Magnolia Bark Extract-Magnolol

IUPAC: 2-(2-hydroxy-5-prop-2-enylphenyl)-4-prop-2-enylphenol

Molecular Formula: C18H18O2 Molecular Weight: 266.33432 CAS no.: 528-43-8

Depositor-Supplied Synonyms Magnolol 2,2'-Bichavicol 5,5'-Diallyl-2,2'-dihydroxybiphenyl NSC 293099 5,5'-di(prop-2-en-1-yl)biphenyl-2,2'-diol Magnolol, 2,2'-Bichavicol (1,1'-Biphenyl)-2,2'-diol, 5,5'-di-2-propenyl- Dehydrodichavicol

Pharmacological Action Anti-Arrhythmia Agents - Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade. Anti-Inflammatory Agents, Non-Steroidal - Anti-inflammatory agents that are not steroids. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions. They are used primarily in the treatment of chronic arthritic conditions and certain soft tissue disorders associated with pain and inflammation. They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects. Certain NSAIDs also may inhibit lipoxygenase enzymes or TYPE C PHOSPHOLIPASES or may modulate T-cell function. (AMA Drug Evaluations Annual, 1994, p 1814-5) Platelet Aggregation Inhibitors - Drugs or agents which antagonize or impair any mechanism leading to blood platelet aggregation, whether during the phases of activation and shape change or following the dense-granule release reaction and stimulation of the prostaglandin-thromboxane system. from MeSH Biomedical Effects and Toxicity

Absorption, Distribution and Excretion To investigate the relationship between magnolol and the clinical effects of Saiboku-To, urinary magnolol excretion was compared in responders and non-responders under long-term Saiboku-To treatment. The clinical outcome of the Saiboku-To treatment was evaluated in nine asthmatic patients at 52 weeks after the onset of the treatment, using individual fluctuation of asthmatic points obtained from the patients' diary cards. Three patients whose clinical conditions were improved by the treatment were termed responders and six others were termed non-responders. The difference in the amounts of the total magnolol excreted were not significant; however, free (or non-conjugated) amounts of magnolol excreted in the responders were 7 times those in the non-responders (P < 0.05). These results suggest that the magnolol might be responsible for the therapeutic effect of Saiboku-To, indicating practical bioavailability in the responders. [Homma M et al; J Pharm Pharmacol 45 (9): 844-6 (1993)] PubMed Abstract from HSDB Mechanism of Action z The effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, on Ca(2+) and Na(+) influx induced by various stimulants were investigated in cultured rat cerebellar granule cells by single-cell fura-2 or SBFI microfluorimetry. Honokiol and magnolol blocked the glutamate- and KCl-evoked Ca(2+) influx with similar potency and efficacy, but did not affect KCl-evoked Na(+) influx. However, honokiol was more specific for blocking NMDA-induced Ca(2+) influx, whereas magnolol influenced with both NMDA- and non-NMDA activated Ca(2+) and Na(+) influx. Moreover, the anti-convulsant effects of these two compounds on NMDA-induced seizures were also evaluated. After honokiol or magnolol (1 and 5 mg/kg, ip) pretreatment, the seizure thresholds of NMRI mice were determined by tail-vein infusion of NMDA (10 mg/mL). Data showed that both honokiol and magnolol significantly increased the NMDA-induced seizure thresholds, and honokiol was more potent than magnolol. These results demonstrated that magnolol and honokiol have differential effects on NMDA and non-NMDA receptors, suggesting that the distinct therapeutic applications of these two compounds for neuroprotection should be considered. [Lin YR et al; Neuropharmacology 49 (4): 542-50 (2005)] PubMed Abstract z Magnolol inhibited phorbol 12-myristate 13-acetate (PMA)-activated rat neutrophil aggregation in a concentration-dependent manner with an IC50 (concentration resulting in 50% inhibition) of 24.2 +/- 1.7 uM. Magnolol suppressed the enzyme activity of neutrophil cytosolic and rat brain protein kinase C (PKC) over the same range of concentrations at which it inhibited the aggregation. Magnolol did not affect PMA-induced cytosolic PKC-alpha and -delta membrane translocation or trypsin-treated rat-brain PKC activity, but attenuated [3H]phorbol 12,13-dibutyrate binding to neutrophil cytosolic PKC. These results suggest that the inhibition of PMA-induced rat neutrophil aggregation by magnolol is probably attributable, at least in part, to the direct suppression of PKC activity through blockade of the regulatory region of PKC. [Wang JP et al; J Pharm Pharmacol 50 (10): 1167-72 (1998)] PubMed Abstract z Magnolol, a substance purified from the bark of Magnolia officialis, inhibits cell proliferation and induces apoptosis in a variety of cancer cells. The aim of this study was to study the effects of magnolol on CGTH W-2 thyroid carcinoma cells. After 24 hr treatment with 80 u M magnolol in serum-containing medium, about 50% of the cells exhibited apoptotic features and 20% necrotic features. Cytochrome-c staining was diffused in the cytoplasm of the apoptotic cells, but restricted to the mitochondria in control cells. Western blot analyses showed an increase in levels of activated caspases (caspase-3 and -7) and of cleaved poly (ADP-ribose) polymerase (PARP) by magnolol. Concomitantly, immunostaining for apoptosis inducing factor (AIF) showed a time-dependent translocation from the mitochondria to the nucleus. Inhibition of either PARP or caspase activity blocked magnolol-induced apoptosis, supporting the involvement of the caspases and PARP. In addition, magnolol activated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and inactivated Akt by decreasing levels of phosphorylated PTEN and phosphorylated Akt. These data suggest that magnolol promoted apoptosis probably by alleviating the inhibitory effect of Akt on caspase 9. Furthermore, inhibition of PARP activity, but not of caspase activity, completely prevented magnolol-induced necrosis, suggesting the notion that it might be caused by depletion of intracellular ATP levels due to PARP activation. These results show that magnolol initiates apoptosis via the cytochrome-c/caspase 3/PARP/AIF and PTEN/Akt/caspase 9/PARP pathways and necrosis via PARP activation. [Huang SH et al; J Cell Biochem 101 (4): 1011-22 (2007)] PubMed Abstract z The mis-regulation of nuclear factor-kappa B (NF-kappaB) signal pathway is involved in a variety of inflammatory diseases that leds to the production of inflammatory mediators. /These/ studies using human U937 promonocytes cells suggested that magnolol ... differentially down-regulated the pharmacologically induced expression of NF-kappaB-regulated inflammatory gene products MMP-9, IL-8, MCP-1, MIP-1alpha, TNF-alpha. Pre-treatment of magnolol blocked TNF-alpha-induced NF-kappaB activation in different cell types as evidenced by EMSA. Magnolol did not directly affect the binding of p65/p50 heterodimer to DNA. Immunoblot analysis demonstrated that magnolol inhibited the TNF-alpha-stimulated phosphorylation and degradation of the cytosolic NF-kappaB inhibitor IkappaBalpha and the effects were dose-dependent. Mechanistically, a non-radioactive IkappaB kinases (IKK) assay using immunoprecipitated IKKs protein demonstrated that magnolol inhibited both intrinsic and TNF-alpha-stimulated IKK