1.
Sources and Composition
1.1
Sources and Structure
7,8-dihydroxyflavone (7,8-DHF) is a flavonoid which has recently gathered awareness due to a screening study to find small molecules with neurotrophic properties similar to brain-derived neurotrophic factor (BDNF).[1] In this study 7,8-DHF was found to be a potent activator of the BDNF signaling pathway, preventing neuronal cell apoptosis in vitro and demonstrating potent neuroprotective effects in mouse models. The neurotrophic properties of 7,8-DHF depend highly on the 7,8-catechol segment of the molecule.[2]
7,8-DHF is a flavonoid first discovered in an attempt to find small neurotrophic molecules with properties similar to BDNF in vitro. Studies in cultured cells and mice have indicated that it may have potent nueroprotective effects.
2.
Molecular Targets
2.1
TrkB
7,8-DHF is most well known for being a direct ligand to the tropomyosin-related kinase B (TrkB) receptor and was initially discovered in a screening study for suitable small molecules that activate this receptor.[1] Subsequent research used this compound in a number of 'proof of concept' studies showing its effects on a variety of cognitive measures in animal models.[3][4][5][6] TrkB normally is activated by the peptide known as brain-derived neurotrophic factor (BDNF) and, upon activation, promotes survival and growth of neurons.[7] 7,8-DHF can mimic these actions with high potency (Kd 1 nM for DNF versus 320 nM for 7,8-DHF[1] ), also via binding to and activating TrkB.[1][1][8] Notably, 7,8-DHF is also capable of crossing the blood-brain barrier when injected into the periphery in animal models, something BDNF itself cannot do.[1][5]
The actions of 7,8-DHF on the TrkB receptor depend on the 7,8-catechol portion of the molecule.[2] Adding a hydroxyl group to the 3' position potentiates binding to TrkB, since 7,3'-dihydroxyflavone and 7,8,3'-trihydroxyflavone appear to be more potent in vitro.[2]
7,8-DHF has potent neurotrophic effects that mimic the endogenous neuropeptide BDNF, also binding to and activating the TrkB receptor.
2.2
PI3K/Akt
7,8-DHF has been noted to increase expression of the antioxidant protein Nrf2, which is downstream of PI3K/Akt signaling.[9] Nrf2 binds to and activates the antioxidant response element (ARE), a DNA sequence that turns on antioxidant genes including the antioxidant protein heme oxygenase 1 (HO-1).[10] 7,8-DHF has been shown to induces HO-1 expression in some cells[9] and also induces 8-oxoguanine DNA glycosylase-1 (OGG1) in a manner dependent on PI3K/Akt.[11]
The exact mechanism by which 7,8-DHF activate PI3K/Akt signaling is not yet known; while PI3K/Akt can be activated in neurons secondary to TrkB,[2] 7,8-DHF has also demonstrated antioxidant effects in cells that do not express this receptor (PC12 and HT-22 cells).[12][13] This suggests that 7,8-DHF may activate Akt signaling via TrkB dependent, and independent mechanisms.[13]
7,8-DHF activates the Nrf2 antioxidant response protein via upstream activation of PI3K/Akt signaling. While this has been shown to occur via activation of TrkB in some models, 7,8-DHF some studies have suggest that 7,7-DHF also activates PI3K/Akt via TrkB-independent mechanisms.
3.
Pharmacology
3.1
Absorption
Some studies attempting to optimize the effects of 7,8-DHF via structural modifications have noted that while 7,8-DHF is orally bioavailable in mice,[2]it is subject to significant first-pass metabolism.[14] While poor absorption is a property inherent to flavonoids,[15] studies measuring the specific oral pharmacokinetic parameters of 7,8-DHF do not appear to have been undertaken.
7,8-DHF is absorbed following oral ingestion in mice, although it is highly metabolized before reaching the blood stream. There is an overall lack of research looking at the details of absorption after oral administration of this supplement.
4.
Neurology
4.1
Neurogenesis
Tropomyosin-related kinase B (TrkB) is a receptor that is responsive to the neural growth factor known as brain-derived neurotrophic factor (BDNF), which, upon activation promotes neuronal growth and protection.[18][19] TrkA is a similar receptor that responds to neural growth factor (NGF).[20]
Flavonoids in general have been known to interact with neurons in a growth-promoting manner.[21] 7,8-DHF in particular has demonstrated a protective effect against apoptosis, with an EC50 of 35 nM, which was greater in potency relative to the flavonoids catechin (100 nM), pinocembrin (100 nM), and diosmetin (500 nM).[1] This was secondary to TrkB activation, did not activate TrkA, and did not require BDNF.[1] The degree of activation was comparable to BDNF when tested in vitro.[1]
Reports on the effect of 7,8-DHF on TrkB receptor expression are mixed. In one study, 7,8-DHF failed to affect TrkB receptor expression, despite activating them in a mouse model of Alzheimer's disease with an estimated oral intake of 5mg/kg over four months.[22] In contrast, another study using this same mouse model of Alzheimer's (5XFAD) an increase in total TrkB receptors after 10 days (5mg/kg injections) while the wild type mice given 7,8-DHF experienced a statistically-insignificant trend toward reduction in total TrkB content.[23] The reduction of total TrkB observed in wild type mice is associated with an increase in active (phosphorylated) TrkB without significant changes in BDNF concentrations.
