Antinociceptive actions of honokiol and magnolol on glutamatergic and inflammatory pain

The antinociceptive effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, were investigated on animal paw licking responses and thermal hyperalgesia induced by glutamate receptor agonists including glutamate, N-methyl-D-aspartate (NMDA), and metabotropic glutamate 5 receptor (mGluR5) activator (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), as well as inflammatory mediators such as substance P and prostaglandin E₂ (PGE₂) in mice. The actions of honokiol and magnolol on glutamate-induced c-Fos expression in the spinal cord dorsal horn were also examined. Our data showed that honokiol and magnolol blocked glutamate-, substance P- and PGE₂-induced inflammatory pain with similar potency and efficacy. Consistently, honokiol and magnolol significantly decreased glutamate-induced c-Fos protein expression in superficial (I-II) laminae of the L4-L5 lumbar dorsal horn. However, honokiol was more selective than magnolol for inhibition of NMDA-induced licking behavioral and thermal hyperalgesia. In contrast, magnolol was more potent to block CHPG-mediated thermal hyperalgesia. These results demonstrate that honokiol and magnolol effectively decreased the inflammatory pain. Furthermore, their different potency on inhibition of nociception provoked by NMDA receptor and mGluR5 activation should be considered.     

Effects of honokiol and magnolol on acute and inflammatory pain models in mice

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.     

Antinociceptive activity of filenadol on inflammatory pain

The novel analgesic filenadol (d,1-erythro-1-(3′,4′-methylenedioxyphenyl)-1-morpholinopropan-2-ol) inhibited phenyl-p-benzoquinone-induced writhing in mice with ID₅₀ values of 68.8 (p.o.), 1.67 (i.v.) and 0.48 (i.c.v.) mg/kg. Hyperalgesia induced by arachidonic acid, PGE₂ or LTB₄ in this test was also decreased by filenadol (ID₅₀ = 24.4, 3.7 and 50.1 mg/kg p.o., respectively). This compound was effective on PGE₂, LTB₄, bradykinin, PAF or IL-1μ-induced decrease in pain threshold in the rat paw pressure model and almost totally suppressed the writhing induced by zymosan in mice, while peritoneal production of 6-ketoPGF_1α was inhibited by 48.5–62 % and only at 100 mg/kg significant inhibition of LTC₄ was achieved. The late phase of formalin-induced pain response in mice was prevented by filenadol, without affecting the oedema. Filenadol is an antinociceptive agent that reduces the hyperalgesic effects of inflammatory mediators besides inhibiting partially the synthesis of eicosanoids.     

Antinociceptive and nociceptive actions of opioids

Although the opioids are the principal treatment options for moderate to severe pain, their use is also associated with the development of tolerance, defined as the progressive need for higher doses to achieve a constant analgesic effect. The mechanisms which underlie this phenomenon remain unclear. Recent studies revealed that cholecystokinin (CCK) is upregulated in the rostral ventromedial medulla (RVM) during persistent opioid exposure. CCK is both antiopioid and pronociceptive, and activates descending pain facilitation mechanisms from the RVM enhancing nociceptive transmission at the spinal cord and promoting hyperalgesia. The neuroplastic changes elicited by opioid exposure reflect adaptive changes to promote increased pain transmission and consequent diminished antinociception (i.e., tolerance).     

Synthesis, cytotoxicity, and antiviral activities of new neolignans related to honokiol and magnolol

A series of new bisphenol derivatives bearing allylic moieties were synthesized as potential analogs of honokiol and/or magnolol. Certain compounds exhibited specific anti-proliferation activity against SVR cells and moderate anti-HIV-1 activity in primary human lymphocytes. Compound 5h was the most potent compound and its anti-tumor activity was evaluated in vivo.     