activity, thus suggesting a critical role of magnolol in abrogating the phosphorylation and degradation of IkappaBalpha. The involvement of IKK was further verified in a HeLa cell NF-kappaB-dependent luciferase reporter system. In this system magnolol suppressed luciferase expression stimulated by TNF-alpha and by the transient transfection and expression of NIK (NF-kappaB-inducing kinase), wild type IKKbeta, constitutively active IKKalpha and IKKbeta, or the p65 subunit. Magnolol was also found to inhibit the nuclear translocation and phosphorylation of p65 subunit of NF-kappaB. In line with the observation that NF-kappaB activation may up-regulate anti-apoptotic genes, it was shown in U937 cells that magnolol enhanced TNF-alpha-induced apoptotic cell death. /The/ results suggest that magnolol or its derivatives may have potential anti-inflammatory actions through IKK inactivation. [Tse AK et al; Mol Immunol 44 (10): 2647-58 (2007)] PubMed Abstract z ... Magnolol, treatment was found to show potent inhibitory effects on cell proliferation in cultured VSMC in the presence of TNF-alpha. These inhibitory effects were associated with reduced extracellular signal-regulated kinase (ERK) 1/2 activity and G1 cell cycle arrest. Magnolol treatment strongly induced the expression of p21WAF1, but resulted in a decrease in cyclin-dependent kinases (CDKs) and cyclins involved in G1 progression. In addition to G1 cell cycle arrest and growth inhibition in VSMC, magnolol also caused the strong inhibition of TNF-alpha-induced matrix metalloproteinase-9 (MMP-9) expression in a dose-dependent manner as determined by zymography and immunoblot. Moreover, magnolol treatment strongly decreased MMP-9 promoter activity in response to TNF-alpha. We further demonstrated that magnolol reduced the transcriptional activity of NF-kappaB and activation protein-1 (AP-1), two important nuclear transcription factors that are involved in MMP-9 expression. Collectively, these results show that magnolol inhibits cell proliferation, G1 to S phase cell cycle progress and MMP-9 expression through the transcription factors NF-kappaB and AP-1 in TNF-alpha-induced VSMC. The findings of the present study reveal a potential mechanism that explains the anti-atherogenic activity of magnolol. [Kim HM et al; Int Immunopharmacol 7 (8): 1083-91 (2007)] PubMed Abstract z Transcriptional activity of nuclear factor kappaB (NF-kappaB) is induced by environmental signals including inflammation, UV irradiation and oxidative stress. It was shown that the NF-kappaB activity greatly contributes to the skin photoaging process. Thus, it is plausible that NF-kappaB inhibitors could directly prevent skin photoaging. ... Magnolia ovovata extract inhibited NF-kappaB-mediated gene expression and ...external swabbing with Magnolia extract /prevented/ skin photoaging processes through keratinocyte hyperproliferation and degradation of collagen fibers in mice skin. ...Magnolol /was identified/ as the solely responsible active compound in Magnolia extract. Magnolol effectively inhibited the NF-kappaB-dependent transcription, but no effect was observed with other inducible transcription factors such as activator protein-1 (AP-1) and cyclic-AMP responsive element-binding protein (CREB). In addition, magnolol was effective in inhibiting the production of basic fibroblast growth factor (bFGF) and matrix metalloprotease-1 (MMP-1) from the cells overexpressing p65, a major subunit of NF-kappaB. Although magnolol did not affect the phosphorylation and degradation of IkappaBalpha, it inhibited the nuclear translocation of the activated NF-kappaB. [Tanaka K et al; Eur J Pharmacol 565 (1-3): 212-9 (2007)] PubMed Abstract z ...This study ... examined whether magnolol prevents oxidized low density lipoprotein (oxLDL)-induced vascular endothelial apoptosis. Incubation of oxLDL with magnolol (2.5-20 uM) inhibited copper-induced oxidative modification via diene formation, thiobarbituric acid reactive substances (TBARS) assay and electrophoretic mobility assay. Apoptotic cell death as characterized by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) stain. ...The production of reactive oxygen species (ROS) /was measured/ by using the fluorescent probe 2',7'-dichlorofluorescein acetoxymethyl ester (DCF-AM), and observed the activity of antioxidant enzymes. Furthermore, several apoptotic signaling pathways which showed NF- kappa B activation, increased cytosolic calcium, alteration of mitochondrial membrane potential, cytochrome c release and activation of caspase 3 were also investigated. ... Magnolol prevented the copper-induced oxidative modification of LDL. Magnolol attenuated the oxLDL-induced ROS generation and subsequent NF- kappa B activation. Furthermore, intracellular calcium accumulation and subsequent mitochondrial membrane potential collapse, cytochrome c release and activation of caspase 3 caused by oxLDL were also inhibited by magnolol. /These/ results suggest that magnolol may have clinical implications in the prevention of atherosclerotic vascular disease through decreasing the oxLDL-induced ROS production... [Ou HC et al; Arch Toxicol 81 (6): 421-32 (2007)] PubMed Abstract z Magnolol (Mag), an active constituent isolated from the Chinese herb Hou p'u (Magnolia officinalis) has long been used to suppress inflammatory processes. Chronic inflammation is well known to be involved in vascular injuries such as atherosclerosis in which interleukin (IL)-6 may participate. Signal transducer and activator of transcription protein 3 (STAT3), a transcription factor involved in inflammation and the cell cycle, is activated by IL-6. In this study, we evaluated whether Mag can serve as an anti-inflammatory agent during endothelial injuries. The effects of Mag on IL-6-induced STAT3 activation and downstream target gene induction in endothelial cells (ECs) were examined. Pretreatment of ECs with Mag dose dependently inhibited IL-6-induced Tyr705 and Ser727 phosphorylation in STAT3 without affecting the phosphorylation of JAK1, JAK2, and ERK1/2. Mag pretreatment of these ECs dose dependently suppressed IL-6-induced promoter activity of intracellular cell adhesion molecule (ICAM)-1 that contains functional IL-6 response elements (IREs). An electrophoretic mobility shift assay (EMSA) revealed that Mag treatment significantly reduced STAT3 binding to the IRE region. Consistently, Mag treatment markedly inhibited ICAM-1 expression on the endothelial surface. As a result, reduced monocyte adhesion to IL-6-activated ECs was observed. Furthermore, Mag suppressed IL-6-induced promoter activity of cyclin D1 and monocyte chemotactic protein (MCP)-1 for which STAT3 activation plays a role. In conclusion, ... Mag inhibits IL-6-induced STAT3 activation and subsequently results in the suppression of downstream target gene expression in ECs. These results provide a therapeutic basis for the development of Mag as an anti-inflammatory agent for vascular disorders including atherosclerosis. [Chen SC et al; Br J Pharmacol 148 (2): 226-32 (2006)] PubMed Abstract z The pathological mechanism of percutaneous transluminal coronary angioplasty-induced restenosis has been attributed to outgrowth of vascular smooth muscle cells. Pretreatment with antioxidants has been shown to reduce restenosis. Magnolol, an