Chemical compound
Tropoflavin , also known as 7,8-dihydroxyflavone , is a
naturally occurring
flavone found in
Godmania aesculifolia ,
Tridax procumbens , and
primula tree leaves.
[2]
[3]
[4] It has been found to act as a
potent and
selective
small-molecule
agonist of the
tropomyosin receptor kinase B (TrkB) (Kd ≈ 320 nM), the main
signaling receptor of the
neurotrophin
brain-derived neurotrophic factor (BDNF).
[5]
[6]
[7] Tropoflavin is both
orally
bioavailable and able to penetrate the
blood–brain barrier .
[8]
[9] A
prodrug of tropoflavin with greatly improved potency and
pharmacokinetics ,
R13 (and, formerly,
R7 ), is under development for the treatment of
Alzheimer's disease .
[10]
[11]
Tropoflavin has demonstrated therapeutic efficacy in
animal models of a variety of
central nervous system disorders,
[7] including
depression ,
[8]
Alzheimer's disease ,
[12]
[13]
[14]
cognitive deficits in
schizophrenia ,
[15]
Parkinson's disease ,
[5]
Huntington's disease ,
[16]
amyotrophic lateral sclerosis ,
[17]
traumatic brain injury ,
[18]
cerebral ischemia ,
[19]
[20]
fragile X syndrome ,
[21] and
Rett syndrome .
[22] Tropoflavin also shows efficacy in animal models of age-associated
cognitive impairment
[23] and enhances
memory consolidation and
emotional learning in healthy rodents.
[24]
[25] In addition, tropoflavin possesses powerful
antioxidant activity independent of its actions on the TrkB receptor,
[26] and protects against
glutamate -induced
excitotoxicity ,
[27]
6-hydroxydopamine -induced
dopaminergic
neurotoxicity ,
[28] and
oxidative stress -induced
genotoxicity .
[29] It was also found to block
methamphetamine -induced
dopaminergic
neurotoxicity , an effect which, in contrast to the preceding, was found to be TrkB-dependent.
[30]
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.
[31]
[32]
Tropoflavin has been found to act as a weak
aromatase inhibitor in vitro (Ki = 10 μM),
[33] though there is evidence to suggest that this might not be the case in vivo .
[5] In addition, it has been found to inhibit
aldehyde dehydrogenase and
estrogen sulfotransferase in vitro (Ki = 35 μM and 1–3 μM, respectively), though similarly to the case of aromatase, these activities have not yet been confirmed in vivo .
[5] Unlike many other
flavonoids , tropoflavin does not show any inhibitory activity on
17β-hydroxysteroid dehydrogenase .
[34] Tropoflavin has also been observed to possess in vitro
antiestrogenic effects at very high concentrations (Ki = 50 μM).
[35]
[36]
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 .
[37] The highly hydroxylated analogue
gossypetin (3,5,7,8,3',4'-hexahydroxyflavone), conversely, appears to be an
antagonist of TrkB in vitro .
[37]
Tropoflavin was also found to decrease mouse sleep in dark phase and reduce hypothalamus level of
orexin A but not orexin B in mice.
[38]
See also
References
^
a
b
US application 20150274692 , Keqiang Ye, "7,8-Dihydoxyflavone and 7,8-substituted flavone derivatives, compositions, and methods related thereto", published 2015-10-01, assigned to Emory University
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^
a
b
c
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PMID
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PMID
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PMID
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S2CID
12198275 .
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PMID
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^ Korkmaz OT, Aytan N, Carreras I, Choi JK, Kowall NW, Jenkins BG, Dedeoglu A (2014).
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PMC
5906793 .
PMID
24637017 .
^ Wu CH, Hung TH, Chen CC, Ke CH, Lee CY, Wang PY, Chen SF (2014).
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2014PLoSO...9k3397W .
doi :
10.1371/journal.pone.0113397 .
PMC
4240709 .
PMID
25415296 .
^ Wang B, Wu N, Liang F, Zhang S, Ni W, Cao Y, Xia D, Xi H (2014). "7,8-dihydroxyflavone, a small-molecule tropomyosin-related kinase B (TrkB) agonist, attenuates cerebral ischemia and reperfusion injury in rats". J. Mol. Histol . 45 (2): 129–40.
doi :
10.1007/s10735-013-9539-y .
PMID
24045895 .
S2CID
10671354 .
^ Uluc K, Kendigelen P, Fidan E, Zhang L, Chanana V, Kintner D, Akture E, Song C, Ye K, Sun D, Ferrazzano P, Cengiz P (2013).
"TrkB receptor agonist 7, 8 dihydroxyflavone triggers profound gender- dependent neuroprotection in mice after perinatal hypoxia and ischemia" . CNS Neurol Disord Drug Targets . 12 (3): 360–70.
doi :
10.2174/18715273113129990061 .
PMC
3674109 .
PMID
23469848 .
