Honokiol

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Abstract from referenced paper [1]

Activated mitophagy and mitochondrial unfolded protein response (UPR^mt) has been reported to protect against mitochondrial dysfunction, which is closely related to the onset of Alzheimer’s disease (AD). Honokiol (HKL, C₁₈H₁₈O₂) is a kind of natural extraction from bark of Magnolia officinalis with anti-AD effect, and our study aims to explore the effect of HKL on mitophagy and UPR^mt in AD. Briefly, male APP/PS1 mice and Aβ oligmer (AβO)-treated primary hippocampal neurons were respectively used to mimic AD in vivo and in vitro. It was determined that HKL significantly ameliorated cognitive impairment and synaptic damages in APP/PS1 mice. Besides, the activated mitophagy and UPR^mt together with inhibited oxidative stress and improved mitochondrial dynamic disorder were further validated in hippocampus of HKL-treated APP/PS1 mice. Meanwhile, HKL-treated mice displayed much higher hippocampal expression and activity of mitochondrial sirtuin 3 (SIRT3). Therefore, SIRT3 knockdown was further achieved in primary hippocampal neurons by effective shRNA, and we determined that HKL improved synaptic damage, mitochondrial dysfunction, mitophagy and UPR^mt in AβO-treated primary hippocampal neurons in a SIRT3-dependent manner. In summary, our study validates the protective effect of HKL on AD, and highlights that HKL exerts anti-AD effect by activating mitophagy and UPR^mt.

Keywords: Alzheimer’s disease; Honokiol;UPR, unfolded protein repsonse; SIRT3, sirtuin 3;

What is Sirt3?

Dr Wenzhen Duan of John Hopkins University wrote an interesting review on sirtuins, primarily Sirt1 and Sirt3. [2]

partial list of enzymes regulated by acetylation/Sirt3 activity [2]

• long-chain acyl coenzyme A dehydrogenase (LCAD) a key enzyme that breaks down fatty acids and generates acetyl-CoA
• other β-oxidation enzymes, including the short-chain L-3-hydroxyacyl-CoA dehydrogenase and the very-long-chain acyl coenzyme A dehydrogase facilitating mitochondrial adaptation to fuel changes.
• l cyclophilin D, which leads to the dissociation of hexokinase II and mitochondria from the outer membrane of the mitochondria, decreases glucose metabolism, and stimulates oxidative phosphorylation
• isocitrate dehydrogenase 2 (IDH2) is one of the first enzyms after acetylCoA enters the TCA cycle pictured below.
• NADH dehydrogenase 1 alpha sub complex subunit 9 (NDUFA9), This is where NADH +H⁺ enters the OXPHOS electron transport chain below.
• complex I. Complex II, of the electron transport chain
• mitochondrial MnSOD a scavenger of reactive oxygen species superoxide.
• 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a mitochondrial enzyme that converts acetyl-CoA into ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone)

Where is Sirt3 expressed?

Noteworthy is how ubiquitous the expression of Sirt3 really is.

Retracing of steps, does reveratrol really activate Sirt3? [3]

Some background on the rcsb.org structure of Sirt3 with bromo-resveratrol was speculated to be an inhibitor of both Sirt1 and Sirt3. This abstract made it uncertain if red wine resveratrol is in fact an activator of both Sirt1 and Sirt3. The 2020 Wang publication spells it out in uncertain terms that not only does resveratrol activate Sirt3, it also promotes angiotensin II induced cardiac cell hypertrophy as a cell culture model of whole organ angiotensin II induced cardiac hypertrophy. [3] The investigators found that Angiotensin II increased the expression of “bad” genes and decrased the expression of “good” genes. [3]. Resveratrol can not only activate the expression of its target Sirt3 but also activate the transcription of autophagy related genes thus promoting the removal of damaged mitgochondria via autophagy. [3] This protective effect was blocked by silencing mRNA that prevented the translation of SIRT3 mRNA into the enzyme. [3] So now that we’ve double checked on honokiol’s polyphenol cousin resveratrol, let’s take a look at this not so well known polyphenol.

Honokiol in cardiac myocytes and mice

A followup study came out of Emory University, North Western fUniversity, and University of Chicago. This group used wildtype (normal) and Sirt3 knockout mice as well as their cultured cardiac myocytes. [4] The following image is from summary Figure 10 [4] Data from the paper deemed particularly interesting are pasted into the summary figure 10 Structurally somewhat similar honokiol was used as the putative Sirt3 agonist. [4]

• Panel 9B This is a Western blot for total mitochondrial Manganese Superoxide Dismutase (MnSOD) showing total (bottom) and just the acetylated (top). The more hnokiol that was added to the myocytes, the less intense the acetylated MnSOD bands while the intensity of the total remains the same. These data point to a direct effect on deleterious signally via reactive oxygen species.
• Panel 9 The authors used a technique called fluorescence anisotropy. What is exciting about these data is that they suggest a direct interaction.
• Panel 4D is an interesting representative visual.
• Panel 9F illustrates the ability of honokiol to activate genes whose transcription is controlled by the PGC1α transcription factor. Transcription factors bind to regulatory elements upstream of the protein coding parts of the protein coding parts of genes. Transcription factors bring in RNA polymerase that transcribes the code into messenger RNA. mRNA is translated into protein by ribosomes.

Not shown are data showing improvements in mitochondrial bioenergetics and much more. The next quetion is , “Is this compound safe?”

