Magnolol

J Nat Prod. 2015 Jan 23;78(1):61-8.

Magnolol Inhibits RANKL-induced osteoclast differentiation of raw 264.7 macrophages through heme oxygenase-1-dependent inhibition of NFATc1 expression.[Pubmed: 25574844]

Magnolol (1) isolated from Magnolia officinalis exhibits many beneficial effects such as anti-inflammatory and antioxidant activity. The aim of this study was to evaluate the effects of Magnolol (1) on RANKL-induced osteoclast differentiation and investigate the underlying molecular mechanisms.
METHODS AND RESULTS:
Treatment with Magnolol (1) significantly inhibited osteoclast differentiation of RAW 264.7 macrophages and bone-resorbing activity of osteoclasts in the RANKL-induced system. Moreover, RANKL-activated JNK/ERK/AP-1 and NF-κB signaling, ROS formation, and NFATc1 activation were attenuated by Magnolol (1). A novel finding of this study is that Magnolol (1) can increase heme oxygenase-1 (HO-1) expression and Nrf2 activation in RANKL-stimulated cells. Blocking HO-1 activity with tin protoporphyrin IX markedly reversed Magnolol (1)-mediated inhibition of osteoclast differentiation, NFATc1 nuclear translocation, and MMP-9 activity, suggesting that HO-1 contributes to the attenuation of NFATc1-mediated osteoclastogenesis by Magnolol (1). Therefore, the inhibitory effect of Magnolol (1) on osteoclast differentiation is due to inhibition of MAPK/c-fos/AP-1 and NF-κB signaling as well as ROS production and up-regulation of HO-1 expression, which ultimately suppresses NFATc1 induction.
CONCLUSIONS:
These findings indicate that Magnolol (1) may have potential to treat bone diseases associated with excessive osteoclastogenesis.

Arch Pharm Res. 2000 Feb;23(1):46-9.

Antifungal activity of magnolol and honokiol.[Pubmed: 10728656]

Two neolignan compounds, Magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl, 1) and honokiol (5,5'-diallyl-2,4'-dihydroxybiphenyl, 2), were isolated from the stem bark of Magnolia obovata and evaluated for antifungal activity against various human pathogenic fungi.
METHODS AND RESULTS:
Compound 1 and 2 showed significant inhibitory activities against Trichophyton mentagrophytes, Microsporium gypseum, Epidermophyton floccosum, Aspergillus niger, Cryptococcus neoformans, and Candida albicans with minimum inhibitory concentrations (MIC) in a range of 25-100 microg/ml.
CONCLUSIONS:
Therefore, compound 1 and 2 could be used as lead compounds for the development of novel antifungal agents.

Eur J Pharmacol. 2004 Aug 2;496(1-3):189-95.

In vitro antibacterial and anti-inflammatory effects of honokiol and magnolol against Propionibacterium sp.[Pubmed: 15288590]

Honokiol and Magnolol, two major phenolic constituents of Magnolia sp., have been known to exhibit antibacterial activities. However, until now, their antibacterial activity against Propionibacterium sp. has not been reported.
METHODS AND RESULTS:
To this end, the antibacterial activities of honokiol and Magnolol were detected using the disk diffusion method and a two-fold serial dilution assay. Honokiol and Magnolol showed strong antibacterial activities against both Propionibacterium acnes and Propionibacterium granulosum, which are acne-causing bacteria. The minimum inhibitory concentrations (MIC) of honokiol and Magnolol was 3-4 microg/ml (11.3-15 microM) and 9 microg/ml (33.8 microM), respectively. In addition, the killing curve analysis showed that Magnolol and honokiol killed P. acnes rapidly, with 10(5) organisms/ml eliminated within 10 min of treatment with either 45 microg (169.2 microM) of Magnolol or 20 microg (75.2 microM) of honokiol per ml. The cytotoxic effect of honokiol and Magnolol was determined by a colorimetric (3-(4,5-dimetyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) (MTT) assay using two animal cell lines, human normal fibroblasts and HaCaT. In this experiment, Magnolol exhibited lower cytotoxic effects than honokiol at the same concentration, but they showed similar cytotoxicity when triclosan was employed as an acne-mitigating agent. In addition, they reduced secretion of interleukin-8 and tumor necrosis factor alpha (TNF-alpha) induced by P. acnes in THP-1 cells indicating the anti-inflammatory effects of them. When applied topically, neither phenolic compound induced any adverse reactions in a human skin primary irritation test.
CONCLUSIONS:
Therefore, based on these results, we suggest the possibility that Magnolol and honokiol may be considered as attractive acne-mitigating candidates for topical application.

Toxicol Appl Pharmacol. 2014 Sep 15;279(3):294-302.