active compound of Magnolia officinalis, has exhibited approximately 1000-fold more potent antioxidant effects than alpha -tocopherol. Using cytometric analysis, an approximate 61% reduction of smooth muscle cells progressing to the S-phase by 0.05 mg magnolol/mL /was demonstrated/. A BrdU incorporation assay also showed a significant reduction (73%) in DNA synthesis attributed to 0.05 mg magnolol/mL. The protein level of the proliferating cell nuclear antigen was suppressed by approximately 48% using 0.05 mg magnolol/mL. This was in agreement with the promoter activity of nuclear factor-kappa B, which was also attenuated by 0.05 mg magnolol/mL. Since receptor-interacting protein and caspase-3 protein expression levels were both increased by magnolol in a dose-dependent manner, the apoptotic pathway may mediate the inhibition of cell growth. /The/ finding that malondialdehyde formation was significantly inhibited by 0.05 mg magnolol/mL further supported the antioxidant effect of magnolol. These studies suggest that magnolol might be a potential pharmacological reagent in preventing balloon injury-induced restenosis.. [Wy CH et al; J Pharmacol Sci 99 (4): 392-9 (2005)] PubMed Abstract z Magnolol inhibited proliferation of human lung squamous carcinoma CH27 cells at low concentrations (10-40 uM), and induced apoptosis at high concentrations (80-100 uM). Treatment with 80 uM magnolol significantly increased the expression of Bad and Bcl-X(S) proteins, whereas it decreased the expression of Bcl-X(L). Overexpression of Bcl-2 protected CH27 cells against magnolol-triggered apoptosis. Magnolol treatment resulted in accumulation of cytosolic cytochrome c and activation of caspase-9 and downstream caspases (caspase-3 and -6). Pretreatment with z-VAD-fmk markedly inhibited magnolol-induced cell death, but did not prevent cytosolic cytochrome c accumulation. Magnolol induced a modest and persistent JNK activation and ERK inactivation in CH27 cells without evident changes in the pr otein levels. The responsiveness of JNK and ERK to magnolol suggests the involvement of these kinases in the initiation of the apoptosis process. These results indicate that regulation of the Bcl-2 family, accumulation of cytosolic cytochrome c, and activation of caspase-9 and caspase-3 may be the effector mechanisms of magnolol-induced apoptosis. from HSDB Interactions z Three neolignans, known as magnolol, honokiol and the new monoterpenylmagnolol, were isolated from the bark of Magnolia officinalis ... . The MeOH extract of this plant and magnolol exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two stage carcinogenesis test... [Konoshima T et al; J Nat Prod 54 (3): 816-22 (1991)] PubMed Abstract z Magnolol has been reported to strongly inhibit the mutagenicity induced by indirect mutagens in the Ames test as well as the clastogenicity induced by benzo(a)pyrene (B(a)P) in the mice micronucleus test. Here, ... the inhibitory effect of magnolol on the DNA damage induced by 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) /was evaluated/ in various organs using the mice alkaline single cell gel electrophoresis (SCG) assay. Animals were treated with a single oral administration of magnolol (0.01, 0.1, 1, 10, and 100 mg/kg), followed by a single intraperitoneal injection of Trp-P-2 (10 mg/kg). The liver, lung, and kidney were removed at 3 hr after treatment and used in SCG assay. The results indicated that magnolol inhibited Trp-P-2-induced DNA damage in various organs. To elucidate the mechanism of this inhibitory effect against Trp-P-2, we investigated the inhibitory effect of magnolol on in vivo CYP1A2 activity using the zoxazolamine paralysis test. Magnolol significantly prolonged zoxazolamine paralysis time and showed an inhibitory effect on in vivo CYP1A2 activity. These results indicate that magnolol has an inhibitory effect on the DNA damage induced by Trp-P-2 in various organs in vivo. This inhibitory mechanism is considered due to in vivo CYP1A2 inhibition. [Saito J et al; Phytother Res. 2009 Jan 12. [Epub ahead of print]] PubMed Abstract z ... The in vivo anti-clastogenic effect of magnolol against clastogenicity induced by B(a)P was evaluated using the micronucleus test in mice. Animals were treated with an oral administration of magnolol (1, 10, and 100 mg/kg) at -24, 0, 24, 48, 72, and 96 hr before a single intraperitoneal injection of B(a)P. Peripheral blood specimens were prepared 48 h after administration of B(a)P, and analyzed by the acridine orange (AO) technique. The results indicated that magnolol inhibited clastogenicity induced by B(a)P at various administration times. In order to elucidate the mechanism behind this effect, we measured the activity of the detoxifying enzymes [UDP-glucuronosyltransferase (UGT) and glutathione-S-transferase (GST)] and antioxidative enzymes [superoxide dismutase (SOD) and catalase] in the liver when treated with an oral administration of magnolol at various administration times. Its effect on clastogenicity created by exposure to oxidative DNA damage-inducing X-ray irradiation was also evaluated using the micronucleus test in mice. Results showed that magnolol increased the activity of both UGT and SOD enzymes, and also inhibited the clastogenicity induced by X-ray irradiation. Magnolol had an anti-clastogenic effect on B(a)P in the micronucleus test as well as an anti-mutagenic effect on indirect mutagens in the Ames test. The anti-clastogenic effect of magnolol was also suggested by the increases in UGT and SOD enzyme activity, and by the attenuation of oxidative damage induced by X-ray irradiation. [Saito J et al; Food Chem Toxicol 46 (2): 694-700 (2008)] PubMed Abstract z ... Anti-mutagenic activity of magnolol against mutagenicity induced by direct mutagens [1-nitropyrene (1-NP), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG)] and indirect mutagens [2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), benzo(a)pyrene (B(a)P), 2-aminoanthracene (2-AA) and 7,12-dimethylbenz[a]anthracene (DMBA)] were investigated using the bacterial mutagenicity test (Ames test). Results show that magnolol strongly inhibits mutagenicity induced by indirect mutagens, but does not affect direct mutagens. To elucidate the mechanism of this effect against indirect mutagens, effect of magnolol on CYP1A1- and CYP1A2-related enzyme activities of ethoxyresorufin-O-deethylase (EROD) and methoxyresorufin-O-demethylase (MROD) were investigated. Magnolol strongly and competitively suppressed these enzyme activities, suggesting it inhibited mutation induced by indirect mutagens through suppression of CYP1A1 and CYP1A2 activity. [Saito J et al; Mutat Res 609 (1): 68-73 (2006)] PubMed Abstract z A23187-induced pleurisy in mice was used to investigate the anti-inflammatory effect of magnolol, a phenolic compound isolated from Chinese medicine Hou p'u (cortex of Magnolia officinalis). A23187-induced protein leakage was reduced by magnolol (10 mg/kg, ip), indomethacin (10 mg/kg, ip) and BW755C (30 mg/kg, ip). A23187-induced polymorphonuclear (PMN) leukocyte infiltration in the pleural cavity was suppressed by magnolol and BW755C, while enhanced by indomethacin. Like BW755C, magnolol reduced both prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels in the pleural fluid