7,8-dihydroxyflavone selectively acts on the TrkB receptor and 'mimics' BDNF, protecting neurons from toxic insults and promoting growth. It appears to be effective when injected into the periphery or orally ingested. Mouse studies suggest that it may exert differential effects on TrkB receptor levels in normal versus diseased states.
When tested in vitro, 500nM of 7,8-DHF over three days promoted dendritic branching and synapse formation, increasing dendritic length, synaptic size, and density by approximately 50%.[22] BDNF (by activating TrkB) is known to promote growth of thin spine density dendrites[24] which has been observed in vivo in diseased mice.[6] Total number of axon terminals may not be increased in response to 7,8-DHF, rather just the density of dendrites.[6]
When tested in a model of scopolamine-induced Alzheimer's, injections of 7,8-DHF (1 mg/kg) have been noted to restore field excitatory postsynaptic potential (fEPSP) to control levels, indicating a restoration of synaptic transmission.[25] In a transgenic model of Alzheimer's disease where hippocampal cells are selectively destroyed (CaM/Tet-DTA mice[26]), 7,8-DHF has shown a restorative effect on synaptic density with 5 mg/kg injections, affecting only the neurons that were damaged.[6] While 7,8-DHF had a restorative effect in 19% of these mice, the authors failed to note any effects on synaptic density in healthy control mice.[6]
7,8-DHF has also been noted to promote regeneration of cut peripheral nerves and motor neurons in vitro (500nM) secondary to acting on TrkB.[27]
Activation of the TrkB receptor has been noted to promote growth in dendrites of neurons. In mouse models for Alzheimer’s, 7,8-DHF injections have been shown to improve synaptic density via increased dendrite formation. 7,8-DHF does not appear to affect synaptic density in cognitively-healthy mice, however, suggesting that it may only potentiate synaptic remodeling in the context of pre-existing damage or injury.
4.2
Neurooxidation
Incubation of 7,8-DHF in PC12 cells has been noted to confer protective effects against an oxidative stressor (6-OHDA)[13] despite these cells not normally expressing the TrkB receptor (although they can be transfected to stably express it[28]), a protective effect that has been replicated against glutamate-induced oxidation in another cell line lacking the TrkB receptor (HT-22).[12]
Neurotoxicity induced by methamphetamine has been reduced with an acute oral preload of 7,8-DHF (30mg/kg in the mouse[29]) with a lower dose of 10mg/kg being effective in subchronic methamphetamine exposure. These protective effects are associated with less dopamine transporter reduction and fewer behavioural abnormalities[29][30] in a manner dependent on the TrkB receptor.[30]
7,8-DHF appears to confer protective effects at the level of the neuron in response to various oxidative stressors, and while its activation of TrkB protects neurons, there seems to be another antioxidative mechanism which allows cells that do not have this receptor to still experience protection.
4.3
Neuroinflammation
7,8-DHF has been noted to have antiinflammatory actions in microglial cells associated with attenuating NF-kB activation in response to LPS, and leading to less activation of MAPK proteins such as p38, JNK, and ERK;[31] these actions are also seen in macrophages[32] and in both cell lines it results in less inflammation-mediated release of the cytokines TNF-α and IL-1β.[31][32]
An antiinflammatory effect of 7,8-DHF in microglial cells has been noted, although the practical relevance of this information and its mechanisms are not yet known.
4.4
Addiction and Obsession
Activaton of TrkB is known to have a potential anti-addiction role seen with cocaine treatment to rats, with the antiaddictive properties being attributed to the endogenous ligand BDNF[33] but this effect was also replicated with 7,8-DHF injections.[34] Activation of TrkB appears to enhance signalling via an NMDA subunit known as GluN2B which is pivotal to these effects.[34]
Activation of TrkB (from BDNF) can have a potential antiaddictive effect in response to cocaine treatment in the rat, and this has been mimicked with 7,8-DHF injections.