Comparison of antioxidant abilities of magnolol and honokiol to scavenge radicals and to protect DNA

The antioxidant properties of magnolol and honokiol were evaluated in the experimental systems of reducing ONOO⁻ and ¹O₂, bleaching β-carotene in linoleic acid (LH) emulsion, and trapping 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS⁺) and 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH), and then were applied to inhibit the oxidation of DNA induced by Cu²⁺/glutathione (GSH) and 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH). Magnolol and honokiol were active to reduce ONOO⁻ and ¹O₂. Honokiol showed a little higher activity to protect LH and to inhibit Cu²⁺/GSH-induced oxidation of DNA than magnolol. In addition, honokiol exhibited higher activities to trap ABTS⁺ and DPPH than magnolol. In particular, honokiol trapped 2.5 radicals while magnolol only trapped 1.8 radicals in protecting DNA against AAPH-induced oxidation. The obtained results suggested that low antioxidant ability of magnolol may be related to the intramolecular hydrogen bond formed between di-ortho-hydroxyl groups, which hindered the hydrogen atom in hydroxyl group to be abstracted by radicals. Therefore, the antioxidant capacity of magnolol was lower than that of honokiol.     

Electrochemical detection of honokiol and magnolol in traditional Chinese medicines using acetylene black nanoparticle-modified electrode

Introduction – Honokiol and magnolol are the active components of Magnolia officinalis, which is a widely used traditional Chinese medicine. Their simultaneous analysis is, therefore, important for the quality control of the product. Objective – To establish a simple, sensitive and rapid electrochemical method for the simultaneous detection of honokiol and magnolol based on the remarkable enhancement effect of acetylene black nanoparticle (AB). Methodology – The AB‐modified electrode was prepared via solvent evaporation. The electrochemical response of honokiol and magnolol was investigated using cyclic voltammetry. The simultaneous detection was performed with differential pulse voltammetry. The method was validated in terms of linearity, sensitivity, precision and accuracy. Results – The linear range for honokiol is 0.5–300 µg/L, and the limit of detection (LOD) is 0.25 µg/L (9.4 × 10^?10 mol/L). For magnolol, the linear range is 10–250 µg/L, and the LOD is 5 µg/L (1.88 × 10^?8 mol/L). Conclusion – The new method was successfully used to determine honokiol and magnolol in a traditional Chinese medicine called Ageratum liquid. Copyright © 2010 John Wiley & Sons, Ltd.     

Antinociceptive effect of intrathecal administration of hypotaurine in rat models of inflammatory and neuropathic pain

Hypotaurine is an intermediate in taurine biosynthesis from cysteine in astrocytes. Although hypotaurine functions as an antioxidant and organic osmolyte, its physiological role in the central nervous system remains unclear. This study used behavioral assessments to determine whether hypotaurine influenced nociceptive transmission in acute, inflammatory, and neuropathic pain. The tail flick, paw pressure, and formalin tests were performed in male Sprague-Dawley rats to examine the effects of the intrathecal administration of hypotaurine (100, 200, 400, 600?μg) on thermal, mechanical, and chemical nociception. Chronic constriction injury (CCI) to the sciatic nerve was induced in the rats, and the electronic von Frey test and plantar test were performed to assess the effects on neuropathic pain. To determine which neurotransmitter pathway(s) was involved in the action of hypotaurine, in this study, we examined how the antagonists of spinal pain processing receptors altered the effect of 600?μg hypotaurine. To explore whether hypotaurine affected motor performance, the Rotarod test was conducted. Hypotaurine had antinociceptive effects on thermal, mechanical, and chemical nociception in the spinal cord. In CCI rats, hypotaurine alleviated mechanical allodynia and thermal hyperalgesia. These effects were reversed completely by pretreatment with an intrathecal injection of strychnine, a glycine receptor antagonist. Conversely, hypotaurine did not affect motor performance. This study demonstrated that intrathecal hypotaurine suppressed acute, inflammatory, and neuropathic pain. Hypotaurine may regulate nociceptive transmission physiologically by activating glycinergic neurons in the spinal cord, and it is a promising candidate for treating various pain states.     