of A23187-induced pleurisy, while indomethacin reduced PGE2 but increased LTB4 formation. In the rat isolated peripheral neutrophil suspension, magnolol (3.7 uM) and BW755C (10 microM) also suppressed the A23187-induced thromboxane B2 (TXB2) and LTB4 formation. These results suggest that magnolol, like BW755C, might be a dual cyclo-oxygenase and lipoxygenase inhibitor. The inhibitory effect of magnolol on the A23187-induced pleurisy is proposed to be, at least partly, dependent on the reduction of the formation of eicosanoids mediators in the inflammatory site. [Wang JP et al; J Pharm Pharmacol 47 (10): 857-60 (1995)] PubMed Abstract from HSDB Antidote and Emergency Treatment z /SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/ z /SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/ z /SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/ from HSDB Human Toxicity Excerpts z /GENOTOXICITY/ The aim is to investigate the effect of Magnolol preserved H460 cells from an oxidative agent tert-butylhydroperoxide (TBHP)-induced cell death. Magnolol augmented cell survival ratio after TBHP challenged. ... DNA damage, detected by the Comet assay, was diminished after treatment of Magnolol. The cells viability decreased after treatment with 0.15 mM TBHP for 24 hr, accompanied by inducing apoptotic death of the cells. Cytotoxicity and apoptosis induced by TBHP were significantly inhibited or attenuated after pretreatment with 20 uM Magnolol. Magnolol contributes to the cells survival through downregulated the p53 phosphorylation and PTEN expression, and upregulated Akt phosphorylation. Taken together, Magnolol was effective against DNA single strand breaks (SSB) formation, cytotoxicity and lipid peroxidation induced by TBHP, and its effects on p53 phosphorylation, PTEN and Akt phosphorylation were due to its antioxidative function, and partially via a p53 dependent mechanism in this protective effects. [Li HB et al; Arch Pharm Res 30 (7): 850-7 (2007)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ Magnolol, isolated from the stem bark of Magnolia officnalis, was found to inhibit proliferation of human HL-60 cells and Jurkat T leukemia cells via inducing apoptosis in a dose- and time-dependent manner. By contrast, magnolol did not cause apoptosis in neutrophils and peripheral blood mononuclear cells of healthy donors. Apoptosis was determined by detection of DNA fragmentation in gel electrophoresis, morphological alternations by flow cytometry, quantification of phosphatidylserine externalization by Annexin V labeling and oligonucleosomal DNA content by TUNEL labeling. Activation of caspase-9, -3 and -2, and the proteolytic cleavage of poly(ADP-ribose) polymerase were found during apoptosis induced by magnolol. In addition, both pan-caspase and selective caspase-9 inhibitor blocked magnolol-induced apoptosis. The apoptosis could also be partially attenuated by caspase-3 and -2 inhibitors. Magnolol induced the reduction of mitochondrial transmembrane potential and the release of cytochrome c into cytoplasm. In conclusion, our findings indicate that magnolol-induced apoptotic signaling is carried out through mitochondria alternations to caspase-9 and that then the downstream effector caspases are activated sequentially... [Zhong WB et al; Anticancer Drugs 14 (3): 211-7 (2003)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ Magnolol (MG) and honokiol (HK) ... were found to enhance HL-60 cell differentiation initiated by low doses of 1,25-dihydroxyvitamin D3 (VD3) and all-trans-retinoic acid (ATRA). Cells expressing membrane differentiation markers CD11b and CD14 were increased from 4% in non-treated control to 8-16% after being treated with 10-30 microM MG or HK. When added to 1 nM VD3, MG or HK increased markers expressing cells from approximately 30% to 50-80%. When either MG or HK was added to 20 nM ATRA, only CD11b, but not CD14, expressing cells were increased from 9% to 24-70%. Under the same conditions, adding MG or HK to VD3 or ATRA treatment further enlarged the G0/G1 cell population and increased the expression of p27(Kip1), a cyclin-dependent kinase inhibitor. Pharmacological studies using PD098059 (a MEK inhibitor), SB203580 (a p38 MAPK inhibitor) and SP600125 (a JNK inh ibitor) suggested that the MEK pathway was important for VD3 and ATRA-induced differentiation and also its enhancement by MG or HK, the p38 MAPK pathway had a inhibitory effect and the JNK pathway had little influence. [Fong WF et al; Int J Biochem Cell Biol 37 (2): 427-41 (2005)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ The effect of magnolol on ionic currents was studied in cultured smooth muscle cells of human trachea with the aid of the patch clamp technique. In whole cell current recordings magnolol reversibly increased the amplitude of K+ outward currents. The increase in outward current caused by magnolol was sensitive to inhibition by iberiotoxin (200 nM) or paxilline (1 microM) but not by glibenclamide (10 uM). In inside out patches, magnolol added to the bath did not modify single channel conductance but effectively enhanced the activity of large conductance Ca2+ activated K+ (BK(Ca)) channels. Magnolol increased the probability of these channel openings in a concentration dependent manner with an EC50 value of 1.5 uM. The magnolol stimulated increase in the probability of channels opening was independent of internal Ca2+. The application of magnolol also shifted the activation curve of BK(Ca) channels to less positive membrane potentials. The change in the kinetic behaviour of BK(Ca) channels caused by magnolol in these cells is the result of an increase in dissociation and gating constants. ... These results provide evidence that, in addition to the presence of antioxidative activity, magnolol is potent in stimulating BK(Ca) channel activity in tracheal smooth muscle cells. The direct stimulation of these BK(Ca) channels by magnolol may contribute to the underlying mechanism by which it acts as an anti-asthmatic compound. [Wu SN et al; Thorax 57 (1): 67-74 (2002)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ ... Magnolol at very low concentrations of 3-10 uM inhibited DNA synthesis and decreased cell number in cultured human cancer cells (COLO-205 and Hep-G2) in a dose-dependent manner, but not in human untransformed cells such as keratinocytes, fibroblasts, and human umbilical vein endothelial cells (HUVEC). Magnolol was not cytotoxic at these concentrations and this indicates that it may have an inhibitory effect on cell proliferation in the subcultured cancer cell lines. [(3)H] thymidine incorporation and flow cytometry analyses revealed that magnolol treatment decreased DNA synthesis and arrested the cells at the G0/G1 phase of the cell cycle. Moreover, the magnolol-induced cell cycle arrest occurred when the cyclin-CDK system was inhibited, just as p21 protein expression was augmented. When magnolol concentration was increased to 100 uM, apoptosis was observed in COLO-205 and Hep-G2 cells, but not in cultured human fibroblasts and HUVEC. COLO-205 cells implanted subcutaneously in nude mice formed solid tumors; subsequent daily ip-injections of magnolol led to profound regression of these tumors of up to 85%. In these tumors, an increase in the expression of p21 protein level