ...

(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%. H ...

and able to penetrate the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

. A

prodrug A prodrug is a pharmacologically inactive 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 ...

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 describing how the body affects a specific su ...

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

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. 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, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

disorders, including depression,

cognitive deficit Cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to the cognition process or different areas of cognition. Cognition, also known as cognitive function, refers to the mental processes of how a person ...

s in

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...

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 (mTBI/concussion) to severe traumati ...

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 in the brain and may be temporary such as in transient ischemic attack or permanent in which there is ...

fragile X syndrome Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder. The average IQ in males with FXS is under 55, while affected females tend to be in the borderline to normal range, typically around 70–85. Physical features may include a lo ...

, and

Rett syndrome Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in girls. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often h ...

. Tropoflavin also shows efficacy in animal models of age-associated

cognitive impairment Cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to the cognition process or different areas of cognition. Cognition, also known as cognitive function, refers to the mental processes of how a person ...

and enhances

memory consolidation Memory consolidation is a category of processes that stabilize a memory trace after its initial acquisition. A memory trace is a change in the nervous system caused by memorizing something. Consolidation is distinguished into two specific processe ...

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

antioxidant Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...

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

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

-induced

excitotoxicity In excitotoxicity, neuron, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamic acid, glutamate become pathologically high, resulting in excessive stimulation of cell surface recept ...

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

-induced

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

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 – specifical ...

, 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 chemical property, 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, bu ...

. 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 use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

-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 exo ...

''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 ...

and estrogen sulfotransferase ''in vitro'' (K_i = 35 μM and 1–3 μM, respectively), although 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. 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 inh ...

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

(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 main enemy or rival of the protagonist and is often depicted as a villain. 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 Diols

See also

References