4.5
Stroke and Tramautic Brain Injury
Administration of 7,8-DHF shortly after hypoxia ischemia (arodent model for stroke), with subsequent injections of 5mg/kg for the next week, in neonates has been noted to exert protective effects in female mice only, who exhibited less cognitive deficit and white matter damage relative to hypoxic control.[35] Similar effects have been seen elsewhere with direct administration of BDNF.[36]
A similar protective effect after instances of cognitive damage has also been seen in adult mice following middle cerebral artery occlusion with 5mg/kg injections of 7,8-DHF[1] and ischemia/reperfusion injury,[37] affecting both sexes.
A protective effect of hippocampal cells in rodents has also been seen with pretreatment with 7,8-DHF before moderate impact injury. The protective effect was seen 24 hours after the injury occurred.[38]
Subchronic administration of 7,8-DHF appears to confer some protective effects in the brain following ischemic (oxygen-depriving) or impact injury to the brain in rodent models.
4.6
Anxiety and Stress
In rats subject to immobilization stress, a subcutaneous injection of 5mg/kg 7,8-DHF two hours before the stressor was able to prevent memory alterations a day later when compared to stressed control; 7,8-DHF did not improve performance in unstressed rats, however.[39] This benefit with 7,8-DHF before immobilization have been noted elsewhere in mice[5] and when it is given 15 days after immobilization (to assess fear extinction, which is known to involve BDNF) it appears to facilitate fear extinction.[5][40]
A single administration of 5mg/kg to rats without any stressor present does not appear to influence anxiety-like behaviour.[5]
Administration of this flavonoid exerts a possible beneficial effect on the effects of stress on learning, which does not extend to nonstressed controls.
4.7
Depression
A mouse model of depression involving social defeat was found to be alleviated by a 10 mg/kg intraperitoneal injection of 7,8-DHF. Specifically, forced swim test and tail suspension tests improved with 7,8-DHF versus a vehicle injection to a similar degree as a 10 mg/kg injection of ketamine. Sucrose preference was also improved, although to a lesser extent than ketamine. Also, the effect of the 7,8-DHF injection wore off 6 days after the injection, while mice injected with ketamine maintained their improvement.[41]
7,8-DHF improved some aspects of depression in a mouse model to a similar extent as ketamine, although not in all aspects, and not for as long a time.
4.8
Memory and Learning
When tested in instances of immobilization stress, 5mg/kg injections (intraperitoneal or subcutaneous) appear to confer anti-amnesiac properties in rats effective both with a single administration prior to the stressor[39] or as a daily injection over the course of four weeks.[42][3]
There are reported cognitive benefits to otherwise healthy aged rodents with 5mg/kg 7,8-DHF injections regarding fear learning[42][3] which is thought to be related to how BDNF signalling (via TrkB) itself helps preserve cognition during aging via rescuing defects in synaptic plasticity.[43]
In rodent models of stress-induced amnesia age-related cognitive decline, activation of TrkB is known to be therapeutic and administration of 7,8-DHF mimicks the benefits seen with activation of this receptor.
A single injection of 5mg/kg 7,8-DHF in otherwise healthy rats has failed to increase spatial memory performance when measured a day later.[39]
Injections of 7,8-DHF to rats (0.3-3mg/kg; 0.1mg/kg ineffective) immediately or three hours after a learning trial appeared to enhance object recognition when tested a day later, with 0.3-1mg/kg performing equally well and 3mg/kg being slightly more effective; this was replicated in both healthy mice and a transgenic model for Alzheimer's disease at 0.1mg/kg.[44]
However, another study in a mouse model of Alzheimer's disease using injections of 5mg/kg 7,8-DHF daily for four weeks found no improvement in cognitive impairment and no change in amyloid precursor protein levels or processing nor on plaque deposition.[45]
There are a few studies in rodents assessing the effects of 7,8-DHF in instances where the rodent is not cognitively unwell, and while a single dose does not seem to have any effect for spacial memory, there may be some nootropic effects with respect to object recognition, although few studies have been done at this point.
5.
Cardiovascular Health
5.1
Blood Pressure
7,8-DHF appears to increase nitric oxide signaling in a manner independent of TrkB and potassium channels. Instead, the mechanism seems to involve reduced extracellular calcium influx and intracellular calcium store release.[46] One study has noted a reduction in blood pressure in spontaneously hypertensive rats when injected with 7,8-DHF (2.5 mg/kg), and there was a weak effect diastolic blood pressure only in normal rats also injected with the same dose. 7,8-DHF reduced blood pressure in this study for about one hour.[46] 7,8-DHF also showed a small effect on diastolic blood pressure when administered orally (10mg/kg) to hypertensive rats, with no effect in normal rats.[46]
7,8-DHF has been noted to have hypotensive properties when injected into rats, although the effect is short-lived and oral administration seems to yield little benefit. The practical relevance of these results is not yet established.
