7,8-DHF is a natural flavonoid which can reach the brain and activate a receptor (TrkB) that promotes neuronal growth. Some animal evidence suggests that 7,8-DHF may have some cognitive and motor benefits and may be nootropic, but no human evidence for these claims exists to date.
7,8-Dihydroxyflavone is most often used for
Sources and Composition
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). 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.
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.
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. 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. TrkB normally is activated by the peptide known as brain-derived neurotrophic factor (BDNF) and, upon activation, promotes survival and growth of neurons. 7,8-DHF can mimic these actions with high potency (Kd 1 nM for DNF versus 320 nM for 7,8-DHF ), also via binding to and activating TrkB. 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.
The actions of 7,8-DHF on the TrkB receptor depend on the 7,8-catechol portion of the molecule. 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.
7,8-DHF has potent neurotrophic effects that mimic the endogenous neuropeptide BDNF, also binding to and activating the TrkB receptor.
7,8-DHF has been noted to increase expression of the antioxidant protein Nrf2, which is downstream of PI3K/Akt signaling. 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). 7,8-DHF has been shown to induces HO-1 expression in some cells and also induces 8-oxoguanine DNA glycosylase-1 (OGG1) in a manner dependent on PI3K/Akt.
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, 7,8-DHF has also demonstrated antioxidant effects in cells that do not express this receptor (PC12 and HT-22 cells). This suggests that 7,8-DHF may activate Akt signaling via TrkB dependent, and independent mechanisms.
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.
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,it is subject to significant first-pass metabolism. While poor absorption is a property inherent to flavonoids, 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.
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. TrkA is a similar receptor that responds to neural growth factor (NGF).
Flavonoids in general have been known to interact with neurons in a growth-promoting manner. 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). This was secondary to TrkB activation, did not activate TrkA, and did not require BDNF. The degree of activation was comparable to BDNF when tested in vitro.
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. 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. 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%. BDNF (by activating TrkB) is known to promote growth of thin spine density dendrites which has been observed in vivo in diseased mice. Total number of axon terminals may not be increased in response to 7,8-DHF, rather just the density of dendrites.
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. In a transgenic model of Alzheimer's disease where hippocampal cells are selectively destroyed (CaM/Tet-DTA mice), 7,8-DHF has shown a restorative effect on synaptic density with 5 mg/kg injections, affecting only the neurons that were damaged. 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.
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.
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.
Incubation of 7,8-DHF in PC12 cells has been noted to confer protective effects against an oxidative stressor (6-OHDA) despite these cells not normally expressing the TrkB receptor (although they can be transfected to stably express it), a protective effect that has been replicated against glutamate-induced oxidation in another cell line lacking the TrkB receptor (HT-22).
Neurotoxicity induced by methamphetamine has been reduced with an acute oral preload of 7,8-DHF (30mg/kg in the mouse) 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 in a manner dependent on the TrkB receptor.
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.
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; these actions are also seen in macrophages and in both cell lines it results in less inflammation-mediated release of the cytokines TNF-α and IL-1β.
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.
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 but this effect was also replicated with 7,8-DHF injections. Activation of TrkB appears to enhance signalling via an NMDA subunit known as GluN2B which is pivotal to these effects.
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.
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. Similar effects have been seen elsewhere with direct administration of BDNF.
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 and ischemia/reperfusion injury, 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.
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.
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. This benefit with 7,8-DHF before immobilization have been noted elsewhere in mice 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.
A single administration of 5mg/kg to rats without any stressor present does not appear to influence anxiety-like behaviour.
Administration of this flavonoid exerts a possible beneficial effect on the effects of stress on learning, which does not extend to nonstressed controls.
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.
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.
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 or as a daily injection over the course of four weeks.
There are reported cognitive benefits to otherwise healthy aged rodents with 5mg/kg 7,8-DHF injections regarding fear learning which is thought to be related to how BDNF signalling (via TrkB) itself helps preserve cognition during aging via rescuing defects in synaptic plasticity.
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.
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.
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.
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.
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. 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. 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.
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.
Obesity and Fat Mass
Direct brain infusions of brain-derived neurotrophic factor (BDNF) have been shown to suppress food intake in rats through a mechanism most likely related to BDNF binding to its receptor, known as TrkB. However, the short half-life and poor penetration of the blood-brain barrier makes BDNF itself a poor candidate for weight loss. Since 7,8-DHF also acts on TrkB 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. 
7,8-DHF may prevent diet-induced obesity in mice through a muscle-dependent mechanism.
Skeletal Muscle and Physical Performance
Neurotrophins (such as BDNF and NT-4) are known to be involved in muscular contractions, where ligand-activated TrkB interacts with presynaptic muscarinic receptors promoting acetylcholine release in motor neurons. Neuromuscular transmission to muscle (diaphragm) in isolated mouse cells is enhanced (32%) by 10µM 7,8-DHF due to enhanced neuromuscular transmission rates. 7,8-DHF did not affect isometric contractile and fatigue properties of the diaphragm muscle, however.
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.
Interactions with Cancer Metabolism
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. Several types of cancer have been shown to overexpress Sp1, indicating that it may be an important molecular target in cancer therapy. 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.
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.
Peripheral Organ Systems
The actions of brain-derived neurotrophic factor (BDNF) on its receptor TrkB are known to enhance cholinergic transmission. This action is mimicked by 7,8-DHF in both diaphragm muscle and intestinal muscle cells. When TrkB is activated by 7,8-DHF in intestinal muscle cells, cholinergic agonist-induced contraction is enhanced in a PLC-dependent manner.
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.
Interactions with Medical Conditions
When incubated with primary neurons in vitro, 7,8-DHF (500 nM) greatly reduced Aβ –induced toxicity in a manner dependent on TrkB.
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. 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.
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.
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. Notably, increased TrkB phosphorylation occurred alongside restoration of memory deficits. 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.
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.
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. 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. Tyrosine hydroxylase is the enzyme which converts tyrosine to L-DOPA, and reduction of this enzyme is a crucial step in the development of Parkinson's disease.
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.
An increase in neuromuscular transmission has been noted with 7,8-DHF incubation (10 µM) in diaphragm muscles of the mouse, which may be relevant to ALS, where the leading cause of death is respiratory failure.
Preliminary animal evidence suggests that 7,8-DHF may have therapeutic potential for ALS, although no human studies have been performed to date.
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.
In a transgenic mouse model of Rett syndrome (Mecp2-null mice), which has reduced BDNF expression relative to healthy controls, both normalization of BDNF concentrations and oral ingestion of 7,8-DHF (80mg/L drinking water; estimated intake of 8-12mg/kg from 2-3mL drank daily) 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.