and the occurrence of apoptosis were observed. z /ALTERNATIVE and IN VITRO TESTS/ ... The inhibitory effect of Magnolia obovata Thunb. bark ethanol extracts on human fibrosarcoma HT-1080 cells invasion in a reconstituted basement membrane [Matrigel (MG)] /was examined/. ... The effective components of the bark ethanol extracts were magnolol and honokiol, two biphenyl compounds. The extracts, magnolol and honokiol, did not affect HT-1080 cells adhesion to MG, but did inhibit HT-1080 cells migration at a high concentration (100 uM). HT-1080 cells secrete matrix metalloproteinase (MMP)-9, which degrades the extracellular matrix as a part of the invasive process. Magnolol and honokiol inhibited the activity of MMP-9, which may have been responsible, in part, for the inhibition of tumor cell invasiveness. [Magase H et al; Planta Med 67 (8): 705-8 (2001)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ To evaluate whether magnolol prevents ischemia/reperfusion injury by inhibiting neutrophil adhesion, /it was/ determined whether magnolol can inhibit adhesion of phorbol-12-myristate-13-acetate (PMA)-activated human neutrophils to a fibrinogen-coated surface in a dose-dependent manner. Using flow cytometric analysis, we observed that magnolol pretreatment (10 min at 37 degrees C) diminished PMA (100 ng/mL)-induced Mac-1 upregulation. PMA also induced rapid intracellular accumulation of superoxide (O2-.) and hydrogen peroxide (H2O2) in neutrophils; magnolol pretreatment attenuated the accumulation of these two substances. Inhibition of reactive oxygen species by superoxide dismutase and/or catalase, which decompose O2-. and H2O2, respectively, also abolished Mac-1 upregulation and neutrophil adhesion. We conclude that magnolol inhibits neutrophil adhesion and that this can account for its anti-ischemia/reperfusion injury effect. /It was proposed/ that the inhibitory effect of magnolol on neutrophil adhesion to the extracellular matrix is mediated, at least in part, by inhibition of the accumulation of reactive oxygen species, which in turn suppresses the upregulation of Mac-1 that is essential for neutrophil adhesion. [Shen YC et al; Eur J Pharmacol 343 (1): 79-86 (1998)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ ...This study examines the protective effect of magnolol on lipid peroxidation-suppressed sperm motility. FeSO4 was used to induced lipid peroxidation and sperm motility was expressed as tail beat frequency (TBF) measured with a sperm head fixation method. Magnolol at 10-9 to 10-7 M significantly reversed the FeSO4-suppressed TBF. Magnolol significantly inhibited the generation of malondialdehyde (MDA), the end product of lipid peroxidation, in sperm. Magnolol protected sperm motility by inhibiting lipid peroxidation in sperm. [Lin MH et al; Arch ANdrol 34 (3): 151-6 (1995)] PubMed Abstract from HSDB Non-Human Toxicity Excerpts z /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ ... The effect of magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) ... in non-obese type 2 diabetic Goto-Kakizaki (GK) rats /was investigated/. The rats were treated orally with magnolol (100 mg/kg body weight) once a day for 13 weeks. In magnolol-treated GK rats, fasting blood glucose and plasma insulin were significantly decreased, and the pancreatic islets also showed strong insulin antigen positivity. Urinary protein and creatinine clearance (Ccr) were significantly decreased. Pathological examination revealed the prevention of the glomeruli enlargement in magnolol-treated GK rats. The overproduction of renal sorbitol, advanced glycation endproducts (AGEs), type IV collagen, and TGF- beta 1 mRNA were significantly reduced in magnolol-treated GK rats. [Sohn EJ et al; Life Sciences 80 (5): 468-75 (2007)] PubMed Abstract z /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Magnolol (5, 10 mg/kg) was orally administered once a day for 14 d to 2- or 4-month-old mice, and evaluation was carried out when the mice were 4 or 6 months old. The density of neurofibrils decreased with aging in the stratum radiatum of the CA1 region in the hippocampus of SAMP1, not SAMR1. Treatment with magnolol significantly prevented the decrease of neurofibrils in the CA1, when it was administered in 2-month-olds. However, administration at 4 months of age did not result in a preventive effect. These findings suggest that the administration of magnolol before the initiation of neuronal loss may result in a protective effect in the hippocampus... z /LABORATORY ANIMALS: Neurotoxicity/ The antinociceptive actions of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, were evaluated using tail-flick, hot-plate and formalin tests in mice. The effects of honokiol and magnolol on the formalin-induced c-Fos expression in the spinal cord dorsal horn as well as motor coordination and cognitive function were examined. Data showed that honokiol and magnolol did not produce analgesia in tail-flick, hot-plate paw-shaking and neurogenic phase of the overt nociception induced by intraplantar injection of formalin. However, honokiol and magnolol reduced the inflammatory phase of formalin-induced licking response. Consistently, honokiol and magnolol significantly decreased formalin-induced c-Fos protein expression in superficial (I-II) laminae of the L4-L5 lumbar dorsal horn. However, honokiol and magnolol did not elicit motor incoordination and memory dysfunction at doses higher than the analgesic dose. These results demonstrate that honokiol and magnolol effectively alleviate the formalin-induced inflammatory pain without motor and cognitive side effects, suggesting their therapeutic potential in the treatment of inflammatory pain. [Lin YR et al; Life Sci 81 (13): 1071-8 (2007)] PubMed Abstract z /LABORATORY ANIMALS: Neurotoxicity/ Honokiol and magnolol are the main constituents simultaneouly identified in the barks of Magnolia officinalis, which have been used in traditional Chinese medicine to treat a variety of mental disorders including depression. ... The present study ... on the antidepressant-like effects of oral administration of the mixture of honokiol and magnolol /was conducted/ in well-validated models of depression in rodents: forced swimming test (FST), tail suspension test (TST) and chronic mild stress (CMS) model. 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. 