Structural analogues of the natural products magnolol and honokiol as potent allosteric potentiators of GABAA receptors

Biphenylic compounds related to the natural products magnolol and 4′-O-methylhonokiol were synthesized, evaluated and optimized as positive allosteric modulators (PAMs) of GABA_A receptors. The most efficacious compounds were the magnolol analog 5-ethyl-5′-hexylbiphenyl-2,2′-diol (45) and the honokiol analogs 4′-methoxy-5-propylbiphenyl-2-ol (61), 5-butyl-4′-methoxybiphenyl-2-ol (62) and 5-hexyl-4′-methoxybiphenyl-2-ol (64), which showed a most powerful potentiation of GABA-induced currents (up to 20-fold at a GABA concentration of 3 μM). They were found not to interfere with the allosteric sites occupied by known allosteric modulators, such as benzodiazepines and N-arachidonoylglycerol. These new PAMs will be useful as pharmacological tools and may have therapeutic potential for mono-therapy, or in combination, for example, with GABA_A receptor agonists.     

Anti‐biofilm and bactericidal effects of magnolia bark‐derived magnolol and honokiol on Streptococcus mutans

Dental caries affects people of all ages and is a worldwide health concern. Streptococcus mutans is a major cariogenic bacterium because of its ability to form biofilm and induce an acidic environment. In this study, the antibacterial activities of magnolol and honokiol, the main constituents of the bark of magnolia plants, toward planktonic cell and biofilm of S. mutans were examined and compared with those of chlorhexidine. The minimal inhibitory concentrations of magnolol, honokiol and chlorhexidine for S. mutans were 10, 10 and 0.25 µg/mL, respectively. In addition, each agent showed bactericidal activity against S. mutans planktonic cells and inhibited biofilm formation in a dose‐ and time‐dependent manner. Magnolol (50 µg/mL) had greater bactericidal activity against S. mutans biofilm than honokiol (50 µg/mL) and chlorhexidine (500 µg/mL) at 5 min after exposure, while all showed scant activity against biofilm at 30 s. Furthermore; chlorhexidine (0.5–500 µg/mL) exhibited high cellular toxicity for the gingival epithelial cell line Ca9‐22 at 1 hr, whereas magnolol (50 µg/mL) and honokiol (50 µg/mL) did not. Thus; it was found that magnolol has antimicrobial activities against planktonic and biofilm cells of S. mutans. Magnolol may be a candidate for prevention and management of dental caries.     

Isolation of anti-Saprolegnia lignans from Magnolia officinalis and SAR evaluation of honokiol/magnolol analogs

To control the fish fungal pathogen Saprolegnia, the effects of the petroleum ether extracts of Magnolia officinalis were evaluated by a rapeseed (Brassicanapus) microplate method in vitro. By loading on an open silica gel column and eluting with petroleum ether-ethyl acetate-methanol, honokiol (C₁₈H₁₈O₂) and magnolol (C₁₈H₁₈O₂) were isolated from Magnolia officinalis. Saprolegnia parasitica growth was inhibited significantly when honokiol concentration was >8.0?mg/L, and magnolol concentration was >9.0?mg/L, with EC₅₀ values of 4.38 and 4.92?mg/L, respectively. Six honokiol and magnolol derivatives were designed, synthesized and evaluated for their anti-Saprolegnia activity. According to the results, double bond and hydroxyl played an important role in inhibiting Saprolegnia. Mechanistically, through the scanning electron microscope observation, honokiol and magnolol could cause the Saprolegnia parasitica mycelium tegumental damage including intensive wrinkles and nodular structures. Moreover, compared to traditional drugs kresoxim-methyl (LC₅₀?=?0.66?mg/L) and azoxystrobin (LC₅₀?=?2.71?mg/L), honokiol and magnolol showed a lower detrimental effect on zebrafish, with the LC₅₀ values of 6.00 and 7.28?mg/L at 48?h, respectively. Overall, honokiol and magnolol were promising lead compounds for the development of commercial drugs anti-Saprolegnia.     

