Honokiol and Sirt3

Back in the day I was assisting a client decipher the scientific literature concerning a compound called honokiol, an extract from magnolia bark. Magnolol is a very similar compound also found magnolia bark extracts. There three targets of hinokiol: the longevity deacetylase sirtuin 3,the Retinoid X receptor alpha transcription factor, and the GABA_A receptor. Benzodiazepine tranquilizers are positive allosteric modulators of the GABA_A chloride channel. Many use PEMF mats for general wellness. Could PEMF mats be used with magnolia bark extracts used in Traditional Chinese Medicine and other traditional medicines. I would personally only combine the two with the supervision of a practitioner schooled in the use of traditional medicines.

What is Sirt3?

In 2013 Dr Wenzhen Duan of John Hopkins University wrote an interesting review on sirtuins, primarily Sirt1 and Sirt3. All we need to know is that Sirt3 is an enzyme that removes an inhibitory acetyl group from a lysine and places it on NAD⁺, something we have a lot of when our mitochondria are producing ATP. When we eat a lot of fat and carbohydrates, the TCA cycle loads with H⁺ and electrons to give us NADH. NADH feeds those electrons into the electron transport chain to fuel the production of ATP. Fig 1 of Duan 2013 gives a good overview of the role of sirtuins in longevity.

A brief nod to three targets of honokiol

Sirtuin was briefly mentioned in the PEMF and Schumann Resonances post. In a cell culture model with human intervertebral disc tissue and a rat IVD model four hours a day of 15 Hz and an undisclosed field strength. PMC free paper. PEMF was found to increase the expression of extracellular matrix proteins while increasing the activity of Sirt1 and autophagy of degenerated nucleus pulposus (NP) cells of intervertebral disc tissue. This will be a separate post. The argument is that honokiol might synergize with PEMF applications. Consult your practitioner before combining PEMF and traditional medicine. It is recommended that you keep your exposure to a small test area before exposing larger portions of your body for longer periods of time

• A 2022 publication suggested that honokiol is effective in ameliorating cognitive impairment and mitochondrial dysfunction in a rodent and cell culture models of Alzheimer’s Disease.(Hou 2022) Activation of sirtuin 3, Sirt3, was the proposed mechanism.
• Honokiol and magnolol are positive allosteric modualators of the GABAA receptor meaning that it takes less gamma amino butyric acid (GABA) to cause this chloride channel to open and hyperpolarize the neuron in question. This inter-relatedness of GABA, the agonist, the GABA receptors A and B, and sirt1 was demonstrated in pancreatic beta cells. Both GABA_A and GABA_B agonists increased Sirt1 and NAD⁺ levels in a manner that was blocked by antagonists of both receptors. (Alexeev 2022)
• Back in 2010 a methanol extract of magnolia bark was screened for compounds that could activate the retinoid X alpha transcription factor. (Prud’homme 2014). These authors were interested in compounds that could activate the transcription factor hetero dimer RXR/LXR (liver X rector).

Instead of getting lost exploring multiple targets of honokiol, let’s focus on just one.

some enzymes regulated by acetylation/Sirt3 activity Duan 2018

• 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)

Note that acetylCoA is where two carbon products of β-oxidation enter the NADH generating TCA cycle. The take home of this image is how half of what the mitochondria is all about the conversion of two carbon units to CO₂ and NADH and FADH₂. The other half of what the mitochondria are about is converting NADH to ATP. A key two part aspect regulating this two part “everything” is adding a two carbon aceylt group to lysines of key enzymes and then transferring them from lysines to NAD⁺. Regulating Sirt3 is understandably a bit deal in mitochondria energetics.

Where is Sirt3 expressed?

Noteworthy is how ubiquitous the expression of Sirt3 really is.

Honokiol in cardiac myocytes and mice Pillai 2015

This study came out of Emory University, North Western University, and University of Chicago. It was a follow up study using the sirtuin agonist resveratrol of red wine fame. This group used wildtype (normal) and Sirt3 knockout mice as well as their cultured cardiac myocytes. The following image is from summary Figure 10. 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.

the PGC1α transcription factor tells the cell to transcribe genes related to mitochondria function. Those transcripts get translated into proteins.

Figure 4 HKL attenuates pre-established cardiac hypertrophy in mice if there is interest in looking at actual data.

Toxicology Studies, Sarrica 2018

The authors were looking at two ethanol/methanol extracts from magnolia apeices. The parts of the magnolia, the species, and the region it was grown have an influence on the relative proportions of magnoliol and honokiol. The genetic toxicology studies seemed limited according to this review. This review also covers honokiol and magnoliol modulation of the GABA A receptor (think sleep and the agonist Ambiene) and cannabinoid receptors CB1, CB2, and GPR55. The GABA A receptor binds gamma amino butyric acid.

Metabolism of honokiol

treatment	outcome
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

My thoughts?

I wrote this post for a client with a child with a lysosomal storage disorder meaning their lysosomes did not degrade dead cellular materials correctly and tended to accumulate debris. Magnolia bark extract seems to be marketed more for stress relief than the usual longevity applications of natural sirtuin activators like resveratrol found in red wine. Could one use a PEMF mat and a magnolia bark extract containing honokiol and magnolol for general wellness? I would recommend doing so with proven safe formulations under teh supervision of a person trained in the use of traditional medicines.

References

• Alexeev M, Grosenbaugh DK, Mott DD, Fisher JL. The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABA(A) receptors. Neuropharmacology. 2012 Jun;62(8):2507-14. PMC free article
• Duan W. Sirtuins: from metabolic regulation to brain aging. Front Aging Neurosci. 2013 Jul 23;5:36. PMC free article
• 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. Epub 2021 Nov 6. PubMed
• Kotani H, Tanabe H, Mizukami H, Makishima M, Inoue M. Identification of a naturally occurring rexinoid, honokiol, that activates the retinoid X receptor. J Nat Prod. 2010 Aug 27;73(8):1332-6 Sci-Hub free article
• 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
• Prud’homme GJ, Glinka Y, Udovyk O, Hasilo C, Paraskevas S, Wang Q. GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity. Biochem Biophys Res Commun. 2014 Sep 26;452(3):649-54. Sci-Hub free
• 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