Magnolol protects neurons against ischemia injury via the downregulation of p38/MAPK, CHOP and nitrotyrosine.[Pubmed: 25038313]

Magnolol is isolated from the herb Magnolia officinalis, which has been demonstrated to exert pharmacological effects. Our aim was to investigate whether Magnolol is able to act as an anti-inflammatory agent that brings about neuroprotection using a global ischemic stroke model and to determine the mechanisms involved.
METHODS AND RESULTS:
Rats were treated with and without Magnolol after ischemia reperfusion brain injury by occlusion of the two common carotid arteries. The inflammatory cytokine production in serum and the volume of infarction in the brain were measured. The proteins present in the brains obtained from the stroke animal model (SAM) and control animal groups with and without Magnolol treatment were compared. Magnolol reduces the total infarcted volume by 15% and 30% at dosages of 10 and 30mg/kg, respectively, compared to the untreated SAM group. The levels of acute inflammatory cytokines, including interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6 were attenuated by Magnolol. Magnolol was also able to suppress the production of nitrotyrosine, 4-hydroxy-2-nonenal (4-HNE), inducible NO synthase (iNOS), various phosphorylated p38 mitogen-activated protein kinases and various C/EBP homologues. Furthermore, this modulation of ischemia injury factors in the SAM model group treated with Magnolol seems to result from a suppression of reactive oxygen species production and the upregulation of p-Akt and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).
CONCLUSIONS:
These findings confirm the anti-oxidative properties of Magnolol, including the inhibition of ischemic injury to neurons; this protective effect seems to involve changes in the in vivo activity of Akt, GSK3β and NF-κB.

Prog Neuropsychopharmacol Biol Psychiatry. 2008 Apr 1;32(3):715-25.

Antidepressant-like effects of the mixture of honokiol and magnolol from the barks of Magnolia officinalis in stressed rodents.[Pubmed: 18093712 ]

Honokiol and Magnolol are the main constituents simultaneously identified in the barks of Magnolia officinalis, which have been used in traditional Chinese medicine to treat a variety of mental disorders including depression. In the present study, we reported on the antidepressant-like effects of oral administration of the mixture of honokiol and Magnolol in well-validated models of depression in rodents: forced swimming test (FST), tail suspension test (TST) and chronic mild stress (CMS) model.
METHODS AND RESULTS:
The mixture of honokiol and Magnolol significantly decreased immobility time in the mouse FST and TST, and reversed CMS-induced reduction in sucrose consumption to prevent anhedonia in rats. However, this mixture was unable to affect ambulatory or rearing behavior in the mouse open-field test. CMS induced alterations in 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels in various brain regions of rats. An increase in serum corticosterone concentrations and a reduction in platelet adenylyl cyclase (AC) activity were simultaneously found in the CMS rats. The mixture of honokiol and Magnolol at 20 and 40 mg/kg significantly attenuated CMS-induced decreases of 5-HT levels in frontal cortex, hippocampus, striatum, hypothalamus and nucleus accumbens. And it markedly increased 5-HIAA levels in frontal cortex, striatum and nucleus accumbens at 40 mg/kg and in frontal cortex at 20 mg/kg in the CMS rats. A subsequent reduction in 5-HIAA/5-HT ratio was found in hippocampus and nucleus accumbens in the CMS rats receiving this mixture. Furthermore, the mixture of honokiol and Magnolol reduced elevated corticosterone concentrations in serum to normalize the hypothalamic-pituitary-adrenal (HPA) hyperactivity in the CMS rats. It also reversed CMS-induced reduction in platelet AC activity, via upregulating the cyclic adenosine monophosphate (cAMP) pathway. These results suggested that the mixture of honokiol and Magnolol possessed potent antidepressant-like properties in behaviors involved in normalization of biochemical abnormalities in brain 5-HT and 5-HIAA, serum corticosterone levels and platelet AC activity in the CMS rats.
CONCLUSIONS:
Our findings could provide a basis for examining directly the interaction of the serotonergic system, the HPA axis and AC-cAMP pathway underlying the link between depression and treatment with the mixture of honokiol and Magnolol.

Biol Pharm Bull. 2006 Dec;29(12):2498-501.