6.
Obesity and Fat Mass
6.1
Metabolic Rate
Direct brain infusions of brain-derived neurotrophic factor (BDNF) have been shown to suppress food intake in rats[47] through a mechanism most likely related to BDNF binding to its receptor, known as TrkB[48]. However, the short half-life and poor penetration of the blood-brain barrier makes BDNF itself a poor candidate for weight loss.[49] Since 7,8-DHF also acts on TrkB[50] and has better bioavailability, it may hold more promise.
This hypothesis was tested by administering 0.16 mg/mL 7,8-DHF in the drinking water of obese mice for 20 weeks who were being fed a high-fat diet. It was found that female, but not male, mice's diet-induced weight gain was attenuated by 7,8-DHF through a muscle TrkB-dependent mechanism, since 7,8-DHF had no such effect on mice which specifically lacked this receptor on their muscles. The female mice given 7,8-DHF also had increased energy expenditure, suggesting that this may be the mechanism by which weight gain was attenuated. [51]
7,8-DHF may prevent diet-induced obesity in mice through a muscle-dependent mechanism.
7.
Skeletal Muscle and Physical Performance
7.1
Muscular Endurance
Neurotrophins (such as BDNF[52] and NT-4[53]) are known to be involved in muscular contractions, where ligand-activated TrkB interacts with presynaptic muscarinic receptors promoting acetylcholine release in motor neurons.[54] Neuromuscular transmission to muscle (diaphragm) in isolated mouse cells is enhanced (32%) by 10µM 7,8-DHF[55] due to enhanced neuromuscular transmission rates. 7,8-DHF did not affect isometric contractile and fatigue properties of the diaphragm muscle, however.[55]
Activation of TrkB is known to potentiate muscle contractions. This was observed when 7,8-DHF was incubated with mouse diaphragm muscles, although fatigue properties in this muscle were not directly affected. It is not yet known if this occurs in skeletal muscle after oral ingestion.
8.
Interactions with Cancer Metabolism
8.1
Molecular Targets
The protein known as Sp1 is a transcription factor found in all mammals and which regulates a wide variety of processes involved in cell differentiation and cell cycle progression.[56] Several types of cancer have been shown to overexpress Sp1, indicating that it may be an important molecular target in cancer therapy.[57] 7,8-DHF has been shown to directly bind to Sp1 and affect this protein's downstream targets, which ultimately can induce apoptosis in a cancer cell line in vitro.[58]
8.2
Oral and Throat
One study found that 10-40µM of 7,8-DHF was able to induce cell cycle arrest and apoptosis in two oral squamous carcinoma cells in vitro in a dose-dependent manner.[58]
9.
Peripheral Organ Systems
9.1
Intestines
The actions of brain-derived neurotrophic factor (BDNF) on its receptor TrkB are known to enhance cholinergic transmission.[54] This action is mimicked by 7,8-DHF in both diaphragm muscle[55] and intestinal muscle cells.[59] When TrkB is activated by 7,8-DHF in intestinal muscle cells, cholinergic agonist-induced contraction is enhanced in a PLC-dependent manner.[59]
TrkB activation in intestinal muscle cells enhances contractions induced by cholinergic agonists. Theoretically this may underlie intestinal distress (reported with other BDNF-related supplements such as Bacopa monnieri, although no human studies have verified this.
10.
Interactions with Medical Conditions
10.1
Alzheimer's Disease
When incubated with primary neurons in vitro, 7,8-DHF (500 nM) greatly reduced Aβ –induced toxicity in a manner dependent on TrkB.[22]
In a mouse model for Alzheimer’s disease, chronic oral ingestion of 7,8-DHF over four weeks (estimated 5 mg/kg) prevented Aβ deposition without affecting Aβ levels, suggesting that TrkB activation may specifically antagonize amyloid plaque formation.[22] Moreover, 7,8-DHF prior to scopolamine treatment in rats reduced Aβ deposition, oxidative stress and synaptic dysfunction while preserving cognitive function. As in the latter mouse study, 7,8-DHF prevented Alzheimer’s-like pathological dysfunction in a manner dependent on TrkB activation.[25]
7,8-DHF has been shown to reduce amyloid plaque formation in animal models for Alzheimer’s disease via TrkB activation.