^ Tian M, Zeng Y, Hu Y, Yuan X, Liu S, Li J, Lu P, Sun Y, Gao L, Fu D, Li Y, Wang S, McClintock SM (2015). "7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome". Neuropharmacology . 89 : 43–53.
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PMID
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S2CID
38120522 .
^ Johnson RA, Lam M, Punzo AM, Li H, Lin BR, Ye K, Mitchell GS, Chang Q (2012).
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PMC
3643819 .
PMID
22194327 .
^ Zeng Y, Lv F, Li L, Yu H, Dong M, Fu Q (2012).
"7,8-dihydroxyflavone rescues spatial memory and synaptic plasticity in cognitively impaired aged rats" . J. Neurochem . 122 (4): 800–11.
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PMID
22694088 .
^ Bollen E, Vanmierlo T, Akkerman S, Wouters C, Steinbusch HM, Prickaerts J (2013). "7,8-Dihydroxyflavone improves memory consolidation processes in rats and mice". Behav. Brain Res . 257 : 8–12.
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PMID
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S2CID
24088558 .
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PMC
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PMID
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ISSN
0021-8561 .
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S2CID
36661121 .
^ Han X, Zhu S, Wang B, Chen L, Li R, Yao W, Qu Z (2014). "Antioxidant action of 7,8-dihydroxyflavone protects PC12 cells against 6-hydroxydopamine-induced cytotoxicity". Neurochem. Int . 64 : 18–23.
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PMID
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S2CID
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PMID
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a
b Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K, et al. (December 2010).
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Aglycones
Monohydroxyflavone Dihydroxyflavones Trihydroxyflavones Tetrahydroxyflavones Pentahydroxyflavones O-methylated flavones
Glycosides
of apigenin of baicalein of hypolaetin of luteolin
Acetylated Sulfated glycosides Polymers Drugs
Food antioxidants Fuel antioxidants Measurements
Angiopoietin
CNTF
EGF (ErbB)
FGF
FGFR1
FGFR2
Agonists:
Ersofermin
FGF (
1 ,
2 (bFGF) ,
3 ,
4 ,
5 ,
6 ,
7 (
KGF ),
8 ,
9 ,
10 (KGF2) ,
17 ,
18 ,
22 )
Palifermin
Repifermin
Selpercatinib
Sprifermin
Trafermin
FGFR3
FGFR4 Unsorted
HGF (c-Met)
IGF
LNGF (p75NTR )
PDGF
RET (GFL)
SCF (c-Kit)
TGFβ
Trk
TrkA
Negative allosteric modulators:
VM-902A
TrkB
Agonists:
3,7-DHF
3,7,8,2'-THF
4'-DMA-7,8-DHF
7,3'-DHF
7,8-DHF
7,8,2'-THF
7,8,3'-THF
Amitriptyline
BDNF
BNN-20
Deoxygedunin
Deprenyl
Diosmetin
DMAQ-B1
HIOC
LM22A-4
N-Acetylserotonin
NT-3
NT-4
Norwogonin (5,7,8-THF)
R7
R13
TDP6
TrkC
VEGF Others
Additional growth factors:
Adrenomedullin
Colony-stimulating factors (see
here instead)
Connective tissue growth factor (CTGF)
Ephrins (
A1 ,
A2 ,
A3 ,
A4 ,
A5 ,
B1 ,
B2 ,
B3 )
Erythropoietin (see
here instead)
Glucose-6-phosphate isomerase (GPI; PGI, PHI, AMF)
Glia maturation factor (GMF)
Hepatoma-derived growth factor (HDGF)
Interleukins /
T-cell growth factors (see
here instead)
Leukemia inhibitory factor (LIF)
Macrophage-stimulating protein (MSP; HLP, HGFLP)
Midkine (NEGF2)
Migration-stimulating factor (MSF; PRG4)
Oncomodulin
Pituitary adenylate cyclase-activating peptide (PACAP)
Pleiotrophin
Renalase
Thrombopoietin (see
here instead)
Wnt signaling proteins
Additional growth factor receptor modulators:
Cerebrolysin (neurotrophin mixture)
ER Tooltip Estrogen receptor
Agonists
Steroidal:
2-Hydroxyestradiol
2-Hydroxyestrone
3-Methyl-19-methyleneandrosta-3,5-dien-17β-ol