Magnolol-induced apoptosis is mediated via the intrinsic pathway with release of AIF from mitochondria in U937 cells.[Pubmed: 17142989]

Magnolol has been reported to have an inhibitory effect on tumor invasion in vitro and in vivo.
METHODS AND RESULTS:
In this study, we found that treatment with 30 microM Magnolol exhibited growth inhibition partly by inducing apoptosis in cultured human leukemia U937 cells and that the apoptosis was induced via the sequential ordering of molecular events; 1) a transient decrease of phosphorylated extracelluar signal-requlated kinase (ERK), 2) translocation of apoptosis inducing factor (AIF) from mitochondria to cytosol concurrent with a decreased membrane potential, and 3) downregulation of bcl-2 protein. Pretreatment of the cells with a pan-caspase inhibitor Z-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) did not prevent the apoptosis induced by Magnolol.
CONCLUSIONS:
These findings indicated that the above-mentioned sequence of intracellular signaling events led to apoptosis in Magnolol-treated U937 cells, which was caspase-independent.

Eur J Pharmacol. 2006 May 10;537(1-3):64-9.

Neuroprotective activity of honokiol and magnolol in cerebellar granule cell damage.[Pubmed: 16631734]

The aim of the present study was to investigate the neuroprotective effects of honokiol and Magnolol, two major bioactive constituents of the bark of Magnolia officinalis, against neuron toxicity induced by glucose deprivation, excitatory amino acids and hydrogen peroxide (H(2)O(2)) in cultured rat cerebellar granule cells.
METHODS AND RESULTS:
Cell membrane damage was measured with a lactate dehydrogenase (LDH) release assay and 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to assess mitochondrial activity, reflecting cell survival. Results showed that honokiol and Magnolol alone did not affect mitochondrial function and cell damage, but significantly reversed glucose deprivation-induced mitochondrial dysfunction and cell damage. The glutamate receptor blocker MK-801 and antioxidant vitamin E also provided protection against this damage. Furthermore, honokiol was more potent than Magnolol in protecting against glutamate-, N-methyl-D-aspartate (NMDA)- and H(2)O(2)-induced mitochondrial dysfunction.
CONCLUSIONS:
These results demonstrated that the neuroprotective effects of honokiol and Magnolol may be related to their anti-oxidative actions and antagonism of excitotoxicity induced by excitatory amino acids, suggesting that both compounds may be potential therapeutic agents for neurodegenerative diseases.

Int Immunopharmacol. 2015 Jun 10. pii: S1567-5769(15)00289-1.

Magnolol ameliorates lipopolysaccharide-induced acute lung injury in rats through PPAR-γ-dependent inhibition of NF-kB activation.[Pubmed: 26072062]

Acute lung injury (ALI) has a high morbidity and mortality rate due to the serious inflammation and edema occurred in lung. Magnolol extracted from Magnolia officinalis, has been reported to exhibit anti-inflammatory, and antioxidant activities. Peroxisome proliferator-activated receptors (PPARs) are known to exert a cytoprotective effect against cellular inflammatory stress and oxidative injury. The aim of this study was to explore the involvement of PPAR-γ in the beneficial effect of Magnolol in lipopolysaccharide (LPS)-induced ALI.
METHODS AND RESULTS:
We found that treatment with Magnolol greatly improved the pathological features of ALI evidenced by reduction of lung edema, polymorphonuclear neutrophil infiltration, ROS production, the levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF), the expression of iNOS and COX-2, and NF-κB activation in lungs exposed to LPS. Importantly, Magnolol is capable of increasing the PPAR-γ expression and activity in lungs of ALI. However, blocking PPAR-γ activity with GW9662 markedly abolished the protective and anti-inflammatory effects of Magnolol.
CONCLUSIONS:
Taken together, the present study provides a novel mechanism accounting for the protective effect of Magnolol in LPS-induced ALI is at least partly attributed to induction of PPAR-γ in lungs, and in turn suppressing NF-κB-related inflammatory responses.

Environ Toxicol Pharmacol. 2015 Jan;39(1):417-23.

Magnolol reduces UVB-induced photodamage by regulating matrix metalloproteinase activity.[Pubmed: 25562310]

In this study, we evaluated the anti-photoaging activity of Magnolol in UV-irradiated hairless mice, and hypothesized that Magnolol would prevent photoaging in these animals. The inhibitory effect of Magnolol on wrinkle formation was determined by analyzing the skin replica, histologically examining the epidermal thickness, and identifying damage to the collagen fibers.
METHODS AND RESULTS:
The protective effects of Magnolol on UVB-induced skin photoaging were examined by determining the level of MMPs and mitogen-activated protein kinases (MAPKs). Exposure to UVB radiation significantly increased skin thickness and wrinkle grade, but Magnolol treatment significantly reduced the average length and depth of wrinkles, and this was correlated with the inhibition of collagen fiber loss. The Magnolol-treated group had remarkably decreased activity levels of MMP-1, -9, and -13 compared to the corresponding levels in the vehicle-treated UVB-irradiated group.
CONCLUSIONS:
These results indicate that Magnolol prevents skin photoaging in UVB-irradiated hairless mice.