A single injection of 7,8-DHF to a transgenic mouse model of Alzheimer's appears to confer similar acute learning benefits for object recognition at 0.1 mg/kg, similar to healthy mice given the same intraperitoneal dose.[44]
7,8-DHF in the drinking water (22 mg/L; estimated 5 mg/kg oral intake) of 5XFAD mice with Alzheimer's disease has been noted to nearly double TrkB phosphorylation (as well as that of MAPKs and Akt) after four months of ingestion without changing TrkB protein content. This was thought to underlie the reduction in synaptic loss compared to 5XFAD control mice.[22] Notably, increased TrkB phosphorylation occurred alongside restoration of memory deficits.[22] Experiments in another transgenic model of Alzheimer's (CaM/Tet-DTA) have noted benefits to dendritic density and spatial memory with 7,8-DHF injections.[6]
7,8-DHF has been shown to reduce oxidative stress and amyloidogenesis while preserving cognitive function in multiple rodent models of Alzheimer's disease. Efficacy has been established with both injection as well as oral ingestion.
10.2
Parkinson's
A mouse model of Parkinson's generated by injecting increasing doses of a chemical known as MPTP of four weeks was partially ameliorated by intraperitoneal injections of 5mg/kg 7,8-DHF.[60] Specifically, motor function in the mice was improved, and tyrosine hydroxylase function was preserved dorsolateral striatum, even when treatment began two weeks through MPTP treatment, suggesting that 7,8-DHF treatment may not only ameliorate symptoms but be disease-modifying in this model of Parkinson's.[60] Tyrosine hydroxylase is the enzyme which converts tyrosine to L-DOPA,[61] and reduction of this enzyme is a crucial step in the development of Parkinson's disease.[62]
10.3
Amyotrophic Lateral Sclerosis
Intraperitoneal administration of 7,8-DHF to an animal model of amyotrophic lateral sclerosis (ALS) appears to confer motor benefits, thought to be related to a preservation of dendritic spines of spinal neurons.[63]
An increase in neuromuscular transmission has been noted with 7,8-DHF incubation (10 µM) in diaphragm muscles of the mouse,[55] which may be relevant to ALS, where the leading cause of death is respiratory failure.[64]
Preliminary animal evidence suggests that 7,8-DHF may have therapeutic potential for ALS, although no human studies have been performed to date.
10.4
Schizophrenia
Intraperitoneal administration of 5 mg/kg 7,8-DHF daily for two weeks in schizophrenic rats appears to confer cognitive benefits including increased spatial learning. This was shown to occur via TrkB activation, also promoting hippocampal synaptic plasticity.[4]
10.5
Rett Syndrome
In a transgenic mouse model of Rett syndrome (Mecp2-null mice[65]), which has reduced BDNF expression relative to healthy controls,[66] both normalization of BDNF concentrations[66] and oral ingestion of 7,8-DHF (80mg/L drinking water; estimated intake of 8-12mg/kg from 2-3mL drank daily)[67] appear to partially benefit physical (running wheel and breathing patterns) and neuronal (hippocampal size) signs of this condition.
Oral ingestion of 7,8-DHF mitigates some of the signs of Rhett syndrome in a mouse model.
References
- ^Jang SW1, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, Wilson WD, Xiao G, Blanchi B, Sun YE, Ye KA selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavoneProc Natl Acad Sci U S A.(2010 Feb 9)
- ^Liu X1, Chan CB, Jang SW, Pradoldej S, Huang J, He K, Phun LH, France S, Xiao G, Jia Y, Luo HR, Ye KA synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effectJ Med Chem.(2010 Dec 9)
- ^Zeng Y1, Lv F, Li L, Yu H, Dong M, Fu Q7,8-dihydroxyflavone rescues spatial memory and synaptic plasticity in cognitively impaired aged ratsJ Neurochem.(2012 Aug)
- ^Yang YJ1, Li YK2, Wang W3, Wan JG1, Yu B1, Wang MZ1, Hu B4Small-molecule TrkB agonist 7,8-dihydroxyflavone reverses cognitive and synaptic plasticity deficits in a rat model of schizophreniaPharmacol Biochem Behav.(2014 Jul)