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. z /GENOTOXICITY/ Magnolol has been reported to strongly inhibit the mutagenicity induced by indirect mutagens in the Ames test as well as the clastogenicity induced by benzo(a)pyrene (B(a)P) in the mice micronucleus test. Here, ... the inhibitory effect of magnolol on the DNA damage induced by 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) /was evaluated/ in various organs using the mice alkaline single cell gel electrophoresis (SCG) assay. Animals were treated with a single oral administration of magnolol (0.01, 0.1, 1, 10, and 100 mg/kg), followed by a single intraperitoneal injection of Trp-P-2 (10 mg/kg). The liver, lung, and kidney were removed at 3 hr after treatment and used in SCG assay. The results indicated that magnolol inhibited Trp-P-2-induced DNA damage in various organs. To elucidate the mechanism of this inhibitory effect against Trp-P-2, we investigated the inhibitory effect of magnolol on in vivo CYP1A2 activity using the zoxazolamine paralysis test. Magnolol significantly prolonged zoxazolamine paralysis time and showed an inhibitory effect on in vivo CYP1A2 activity. These results indicate that magnolol has an inhibitory effect on the DNA damage induced by Trp-P-2 in various organs in vivo. This inhibitory mechanism is considered due to in vivo CYP1A2 inhibition. [Saito J et al; Phytother Res. 2009 Jan 12. [Epub ahead of print]] PubMed Abstract z /GENOTOXICITY/ ... Tthe in vivo anti-clastogenic effect of magnolol against clastogenicity induced by B(a)P was evaluated using the micronucleus test in mice. Animals were treated with an oral administration of magnolol (1, 10, and 100 mg/kg) at -24, 0, 24, 48, 72, and 96 hr before a single intraperitoneal injection of B(a)P. Peripheral blood specimens were prepared 48 h after administration of B(a)P, and analyzed by the acridine orange (AO) technique. The results indicated that magnolol inhibited clastogenicity induced by B(a)P at various administration times. In order to elucidate the mechanism behind this effect, we measured the activity of the detoxifying enzymes [UDP-glucuronosyltransferase (UGT) and glutathione-S-transferase (GST)] and antioxidative enzymes [superoxide dismutase (SOD) and catalase] in the liver when treated with an oral administration of magnolol at various administration times. Its effect on clastogenicity created by exposure to oxidative DNA damage-inducing X-ray irradiation was also evaluated using the micronucleus test in mice. Results showed that magnolol increased the activity of both UGT and SOD enzymes, and also inhibited the clastogenicity induced by X-ray irradiation. Magnolol had an anti-clastogenic effect on B(a)P in the micronucleus test as well as an anti-mutagenic effect on indirect mutagens in the Ames test. The anti-clastogenic effect of magnolol was also suggested by the increases in UGT and SOD enzyme activity, and by the attenuation of oxidative damage induced by X-ray irradiation. [Saito J et al; Food Chem Toxicol 46 (2): 694-700 (2008)] PubMed Abstract z /GENOTOXICITY/ ... Anti-mutagenic activity of magnolol against mutagenicity induced by direct mutagens [1-nitropyrene (1-NP), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG)] and indirect mutagens [2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), benzo(a)pyrene (B(a)P), 2-aminoanthracene (2-AA) and 7,12-dimethylbenz[a]anthracene (DMBA)] were investigated using the bacterial mutagenicity test (Ames test). Results show that magnolol strongly inhibits mutagenicity induced by indirect mutagens, but does not affect direct mutagens. To elucidate the mechanism of this effect against indirect mutagens, effect of magnolol on CYP1A1- and CYP1A2-related enzyme activities of ethoxyresorufin-O-deethylase (EROD) and methoxyresorufin-O-demethylase (MROD) were investigated. Magnolol strongly and competitively suppressed these enzyme activities, suggesting it inhibited mutation induced by indirect mutagens through suppression of CYP1A1 and CYP1A2 activity. [Saito J et al; Mutat Res 609 (1): 68-73 (2006)] PubMed Abstract z /GENOTOXICITY/ To study the genotoxic potential of Magnolia bark extract (MBE), a bacterial reverse mutation assay and an in vivo micronucleus test were conducted. Compositional analysis of the test substance revealed that MBE contains 94% magnolol and 1.5% honokiol. MBE exerted no mutagenic activity in various bacterial strains of Salmonella typhimurium and in Escherichia coli WP2 uvrA, either in the absence or presence of metabolic activation at all doses tested. In the micronucleus test, various doses of MBE did not affect the proportions of immature to total erythrocytes, nor did it increase the number of micronuclei in the immature erythrocytes of Swiss albino mice. The results of these studies demonstrate that MBE is not genotoxic under the conditions of the in vitro bacterial reverse mutation assay and the in vivo micronucleus test, and support the safety of MBE for dietary consumption. [Li N et al; Regul Toxicol Pharmacol 49 (3): 154-9 (2007)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ Magnolol stimulates adrenal steroidogenesis and induces the distributional changes of p160 and adipose differentiation-related protein (ADRP) in rat adrenal cells. This study investigated the underlying signaling mechanisms involved in these processes. Magnolol (30uM) caused a time-dependent increase in the phosphorylation of extracellular signal-related kinase (ERK) in cultured adrenal cells. The following evidence supports a link between ERK activation and p160 translocation. First, the magnolol-induced redistribution of p160 from the lipid droplet surface to the cytosol, resulting in the decrease in the percentages of p160-positive cells, and this decrease in p160-positive cells was completely blocked by pretreatment with either of the MAPK-ERK kinase (MEK) inhibitors PD98059 or U0126. Second, magnolol did not significantly decrease total p160 protein levels but caused an increase in threonine phosphorylation of p160, which reached a maximum after 5 min of magnolol treatment, and this magnolol-induced phosphorylation of p160 was prevented by pretreatment with U0126, suggesting the involvement of ERK. In addition, magnolol decreased both ADRP immunostaining intensity at the lipid droplet surface and the percentage of ADRP-positive cells. This was further confirmed biochemically by the decrease in ADRP levels in total cell homogenates and in lipid droplet fractions. Magnolol-induced decrease in ADRP staining at the lipid droplet surface was not affected by pretreatment with PD98059 or U0126, indicating that ERK signaling was not involved in this event. Furthermore, treatment with 30 uM magnolol for 6 ht resulted in about 50% decrease in ADRP protein level. Therefore, decreased protein levels of p160 and ADRP at the lipid droplet surface induced by magnolol were mediated via two different mechanisms: phosphorylation of p160 and downregulation of ADRP expression, respectively. [Chien CL et al; Histochem Cell Biol 123 (4-5): 429-39 (2005)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ The aims of the present study were to examine the effect of magnolol on lipolysis in sterol ester (SE)-loaded 3T3-L1 preadipocytes and to determine the signaling mechanism involved. ... Magnolol treatment resulted in a decreased number and surface area of lipid droplets, accompanied by release of glycerol. The lipolytic effect of magnolol was not mediated by PKA based on the facts that magnolol did not induce an elevation of intracellular cAMP levels, and protein kinase A (PKA) inhibitor KT5720 did not block magnolol-induced lipolysis. Calcium/calmodulin-dependent protein kinase (CaMK) was involved in this signaling pathway, since magnolol-induced a transient rise of intracellular [Ca(2+)] and Ca(2+) influx across the plasma membrane, and CaMK inhibitor significantly abolished magnolol-induced lipolysis. Moreover, magnolol increased the relative levels of phosphorylated extracellular signal-related kinases (ERK1 and ERK2). In support of the involvement ERK, ... magnolol-induced lipolysis was inhibited by PD98059, an inhibitor of mitogen-activated protein kinase kinase (MEK), and PD98059 reversed magnolol-induced