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Adhyperforin is a phytochemical that is a member of the plant genus Hypericum, which includes plants such as St. John's Wort. It has a very similar pharmacological profile to hyperforin and acts as a TRPC6 ion channel activator, meaning it inhibits the reuptake of neurotransmitters such as serotonin, norepinephrine, dopamine, GABA, and glutamate.

A phloroglucinol derivative of H. perforatum, adhyperforin is primarily used as an antidepressant. It is part of the lipophilic extract of St. John's Wort, and demonstrates a variety of therapeutic effects, including treatment of wounds, burns, cuts, hemorrhoids, gastric spasms, insomnia, and muscular pain.

Chemical Properties
Adhyperforin is soluble in methanol and ethanol. When fully dissolved, it produces a slightly colored solution. Like other hyperforins, adhyperforin is extremely unstable, particularly when solid. Solid adhyperforin will break down rapidly when exposed to oxygen and light. Its complete degradation process takes approximately 25 minutes.

Compound History
While St. John's Wort is known for its antidepressive properties, hyperforin was conventionally assumed to be the factor responsible for its therapeutic effects. A number of studies used hyperforin-enriched lipophilic extracts to demonstrate hyperforin's role in decreasing neurotransmitter reuptake. In 2003, experiments using St. John's Wort with hyperforin and hypericin extracts revealed that neither were necessary to produce St. John's Wort's antidepressive effects. Following this discovery, the role of adhyperforin in St. John's Wort has been increasingly investigated.

Pharmacodynamics
Adhyperforin is more potent than hyperforin, another phloroglucinol derivative of H. perforatum. Both compounds are among the primary active ingredients of St. John’s Wort, but other derivatives found in the lipophilic portion of the plant are also necessary for St. John's Wort to be able to exert its full effect.

Although the binding site for adhyperforin on the TRPC6 ion channel is still unknown, binding of adhyperforin to its receptor results in similar antidepressive effects to those of selective serontonin reuptake inhibitors and norepinephrine reuptake inhibitors. Adhyperforin has been shown to inhibit the reuptake of serotonin, norepinephrine, dopamine, and choline neurotransmitters when administered at potencies comparable to those of existing drugs. While adhyperforin demonstrates high binding affinities for NET and SERT, the exact mechanism for the inhibitory activity of adhyperforin on dopamine reuptake remains unclear. Further investigation is needed to determine the components of this pathway.

Adhyperforin also inhibits reuptake of GABA and glutamate via activation of TRPC6. Additionally, adhyperforin activates the pregnane X receptor. As a triple-reuptake inhibitor, adhyperforin is able to increase the amount of monoamines in the synaptic cleft.

Pharmacokinetics
Pharmacokinetic study of isolated adhyperforin remains to be conducted in humans.

In mouse models, adhyperforin has an ID50 value of 0.30mmol cm-2. Adhyperforin also exhibits strong binding affinities to SERT (Ki=18.75±7.76 μg/ml) and NET (Ki=4.03±0.37 μg/ml).

Treatment
St. John’s Wort has historically been used in traditional healing practices. The lipophilic extract of St. John's Wort, which primarily contains adhyperforin and hyperforin as active ingredients, is often used by traditional healers to act as an antimicrobial or anti-inflammatory agent. In modern allopathic medicine, adhyperforin and hyperforin contribute to St. John's Wort's antidepressive effects, as well. While the medicinal properties of St. John's Wort are well understood in humans, the effects of adhyperforin alone have not been extensively studied.

The effects of adhyperforin administration have been briefly explored in animal models, particularly in rats. Rat models support adhyperforin as a potential antidepressant. Behavioral testing assays conducted with rats have illustrated that treatment with adhyperforin successfully antagonized the effects of reserpine. When administered to a rat model for chronic unpredictable mild stress, adhyperforin significantly improved rats’ anhedonia and hypoactivity, further demonstrating antidepressant-like properties.

In mouse models, solutions containing both adhyperforin and hyperforin inhibit edema. The application of the oily extract of St. John’s Wort, which contains hyperforin and adhyperforin, has also been shown to reduce ear inflammation in rats. This suggests that adhyperforin may perform an antiphlogistic role in the body.

As St. John's Wort continues to be a widely administered herbal oral and topical medication, adhyperforin is also widely, albeit perhaps unknowingly, used.

Side Effects
At this point, little is known about what adhyperforin's potential side effects would be if administered as an antidepressant alone--further research and clinical trials still need to be conducted. It is believed, however, that H. perforatum extracts such as adhyperforin may have an advantage over drugs that are traditionally associated with the treatment of depression, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, because the H. perforatum extracts may have fewer side effects and be cheaper than the available alternatives.

Synthesis/Derivation
Adhyperforin is traditionally isolated from the generative parts of St. John’s Wort plants, particularly from their unripe fruit and flowering parts. Plant material collected when fruits are developing or at the end of their flowering periods yields greater amounts of adhyperforin product than does derivation from fruits during the middle of the flowering season. Regardless of the time at which a sample is obtained, isolation of adhyperforin typically yields ten times less product than does isolation of hyperforin. This ratio depends upon plant processing time, plant locale, and plant environment.

The process itself used to isolate adhyperforin from St. John’s Wort is similar to the isolation method used for hyperforin.

Newer synthesis and isolation methods involve the use of Accelerated Solvent Extraction (ASE) coupled with High-Performance Counter-Current Chromatography (HPCCC) technology. Such methods are promising as they reduce the time necessary for collection, retain a higher adhyperforin purity, and yield high levels of all phloroglucinol extracts.

Other methods utilize supercritical fluid extraction (SFE) with carbon dioxide to isolate all lipophilic compounds from St. John's Wort. SFE is comparable to ultrasonic or boiling methods of isolation in terms of yield of adhyperforin produced.

In order to enhance adhyperforin production, exogenous L-isoleucine and L-threonine is added to shoot cultures. Not all amino acid supplementation causes enhanced production of adhyperforin; for example, the addition of L-valine and L-leucine to root extracts of St. John's Wort does not result in greater yields of adhyperforin.

While the biosynthesis of adhyperforin is often studied in H. perforatum cells, H. calycinum cells are also a useful system for evaluating adhyperforin activity. Because adhyperforin is derived from methylbutyryl-CoA, which is present in higher levels in H. calycinum cells than in H. perforatum, higher yields of adhyperforin are produced from H.calycinum cells. Quantitatively, as in H.perforatum cells, in H. calycinum cell cultures, adhyperforin is produced at ten times the level of hyperforin produced.