- ^Andero R1, Heldt SA, Ye K, Liu X, Armario A, Ressler KJEffect of 7,8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learningAm J Psychiatry.(2011 Feb)
- ^Castello NA, Nguyen MH, Tran JD, Cheng D, Green KN, LaFerla FM7,8-Dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of Alzheimer disease-like neuronal lossPLoS One.(2014 Mar 10)
- ^Yoshii A1, Constantine-Paton MPostsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and diseaseDev Neurobiol.(2010 Apr)
- ^Bernard-Gauthier V1, Boudjemeline M, Rosa-Neto P, Thiel A, Schirrmacher RTowards tropomyosin-related kinase B (TrkB) receptor ligands for brain imaging with PET: radiosynthesis and evaluation of 2-(4-{(18)F}fluorophenyl)-7,8-dihydroxy-4H-chromen-4-one and 2-(4-({N-methyl-(11)C}-dimethylamino)phenyl)-7,8-dihydroxy-4H-chromen-4-oneBioorg Med Chem.(2013 Dec 15)
- ^Ryu MJ1, Kang KA, Piao MJ, Kim KC, Zheng J, Yao CW, Cha JW, Hyun CL, Chung HS, Park JC, Cho SJ, Hyun JWEffect of 7, 8-dihydroxyflavone on the up-regulation of Nrf2-mediated heme oxygenase-1 expression in hamster lung fibroblastsIn Vitro Cell Dev Biol Anim.(2014 Jun)
- ^Su ZY1, Shu L, Khor TO, Lee JH, Fuentes F, Kong ANA perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, nrf2, and epigenomicsTop Curr Chem.(2013)
- ^Kim KC1, Lee IK, Kang KA, Cha JW, Cho SJ, Na SY, Chae S, Kim HS, Kim S, Hyun JW7,8-Dihydroxyflavone suppresses oxidative stress-induced base modification in DNA via induction of the repair enzyme 8-oxoguanine DNA glycosylase-1Biomed Res Int.(2013)
- ^Chen J1, Chua KW, Chua CC, Yu H, Pei A, Chua BH, Hamdy RC, Xu X, Liu CFAntioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicityNeurosci Lett.(2011 Jul 25)
- ^Han X1, Zhu S2, Wang B3, Chen L3, Li R3, Yao W2, Qu Z4Antioxidant action of 7,8-dihydroxyflavone protects PC12 cells against 6-hydroxydopamine-induced cytotoxicityNeurochem Int.(2014 Jan)
- ^Liu X1, Chan CB, Qi Q, Xiao G, Luo HR, He X, Ye KOptimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depressionJ Med Chem.(2012 Oct 11)
- ^Otake Y1, Hsieh F, Walle TGlucuronidation versus oxidation of the flavonoid galangin by human liver microsomes and hepatocytesDrug Metab Dispos.(2002 May)
- ^Harris RM1, Wood DM, Bottomley L, Blagg S, Owen K, Hughes PJ, Waring RH, Kirk CJPhytoestrogens are potent inhibitors of estrogen sulfation: implications for breast cancer risk and treatmentJ Clin Endocrinol Metab.(2004 Apr)
- ^Keung WM1, Klyosov AA, Vallee BLDaidzin inhibits mitochondrial aldehyde dehydrogenase and suppresses ethanol intake of Syrian golden hamstersProc Natl Acad Sci U S A.(1997 Mar 4)
- ^Noble EE1, Billington CJ, Kotz CM, Wang CThe lighter side of BDNFAm J Physiol Regul Integr Comp Physiol.(2011 May)
- ^Kaplan DR1, Miller FDNeurotrophin signal transduction in the nervous systemCurr Opin Neurobiol.(2000 Jun)
- ^Arevalo JC1, Conde B, Hempstead BL, Chao MV, Martin-Zanca D, Perez PTrkA immunoglobulin-like ligand binding domains inhibit spontaneous activation of the receptorMol Cell Biol.(2000 Aug)
- ^Spencer JPFood for thought: the role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performanceProc Nutr Soc.(2008 May)
- ^Zhang Z1, Liu X2, Schroeder JP3, Chan CB2, Song M4, Yu SP4, Weinshenker D3, Ye K27,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer's diseaseNeuropsychopharmacology.(2014 Feb)
- ^Devi L1, Ohno M7,8-dihydroxyflavone, a small-molecule TrkB agonist, reverses memory deficits and BACE1 elevation in a mouse model of Alzheimer's diseaseNeuropsychopharmacology.(2012 Jan)
- ^Tyler WJ1, Pozzo-Miller LDBDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapsesJ Neurosci.(2001 Jun 15)
- ^Chen C1, Li XH, Zhang S, Tu Y, Wang YM, Sun HT7,8-dihydroxyflavone ameliorates scopolamine-induced Alzheimer-like pathologic dysfunctionRejuvenation Res.(2014 Jun)