ERK phosphorylation. Further, the relationship between CaMK and ERK was connected by the finding that CaMK inhibitor also blocked magnolol-induced ERK phosphorylation. Taken together, these findings suggest that magnolol-induced lipolysis is both CaMK- and ERK-dependent, and this lipolysis signaling pathway is distinct from the traditional PKA pathway. ERK phosphorylation is reported to enhance lipolysis by direct activation of hormone sensitive lipase (HSL), thus magnolol may likely activate HSL through ERK and increase lipolysis of adipocytes. [Huang SH et al; J Cell Biochem 91 (5): 1021-9 (2004)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ ... Whether the neuroprotective effect of magnolol involve modulating inflammatory mediators, prostaglandin E2 (PGE2) and nitric oxide (NO), induced by KCN (hypoxia) or KCN plus lipopolysaccharide (LPS) /was examined/. In glucose-absent (hypoglycemia) media, KCN or KCN plus LPS induced increases in lactate dehydrogenase (LDH) activity by 32% and 34%, and PGE2 production by 12% and 32%, respectively. Both LDH and PGE2 increases were suppressed by 100 uM magnolol. In addition, although KCN or LPS alone did not increase NO generation, KCN plus LPS increased NO generation. This increase was reduced by 100 uM magnolol or 10 uM L-NAME, but the LDH increase and PGE2 production were not reduced by L-NAME. These findings suggest that the protective effects of magnolol against brain damage by KCN or KCN plus LPS in hypoglycemic media may involve inhibition of PGE2 production, but inhibition of NO generation may not be important. [Lee MM et al; Chin J Physiol 43 (2): 61-7 (2000)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ 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. 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. 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. [Lin YR et al; Eur J Pharmacol 537 (1-3): 64-9 (2006)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ The aim of this study was to investigate the protective effect of honokiol and magnolol on hepatocyte injury induced by either tertiary butyl hydroperoxide (tBH)- or D-galactosamine (GalN). The cellular leakage of LDH and AST, and cell death by treatment with 1.5 mM tBH for 1 hr, were significantly inhibited by treatment with honokiol (40 and 20 uM) or magnolol (40 uM). Treatment with honokiol or magnolol significantly inhibited lipid peroxidation in both cells and media, the generation of intracellular reactive oxygen species (ROIs), and intracellular glutathione (GSH) depletion induced by tBH. The cellular leakage of LDH and AST, and cell death, by 24-hour treatment with 30 mM GalN were significantly inhibited by treatment with honokiol (20, 5 and 1 uM) or magnolol (20, 5 and 1 uM). Treatment with honokiol (20, 5 and 1 microM) or magnolol (20 and 5 uM) significantly inhibited the intracellular GSH depletion induced by GalN. The hepatoprotective effects of honokiol and magnolol on oxidative stress induced by tBH were probably the result of their antioxidant activity. Honokiol and magnolol also had a protective effect against GalN-induced hepatotoxicity, which was used as an alternate model to oxidative stress, acting by inhibiting intracellular GSH depletion. [Park EJ et al; Planta Med 69 (1): 33-7 (2003)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ The influence of the plant product magnolol on neutrophil superoxide anion (O2-*) generation has been investigated in the rat. Intraperitoneal injection of magnolol (30 mg/kg) significantly inhibited the formylmethionyl-leucyl-phenylalanine (fMLP)-induced respiratory burst in rat whole blood ex-vivo. Magnolol also inhibited the 02-* generation with an IC50 (concentration resulting in 50% inhibition) of 15.4+/-1.6 uM and O2 consumption in rat neutrophils in-vitro. Magnolol weakly inhibited the O2-* generation in the xanthine-xanthine oxidase system, decreased cellular cyclic AMP level and had no effect on cyclic GMP levels. It weakly inhibited neutrophil cytosolic protein kinase C activity but did not alter porcine heart protein kinase A activity. Magnolol attenuated fMLP-induced protein tyrosine phosphorylation with an IC50 of 24.0+/-1.9 uM and the phosphorylation of mitogen-activated protein kinase p42/44 with an IC50 of 28.5+/-4.5 uM. However, magnolol alone activated neutrophil phospholipase D activity as determined by the formation of phosphatidic acid and phosphatidyl-ethanol in the presence of ethanol. In the presence of NADPH, the arachidonate-activated NADPH oxidase activity in a cell-free system was weakly suppressed by magnolol. These results suggest that the inhibition of respiratory burst in fMLP-activated neutrophils by magnolol is probably attributable mainly to the attenuation of protein tyrosine phosphorylation and p42/44 mitogen-activated protein kinase activation, and partly to the suppression of protein kinase C and NADPH oxidase activities. [Wang JP et al; J Pharm Pharmacol 51 (3): 285-94 (1999)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ ... In guinea pig isolated ileum, both magnolol and honokiol inhibited contraction to acetylcholine. The herbal extracts also produced inhibitory responses, in an order of decreasing efficacy: ethanol extract >50% ethanol extract > water extract. The differences in inhibitory efficacies among the three extracts were similar to the differences in their magnolol and honokiol contents. Further examination demonstrated that two mixtures containing solely magnolol and honokiol at concentrations identical to those determined in the ethanol and water extracts exhibited similar levels of anti-spasmodic effects as their respective extracts while a "blank" ethanol extract free of magnolol and honokiol failed to produce any response. These observations suggest that the magnolol and honokiol contents account for the anti-spasmodic effects of M. officinalis extracts in guinea pig isolated ileum. [Chan SKS et al; Planta Medica 74 (4): 381-4 (2008)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ Routine experimental methods using isolated gastric fundus strips of rats and isolated ileum segments of guinea pigs were adopted to measure the smooth muscle tension. The effects of magnolol 10-3, 10-4, 10-5 mol/L, and honokiol 10-4, 10-5, 10-6 mol/L on the contractility of gastric fundus strips of rats and ileum of guinea pigs induced by acetylcholine (Ach) and 5-hydroxytryptamine (5-HT) was assessed respectively. The method using nuclein and pigment methylene blue was adopted to measure the gastric retention rate of nuclein and the intestinal propulsive ratio of a nutritional semi-solid meal for assessing the effect of magnolol and honokiol (0.5, 2, 20 mg/kg) on gastric emptying and intestinal propulsion. RESULTS: Magnolol and honokiol significantly inhibited the contractility of isolated gastric fundus strips of rats treated with Ach or 5-HT and isolated ileum guinea pigs treated with Ach or CaCl2, and both of them behaved as non-competitive muscarinic antagonists. Magnolol and honokiol inhibited the contraction induced by Ach in Ca2+-free medium and extracellular Ca2+-dependent contraction induced by Ach. Each group of magnolol and honokiol experiments significantly decreased the residual rate of nuclein in the stomach and increased the intestinal propulsive