All Things Dihydrohonokiol-Beta

Anxiety disorders are the most prevalent mental disorders in modern society and are associated with tremendous healthcare costs and a high burden of disease.

Alarmingly, large surveys suggest that up to 33.7% of the population will be affected by an anxiety disorder during their lifetime [1]. Although helpful prescription medications are available to help these conditions, such as benzodiazepines, they are not recommended for routine use [2]. This fact, and the potential for side effects and withdrawal symptoms highlights possible avenues for alternative non-pharmacological solutions.

Honokiol was first reported as a component of Magnolia obovata, otherwise called the Japanese cucumber tree. Magnolia bark extracts that include honokiol and magnolol are known to activate cannabinoid receptors, with the potential to reduce pain and inflammation, elevate mood, and exert powerful antioxidant effects [3].

Honokiol is one of the key compounds found in traditional Asian medicines [4] and herbal teas, such as houpo and saiboku-tu. Most interestingly, honokiol has been described as possessing anti-angiogenic, anti-inflammatory, and anti-tumor properties in preclinical settings, without any appreciable toxic effects [5-7]. These findings have generated attention for the applications of honokiol as a therapeutic agent, particularly with respect to cancer/tumor suppression.

From a mechanistic standpoint, honokiol blocks signaling in tumors with defective p53 function [5]. The p53 gene is a well-known tumor suppressor gene, in that it stops the formation of tumors, and has been called “the guardian of the genome” [8,9].

Alongside these exciting anti-cancer properties, honokiol has been shown in animal models to possess anti-anxiety (anxiolytic) effects and could have therapeutic potential for pain, cerebrovascular injury, epilepsy, and cognitive disorders such as Alzheimer’s disease [10]. Honokiol can readily cross the blood-brain and blood-cerebrospinal fluid barriers [11], a fact that underpins these beneficial effects.

Early research proposed that metabolites of honokiol might be responsible for its anti-anxiety effect [12], with one in particular being dihydrohonokiol. The synthesis, mechanisms, and profile of this metabolite will be the focus of today’s article.

What is dihydrohonokiol-beta?

Research from the turn of the century proposed that reduced forms of honokiol might yield enhanced anxiolytic activity compared with its parent compound [12,13]. The most promising of these was dihydrohonokiol-beta (DHH-B or 3'-(2 propenyl)-5-propyl-(1,1'-biphenyl)-2,4'-diol), a partially reduced honokiol derivative [13].

How does DHH-B work and what are its benefits?

Studies in mice suggest that DHH-B may act as a benzodiazepine receptor agonist, and its anxiolytic-like activity might be mediated through the GABA-A receptor [12,13]. GABA receptors respond to the neurotransmitter gamma-aminobutyric acid (GABA), which plays an integral role in controlling the powerful emotions of stress, anxiety, and fear [14].

The anxiolytic-like effect of DHH-B was negated by a benzodiazepine receptor blocker (flumazenil) and not by a GABA receptor blocker (bicuculline), but interestingly, DHH-B did not induce any of the withdrawal symptoms associated with benzodiazepines, such as disrupted learning and memory [15].

The potent anxiolytic effects of DHH-B in rodents are partly due to its protective action on neurons, shielding them from ammonia-induced increases in chloride ions, by stimulating GABA-C receptors [16].

Therefore, in contrast to established medications like diazepam, there is less likelihood of eliciting motor dysfunction, sedation, or disinhibition with honokiol and its derivatives such as DHH-B, whilst still reaping the anxiolytic effects due to the divergent pathways of action [12,15].

There is also evidence to suggest that DHH-B has a neuroprotective action against amyloid beta proteins (associated with Parkinson’s disease) in rat hippocampal neurons, mainly through its activity on GABA-C receptors [17].

What are GABA-C receptors?

GABA is the main inhibitory neurotransmitter in the central nervous system, and GABA receptors that are present on the cell membrane interact with it to reduce the excitability of neurons.

GABA-A receptors have a diverse molecular composition and are the targets of many therapeutic compounds (such as general anesthetics, sedative drugs, and alcohols). Although present in many brain regions, GABA-C receptors are particularly concentrated in the retinal neurons and may have a major role in processing signals from the retinal apparatus.

In contrast with the GABA-A receptors which elicit fast and transient responses, GABA-C receptors bring about slow and sustained responses. They are also linked to chloride channels that have their own distinct properties, and are not modulated by compounds known to affect GABA-A receptors, such as benzodiazepines and barbiturates [18,19].

What about dosing?

Unfortunately, there are no studies of DHH-B in humans, with existing research conducted in rodent and cell-based models to understand the mechanisms of DHH-B action. As such, there is no published dosing information available from which to get a rational, substantiated figure. As more research and knowledge from human trials becomes available on DHH-B, a more concrete dosing figure for this will become apparent.

Contraindications

Although DHH-B has shown early promise as an anxiolytic, those that would like to substitute their prescription anxiety medication (such as benzodiazepines) should consult their physician before doing so.

Summary

In today’s article we discussed anxiety disorders as a major societal problem and provided some information on the potent anxiolytic effect of DHH-B, a partially reduced derivative of honokiol.

Magnolia bark extracts, including magnolol and honokiol, are potent anxiolytics due to their action on GABA receptors [20], but could also offer promising applications as anti-cancer compounds.

Although existing research has only been conducted in cell-based or rodent models, these studies highlight the promise of DHH-B as an anti-anxiety compound as well as a neuroprotective against Parkinson’s disease.

To date, no dosing information is available in the published literature for humans, however the potential for DHH-B as an alternative to traditional prescription medications for helping anxiety could be far-reaching.

References

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