- ^Lin AJ1, Castello NA, Lee G, Green KN, Durkin AJ, Choi B, LaFerla F, Tromberg BJIn vivo optical signatures of neuronal death in a mouse model of Alzheimer's diseaseLasers Surg Med.(2014 Jan)
- ^English AW1, Liu K, Nicolini JM, Mulligan AM, Ye KSmall-molecule trkB agonists promote axon regeneration in cut peripheral nervesProc Natl Acad Sci U S A.(2013 Oct 1)
- ^Iwasaki Y1, Ishikawa M, Okada N, Koizumi SInduction of a distinct morphology and signal transduction in TrkB/PC12 cells by nerve growth factor and brain-derived neurotrophic factorJ Neurochem.(1997 Mar)
- ^Ren Q1, Zhang JC, Ma M, Fujita Y, Wu J, Hashimoto K7,8-Dihydroxyflavone, a TrkB agonist, attenuates behavioral abnormalities and neurotoxicity in mice after administration of methamphetaminePsychopharmacology (Berl).(2014 Jan)
- ^Ren Q1, Zhang JC, Fujita Y, Ma M, Wu J, Hashimoto KEffects of TrkB agonist 7,8-dihydroxyflavone on sensory gating deficits in mice after administration of methamphetaminePharmacol Biochem Behav.(2013 May)
- ^Park HY1, Park C2, Hwang HJ3, Kim BW4, Kim GY5, Kim CM6, Kim ND1, Choi YH77,8-Dihydroxyflavone attenuates the release of pro-inflammatory mediators and cytokines in lipopolysaccharide-stimulated BV2 microglial cells through the suppression of the NF-κB and MAPK signaling pathwaysInt J Mol Med.(2014 Apr)
- ^Park HY1, Kim GY, Hyun JW, Hwang HJ, Kim ND, Kim BW, Choi YH7,8-Dihydroxyflavone exhibits anti-inflammatory properties by downregulating the NF-κB and MAPK signaling pathways in lipopolysaccharide-treated RAW264.7 cellsInt J Mol Med.(2012 Jun)
- ^Bahi A1, Boyer F, Chandrasekar V, Dreyer JLRole of accumbens BDNF and TrkB in cocaine-induced psychomotor sensitization, conditioned-place preference, and reinstatement in ratsPsychopharmacology (Berl).(2008 Aug)
- ^Otis JM1, Fitzgerald MK, Mueller DInfralimbic BDNF/TrkB enhancement of GluN2B currents facilitates extinction of a cocaine-conditioned place preferenceJ Neurosci.(2014 Apr 23)
- ^Uluc K1, Kendigelen P, Fidan E, Zhang L, Chanana V, Kintner D, Akture E, Song C, Ye K, Sun D, Ferrazzano P, Cengiz PTrkB receptor agonist 7, 8 dihydroxyflavone triggers profound gender- dependent neuroprotection in mice after perinatal hypoxia and ischemiaCNS Neurol Disord Drug Targets.(2013 May 1)
- ^Almli CR1, Levy TJ, Han BH, Shah AR, Gidday JM, Holtzman DMBDNF protects against spatial memory deficits following neonatal hypoxia-ischemiaExp Neurol.(2000 Nov)
- ^Wang B1, Wu N, Liang F, Zhang S, Ni W, Cao Y, Xia D, Xi H7,8-dihydroxyflavone, a small-molecule tropomyosin-related kinase B (TrkB) agonist, attenuates cerebral ischemia and reperfusion injury in ratsJ Mol Histol.(2014 Apr)
- ^Chen L, Gao X, Zhao S, Hu W, Chen JThe Small-Molecule TrkB Agonist 7, 8-Dihydroxyflavone Decreases Hippocampal Newborn Neuron Death After Traumatic Brain InjuryJ Neuropathol Exp Neurol.(2015 Jun)
- ^Andero R1, Daviu N, Escorihuela RM, Nadal R, Armario A7,8-dihydroxyflavone, a TrkB receptor agonist, blocks long-term spatial memory impairment caused by immobilization stress in ratsHippocampus.(2012 Mar)
- ^Baker-Andresen D1, Flavell CR, Li X, Bredy TWActivation of BDNF signaling prevents the return of fear in female miceLearn Mem.(2013 Apr 15)
- ^Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, Han M, Hashimoto KComparison of ketamine, 7,8-dihydroxyflavone, and ANA-12 antidepressant effects in the social defeat stress model of depressionPsychopharmacology (Berl).(2015 Dec)
- ^Zeng Y1, Liu Y, Wu M, Liu J, Hu QActivation of TrkB by 7,8-dihydroxyflavone prevents fear memory defects and facilitates amygdalar synaptic plasticity in agingJ Alzheimers Dis.(2012)
- ^Zeng Y1, Tan M, Kohyama J, Sneddon M, Watson JB, Sun YE, Xie CWEpigenetic enhancement of BDNF signaling rescues synaptic plasticity in agingJ Neurosci.(2011 Dec 7)
- ^Bollen E1, Vanmierlo T, Akkerman S, Wouters C, Steinbusch HM, Prickaerts J7,8-Dihydroxyflavone improves memory consolidation processes in rats and miceBehav Brain Res.(2013 Nov 15)