ratio in mice... [Zhang WW et al; World J Gastroenterol 11 (28): 4414-8 (2005)] PubMed Abstract z /ALTERNATIVE and IN VITRO TESTS/ The aim of this study was to investigate the influence of magnolol and honokiol on smooth muscle tone in porcine trachea. Magnolol and honokiol (0.1 - 100 uM) inhibited carbachol- and high K +-induced muscle contractions in a concentration-dependent fashion, but did not affect basal muscle tension. After washout of these pretreatments, carbachol- and high K +-evoked muscle contractions were still abolished, suggesting that the inhibition was irreversible. Magnolol and honokiol also concentration-dependently decreased the Ca 2+-dependent muscle contraction induced by high K + depolarization. Ca 2+ channel antagonists attenuated carbachol-induced muscular response by approximately 30 %, but did not further potentiate the inhibitory actions of magnolol and honokiol on muscle contraction. However, the inhibitory effects of magnolol and h onokiol on carbachol-evoked muscular contractile response were partially reversed after removal of Ca 2+ channel antagonist pretreatment. Alternatively, caffeine-elicited muscle contractions were not altered by magnolol, honokiol, and verapamil. In conclusion, the relaxant effects of magnolol and honokiol on porcine tracheal smooth muscle suggest an association with the blockade of Ca 2+ influx through voltage-operated Ca 2+ channels instead of Ca 2+ release from intracellular Ca 2+ stores. The magnolol- and honokiol-induced inhibitions on tracheal smooth muscle contraction may be relevant to the claimed therapeutic effects of the extract from magnolia bark and contribute to their pharmacological effects by acting as anti-asthmatic agents. [Ko CH et al; Planta Med 69 (6): 532-6 (2003)] PubMed Abstract z /IMMUNOTOXICITY/ The antiallergic effects of magnolol and honokiol, isolated from the bark of Magnolia obovata (family Magnoliaceae), were investigated both in vitro and in vivo. Magnolol and honokiol potently inhibited passive cutaneous anaphylaxis reactions in mice induced by IgE-antigen complex as well as compound 48/80-induced scratching behaviors. These constituents exhibited not only potent inhibitory activity on the degranulation of RBL-2H3 cells induced by IgE-antigen complex, with IC(50) values of 45 and 55 uM, respectively, but also inhibited the protein expressions of IL-4 and TNF-alpha. Based on these findings, magnolol and honokiol may improve IgE-induced allergic diseases. [Han SJ et al; Biol Pharm Bull 30 (11): 2201-3 (2007)] PubMed Abstract z /IMMUNOTOXICITY/ Magnolol, isolated from Magnolia officinalis, inhibited mouse hind-paw edema induced by carrageenan, compound 48/80, polymyxin B and reversed passive Arthus reaction. Acetic acid-induced writhing response was depressed by magnolol, indomethacin and ibuprofen. The lethality of endotoxin challenge was reduced by pretreatment with magnolol, indomethacin and BW755C, a dual cyclo-oxygenase/lipoxygenase inhibitor. The recovered myeloperoxidase activity in edematous paw was significantly decreased in mice pretreated with magnolol and BW755C. Suppression of edema was demonstrated not only in normal mice but also in adrenalectomized animals. Magnolol was less potent on reducing PGD2 formation in rat mast cell than that of indomethacin. Unlike dexamethasone, magnolol did not increase liver glycogen level. The results suggest that the anti-inflammatory effect of magnolol was neither mediated by glucocorticoid activity nor through releasing steroid hormones from adrenal gland. The action of magnolol is proposed to be dependent on reducing the level of eicosanoid mediators. [Wang JP et al; Naunyn Schmiedebergs Arch Pharmacol 346 (6): 707-12 (1992)] PubMed Abstract z /OTHER TOXICITY INFORMATION/ Three weeks prior to the experiment 10 rats underwent a portosystemic shunt operation according to Bengmerk's method. The rats were divided into three groups. Group 1 (GI) was the control group, Group 2 (GII) and Group 3 (GIII) the magnolol-treated groups. GI and GII were subjected to 2 hr and GIII to 3 hr of WI/R by clamping the portal vein and hepatic artery under ether anesthesia. ... All the control rats died after 2 hr WI/R. Apoptotic cells were detected under microscopy as well as by DNA assay. Magnolol-treated groups tolerated warm ischemia-reperfusion for 2 hr and significantly less apoptotic cells were observed (198 +/- 22 vs 42.6 +/- 28). But magnolol-treated rats could not tolerate 3 hr warm ischemia-reperfusion. RT-PCR of liver tissue shows that there is an upregulated expression of the anti-apoptotic Bcl-xL gene and suppression of the Bcl-xS gene in GII. /It was concluded that / magnolol has an anti-apoptotic effect and protects the liver against WI/R for 2 hr but not for 3 hr through upregulation of the anti-apoptotic Bcl-XL gene and suppression of the Bcl-xS gene. [Jawan B et al; J Surg Res 110 (2): 378-82 (2003)] PubMed Abstract z /OTHER TOXICITY INFORMATION/ ... The cardioprotective activity of magnolol was evaluated in an open-chest anesthetized rat model of myocardial ischemia/reperfusion injury. The results demonstrated that pretreatment with magnolol (0.2 and 0.5 ug/kg, iv bolus) at 10 min before 45 min of left coronary artery occlusion, significantly suppressed the incidence of ventricular fibrillation and mortality when compared with the control group. Magnolol (0.2 and 0.5 ug/kg) also significantly reduced the total duration of ventricular tachycardia and ventricular fibrillation. After 1 hr of reperfusion, pretreatment with magnolol (0.2 and 0.5 ug/kg) caused a significant reduction in infarct size. In addition, magnolol (0.2 ug/kg) significantly reduced superoxide anion production and myeloperoxidase activity, an index of neutrophil infiltration in the ischemic myocardium. In addition, pretreatment with magnolol (0.2 and 0.5 ug/kg) suppressed ventricular arrhythmias elicited by reperfusion following 5 min of ischemia. [Lee YM et al; Eur J Pharmacol 422 (1-3_: 159-67 (2001)] PubMed Abstract z /OTHER TOXICITY INFORMATION/ ... To determine whether magnolol can modulate the course of sepsis, survival rate and biochemical parameters were analyzed in rats with sepsis with various treatment protocols. Magnolol at doses ranging from 10-9 g/kg to 10-5 g/kg was administered either before or after induction of sepsis by cecal ligation and puncture. Magnolol did not modulate the course of sepsis induced by two cecal punctures. When one cecal puncture was performed, a moderately evolving type of sepsis was induced, and the survival rate of affected rats was significantly improved by pretreatment with 10-7 g/kg magnolol. The beneficial effect was partially retained if magnolol was administered 6 hours after onset of sepsis when a higher dose (10-5 g/kg) was used. The intensity of lipid peroxidation in plasma, liver, and lung of septic rats was also attenuated in a treatment-dependent manner. Magnolol at this dose range exerted these beneficial effects probably through its antioxidant efficacy. These significant results may suggest magnolol as a candidate agent for the treatment of sepsis. [Kong CW et al; Shock 13 (1): 24-8 (2000)] PubMed Abstract from HSDB Non-Human Toxicity Values LD50 Mouse oral 2200 mg/kg /from table/

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