3α-Androstanediol
3α,5α-Dihydrolevonorgestrel
3β,5α-Dihydrolevonorgestrel
3α-Hydroxytibolone
3β-Hydroxytibolone
3β-Androstanediol
4-Androstenediol
4-Androstenedione
4-Fluoroestradiol
4-Hydroxyestradiol
4-Hydroxyestrone
4-Methoxyestradiol
4-Methoxyestrone
5-Androstenediol
7-Oxo-DHEA
7α-Hydroxy-DHEA
7α-Methylestradiol
7β-Hydroxyepiandrosterone
8,9-Dehydroestradiol
8,9-Dehydroestrone
8β-VE2
10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED)
11β-Chloromethylestradiol
11β-Methoxyestradiol
15α-Hydroxyestradiol
16-Ketoestradiol
16-Ketoestrone
16α-Fluoroestradiol
16α-Hydroxy-DHEA
16α-Hydroxyestrone
16α-Iodoestradiol
16α-LE2
16β-Hydroxyestrone
16β,17α-Epiestriol (16β-hydroxy-17α-estradiol)
17α-Estradiol (
alfatradiol )
17α-Dihydroequilenin
17α-Dihydroequilin
17α-Epiestriol (16α-hydroxy-17α-estradiol)
17α-Ethynyl-3α-androstanediol
17α-Ethynyl-3β-androstanediol
17β-Dihydroequilenin
17β-Dihydroequilin
17β-Methyl-17α-dihydroequilenin
Abiraterone
Abiraterone acetate
Alestramustine
Almestrone
Anabolic steroids (e.g.,
testosterone and
esters ,
methyltestosterone ,
metandienone (methandrostenolone) ,
nandrolone and
esters , many others; via estrogenic metabolites)
Atrimustine
Bolandiol
Bolandiol dipropionate
Butolame
Clomestrone
Cloxestradiol
Conjugated estriol
Conjugated estrogens
Cyclodiol
Cyclotriol
DHEA
DHEA-S
ent -Estradiol
Epiestriol (16β-epiestriol, 16β-hydroxy-17β-estradiol)
Epimestrol
Equilenin
Equilin
ERA-63 (ORG-37663)
Esterified estrogens
Estetrol
Estradiol
Estramustine
Estramustine phosphate
Estrapronicate
Estrazinol
Estriol
Estrofurate
Estrogenic substances
Estromustine
Estrone
Etamestrol (eptamestrol)
Ethinylandrostenediol
Ethinylestradiol
Ethinylestriol
Ethylestradiol
Etynodiol
Etynodiol diacetate
Hexolame
Hippulin
Hydroxyestrone diacetate
Lynestrenol
Lynestrenol phenylpropionate
Mestranol
Methylestradiol
Moxestrol
Mytatrienediol
Nilestriol
Norethisterone
Noretynodrel
Orestrate
Pentolame
Prodiame
Prolame
Promestriene
RU-16117
Quinestradol
Quinestrol
Tibolone
Xenoestrogens:
Anise -related (e.g.,
anethole ,
anol ,
dianethole ,
dianol ,
photoanethole )
Chalconoids (e.g.,
isoliquiritigenin ,
phloretin ,
phlorizin (phloridzin) ,
wedelolactone )
Coumestans (e.g.,
coumestrol ,
psoralidin )
Flavonoids (incl.
7,8-DHF ,
8-prenylnaringenin ,
apigenin ,
baicalein ,
baicalin ,
biochanin A ,
calycosin ,
catechin ,
daidzein ,
daidzin ,
ECG ,
EGCG ,
epicatechin ,
equol ,
formononetin ,
glabrene ,
glabridin ,
genistein ,
genistin ,
glycitein ,
kaempferol ,
liquiritigenin ,
mirificin ,
myricetin ,
naringenin ,
penduletin ,
pinocembrin ,
prunetin ,
puerarin ,
quercetin ,
tectoridin ,
tectorigenin )
Lavender oil
Lignans (e.g.,
enterodiol ,
enterolactone ,
nyasol (cis -hinokiresinol) )
Metalloestrogens (e.g.,
cadmium )
Pesticides (e.g.,
alternariol ,
dieldrin ,
endosulfan ,
fenarimol ,
HPTE ,
methiocarb ,
methoxychlor ,
triclocarban ,
triclosan )
Phytosteroids (e.g.,
digitoxin (
digitalis ),
diosgenin ,
guggulsterone )
Phytosterols (e.g.,
β-sitosterol ,
campesterol ,
stigmasterol )
Resorcylic acid lactones (e.g.,
zearalanone ,
α-zearalenol ,
β-zearalenol ,
zearalenone ,
zeranol (α-zearalanol) ,
taleranol (teranol, β-zearalanol) )
Steroid -like (e.g.,
deoxymiroestrol ,
miroestrol )
Stilbenoids (e.g.,
resveratrol ,
rhaponticin )
Synthetic xenoestrogens (e.g.,
alkylphenols ,
bisphenols (e.g.,
BPA ,
BPF ,
BPS ),
DDT ,
parabens ,
PBBs ,
PHBA ,
phthalates ,
PCBs )
Others (e.g.,
agnuside ,
rotundifuran )
Mixed (
SERMs Tooltip Selective estrogen receptor modulators ) Antagonists
Coregulator-binding modulators:
ERX-11
GPER Tooltip G protein-coupled estrogen receptor
Agonists Antagonists Unknown