- ^Zhou W, Li X, Huang D, Zhou W, Li T, Song WNo significant effect of 7,8-dihydroxyflavone on APP processing and Alzheimer-associated phenotypesCurr Alzheimer Res.(2015)
- ^Huai R1, Han X, Wang B, Li C, Niu Y, Li R, Qu ZVasorelaxing and antihypertensive effects of 7,8-dihydroxyflavoneAm J Hypertens.(2014 May)
- ^Pelleymounter MA, Cullen MJ, Wellman CLCharacteristics of BDNF-induced weight lossExp Neurol.(1995 Feb)
- ^Numakawa T, Suzuki S, Kumamaru E, Adachi N, Richards M, Kunugi HBDNF function and intracellular signaling in neuronsHistol Histopathol.(2010 Feb)
- ^Poduslo JF, Curran GLPermeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNFBrain Res Mol Brain Res.(1996 Mar)
- ^Yu Q, Chang Q, Liu X, Wang Y, Li H, Gong S, Ye K, Lin XProtection of spiral ganglion neurons from degeneration using small-molecule TrkB receptor agonistsJ Neurosci.(2013 Aug 7)
- ^Chan CB, Tse MC, Liu X, Zhang S, Schmidt R, Otten R, Liu L, Ye KActivation of muscular TrkB by its small molecular agonist 7,8-dihydroxyflavone sex-dependently regulates energy metabolism in diet-induced obese miceChem Biol.(2015 Mar 19)
- ^Lohof AM1, Ip NY, Poo MMPotentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNFNature.(1993 May 27)
- ^Garcia N1, Santafe MM, Tomas M, Lanuza MA, Besalduch N, Tomas JNeurotrophin-4 couples to locally modulated ACh release at the end of neuromuscular synapse maturationNeurosci Lett.(2010 Jan 1)
- ^Garcia N1, Tomàs M, Santafé MM, Besalduch N, Lanuza MA, Tomàs JThe interaction between tropomyosin-related kinase B receptors and presynaptic muscarinic receptors modulates transmitter release in adult rodent motor nerve terminalsJ Neurosci.(2010 Dec 8)
- ^Mantilla CB1, Ermilov LGThe novel TrkB receptor agonist 7,8-dihydroxyflavone enhances neuromuscular transmissionMuscle Nerve.(2012 Feb)
- ^Davie JR1, He S, Li L, Sekhavat A, Espino P, Drobic B, Dunn KL, Sun JM, Chen HY, Yu J, Pritchard S, Wang XNuclear organization and chromatin dynamics--Sp1, Sp3 and histone deacetylasesAdv Enzyme Regul.(2008)
- ^Li L1, Davie JRThe role of Sp1 and Sp3 in normal and cancer cell biologyAnn Anat.(2010 Sep 20)
- ^Lee RH1, Shin JC2, Kim KH3, Choi YH4, Chae JI1, Shim JH3Apoptotic effects of 7,8-dihydroxyflavone in human oral squamous cancer cells through suppression of Sp1Oncol Rep.(2015 Feb)
- ^Al-Qudah M1, Anderson CD, Mahavadi S, Bradley ZL, Akbarali HI, Murthy KS, Grider JRBrain-derived neurotrophic factor enhances cholinergic contraction of longitudinal muscle of rabbit intestine via activation of phospholipase CAm J Physiol Gastrointest Liver Physiol.(2014 Feb 15)
- ^Sconce MD1, Churchill MJ1, Moore C1, Meshul CK2Intervention with 7,8-Dihydroxyflavone Blocks Further Striatal Terminal Loss and Restores Motor Deficits in a Progressive Mouse Model of Parkinson's DiseaseNeuroscience.(2015 Feb 2)
- ^Kaufman S1Tyrosine hydroxylaseAdv Enzymol Relat Areas Mol Biol.(1995)
- ^Zhu Y1, Zhang J, Zeng YOverview of tyrosine hydroxylase in Parkinson's diseaseCNS Neurol Disord Drug Targets.(2012 Jun 1)
- ^Korkmaz OT1, Aytan N2, Carreras I3, Choi JK4, Kowall NW2, Jenkins BG4, Dedeoglu A57,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosisNeurosci Lett.(2014 Apr 30)
- ^Lechtzin NRespiratory Effects of Amyotrophic Lateral Sclerosis: Problems and SolutionsRespir Care.(2006 Aug)
- ^Shahbazian M1, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Noebels J, Armstrong D, Paylor R, Zoghbi HMice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3Neuron.(2002 Jul 18)
- ^Chang Q1, Khare G, Dani V, Nelson S, Jaenisch RThe disease progression of Mecp2 mutant mice is affected by the level of BDNF expressionNeuron.(2006 Feb 2)
- ^Johnson RA1, Lam M, Punzo AM, Li H, Lin BR, Ye K, Mitchell GS, Chang Q7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndromeJ Appl Physiol (1985).(2012 Mar)