Toxicology Studies

Not all vendors on Amazon or Ebay tell us what compounds are in their extracts of magnolia bark. They also don’t tell us what methodology they use to extract the bark. The good thing about Clinical Synergy is that they seem to know that it is mostly honokiol with no magnoliol.

The parts of the magnolia, the species, and the region it was grown have an influence on the relative proportions of magnoliol and honokiol. [5] The genetic toxicology studies seemed limited according to this review. [5]

This review also covers honokiol and magnoliol modulation of the GABA A receptor and cannabinoid receptors CB1, CB2, and GPR55. The GABA A receptor binds gamma amino butyric acid.

Metabolism of honokiol

treatment
Single or repeated doses of [14C] magnolol were orally or i. p. administered to male Wistar rats	Radioactivity mainly distributed in the gastrointestinal tract and liver, but also in kidney, pancreas and lung. A similar excretion dynamic was observed after a single oral and i. p. administration. Within 12 – 24 h more than 72% of magnolol was excreted in feces and 24% in urine. Repeated oral doses resulted in the accumulation of magnolol sulfates/glucuronides but not free magnolol
Magnolol was orally administered at the dose of 20 mg/kg b. w. to male Sprague-Dawley rats	Thirty minutes after the administration the concentration of glucoronidated magnolol and free magnolol were 1.79 µg/mL and 0.16 µg/mL, respectively
Magnolol was orally administered at 5 – 100 mg/kg/b. w. to male Sprague-Dawley rats	The absorption half-life was 0.63 h, the elimination half-life 2.33 h, the time of maximum concentration 1.12 h, and the maximum concentration is 0.16 µg/mL. Oral bioavailability was 4 – 9%. The locomotor activity, measured as indicative of the pharmacodynamic profile, was affected starting from 20 mg/kg/b. w.
Magnolol was administered i. v. at 2 – 10 mg/kg b. w. to male Sprague-Dawley rats	Increasing dosages have same half-life but increasing AUC. Magnolol distributes evenly in different brain regions with concentration higher than plasma
Magnolol was administered to male Sprague-Dawley rats as a single i. v. dose 20 mg/kg b. w. or as single or multiple oral doses (50 mg/kg/b. w.)	Comparable levels of magnolol and magnolol glucuronides were found in the blood after i. v. administration whereas in orally treated rats the levels of magnolol glucuronides and sulfates were higher than that of free magnolol. The highest concentrations were found in the liver. Magnolol was found also in kidney, brain, lung, and heart
Honokiol was administered i. v. to male Sprague-Dawley rats at the dose of 5 – 10 mg/kg b. w.	A biphasic process consisting of a rapid distribution phase followed by a slower elimination phase was observed from the plasma concentration-time curves
Honokiol was orally administered to male Wistar rats at 40 mg/kg/b. w.	Honokiol was rapidly absorbed reaching its maximal plasma concentration within 20 min. It was rapidly metabolized to mono-glucuronidated honokiol and slowly eliminated (T1/2 = 290.4 min). Honokiol rapidly distributed in liver, kidney, and brain. The concentrations of honokiol and its metabolites were highest in liver, followed by kidney and brain. At central level only honokiol was detected indicating that its metabolites cannot cross the blood-brain barrier
M. officinalis cortex extract (corresponding to 12.78 mg/kg b. w. of magnolol) was administered intragastrically to male Sprague-Dawley rats	Within the first 35 min of administration, magnolol and honokiol crossed the blood brain barrier and accumulated in different brain regions
Healthy subjects and asthmatic patients were treated with 5 g/d of Saiboku-To (corresponding to 2.1 mg/d of magnolol)	Both asthmatic patients and the healthy subjects excreted the 10% of administered magnolol in the urine within 9 h. About the 95% of urinary magnolol were glucuronidated

Future outlook?

It is maybe a little troubling that Clinical Synergy is packaging their honokiol as a GABAA receptor modulator and then advertising it elsewhere as treatment for Alzheimer’s via the mitochondrial unfolded protein response. [1] Then another study suggests that it acts as a mitochondrial Sirt3 activator. [4] A rather extensive review on mostly rodent toxicology studies suggests that honokiol is safe. [5] The data certainly seem exciting. Clinical Synergy seems to care about purity.

References

1. Hou M, Bao W, Gao Y, Chen J, Song G. Honokiol improves cognitive impairment in APP/PS1 mice through activating mitophagy and mitochondrial unfolded protein response. Chem Biol Interact. 2022 Jan 5;351:109741. doi: 10.1016/j.cbi.2021.109741. Epub 2021 Nov 6. PubMed
2. Duan W. Sirtuins: from metabolic regulation to brain aging. Front Aging Neurosci. 2013 Jul 23;5:36. PMC free article
3. Wang HN, Li JL, Xu T, Yao HQ, Chen GH, Hu J. Effects of Sirt3‑autophagy and resveratrol activation on myocardial hypertrophy and energy metabolism. Mol Med Rep. 2020 Aug;22(2):1342-1350 PMC free article
4. Pillai VB, Samant S, Sundaresan NR, Raghuraman H, Kim G, Bonner MY, Arbiser JL, Walker DI, Jones DP, Gius D, Gupta MP. Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat Commun. 2015 Apr PMC free article
5. Sarrica A, Kirika N, Romeo M, Salmona M, Diomede L. Safety and Toxicology of Magnolol and Honokiol. Planta Med. 2018 Nov;84(16):1151-1164. PMC free article