Effects of magnolol and honokiol blend on performance,egg quality,hepatic lipid metabolism,and intestinal morphology of hens at late laying cycle

Magnolol and its isomer honokiol are polyphenols with anti-oxidative and anti-inflammatory activities. We evaluated the effects of magnolol and honokiol supplementation alone or in combination with hen diets during the late laying cycle. A total of 540 Jingfen pink-shell laying hens (50 weeks old) were randomly assigned to six treatments: a control diet and diets supplemented with 300 mg/kg magnolol (M₃₀₀), honokiol (H₃₀₀), or 300 mg/kg total phenols with a magnolol/honokiol ratio of 2:1 (M₂₀₀H₁₀₀), 1:2 (M₁₀₀H₂₀₀), and 1:1 (M₁₅₀H₁₅₀). Compared with that of the control, all supplementation groups had higher laying rates and the M₃₀₀, M₁₀₀H₂₀₀, and M₁₅₀H₁₅₀ groups showed comparatively lower feed conversion ratios. Magnolol and honokiol supplementation increased the Haugh units of fresh eggs at week 62 and alleviated the decline of the Haugh units of eggs stored for 14 days. Compared with that of the control group, the serum total antioxidant capacity of the M₁₀₀H₂₀₀ and M₁₅₀H₁₅₀ groups significantly increased, and all supplementation groups had higher total antioxidant capacity and lower malondialdehyde content in the liver. With respect to lipid metabolism, the M₂₀₀H₁₀₀ and M₁₅₀H₁₅₀ groups had lower total and relative liver weights compared with those of the control and H₃₀₀ groups. The mRNA expression levels of CCAAT enhancer binding protein alpha, sterol regulatory element binding protein-1, fatty acid synthase and stearyl coenzyme A desaturase 1 involved in lipogenesis; microsomal triglyceride transfer protein and apolipoprotein B involved in fatty acid transport; and the proinflammatory cytokine interleukin-1 beta were lower in all supplementation groups compared with those in the control. With respect to gut health, the heights of the jejunum and ileum villi significantly increased in all supplementation groups compared with those of the control, and the jejunum villus heights of the M₃₀₀ and M₁₅₀H₁₅₀ groups were higher than those of the H₃₀₀ and M₁₀₀H₂₀₀ groups. The H₃₀₀ and M₁₅₀H₁₅₀ groups had higher mRNA expression levels of zonula occludens-1 in the ileum compared with those in the control and M₃₀₀ groups, whereas all supplementation groups had higher mRNA levels of claudin-1 than that of the control group. In conclusion, magnolol and honokiol improved hen performance and the albumen quality of fresh and stored eggs by improving the antioxidant capacity, liver lipid metabolism, and intestinal health of laying hens. The combination of magnolol and honokiol at a 1:1 ratio may be an optimal choice for hen diet supplementation.     

Antinociceptive effect of chrysin in diabetic neuropathy and formalin-induced pain models

ABSTRACT

Chrysin, a natural flavonoid, is the main ingredient of many medicinal plants, which shows potent pharmacological properties. In the present study, the antinociceptive effects of chrysin were examined in ICR mice. Chrysin orally administered at the doses of from 10 to 100?mg/kg exerted the reductions of formalin-induced pain behaviors observed during the second phase in the formalin test in a dose-dependent manner. In addition, the antinociceptive effect of chrysin was further characterized in streptozotocin-induced diabetic neuropathy model. Oral administration chrysin caused reversals of decreased pain threshold observed in diabetic-induced peripheral neuropathy model. Intraperitoneally (i.p.) pretreatment with naloxone (a classic opioid receptor antagonist), but not yohimbine (an antagonist of α2-adrenergic receptors) or methysergide (an antagonist of serotonergic receptors), effectively reversed chrysin-induced antinociceptive effect in the formalin test. Moreover, chrysin caused a reduction of formalin-induced up-regulated spinal p-CREB level, which was also reversed by i.t. pretreated naloxone. Finally, chrysin also suppressed the increase of the spinal p-CREB level induced by diabetic neuropathy. Our results suggest that chrysin shows an antinociceptive property in formalin-induced pain and diabetic neuropathy models. In addition, spinal opioid receptors and CREB protein appear to mediate chrysin-induced antinociception in the formalin-induced pain model.     

谷氨酸性突触在痛觉和记忆中的突触和分子机制

谷氨酸是哺乳动物脑中的兴奋性递质。中枢神经系统的谷氨酸性突触广泛参与痛觉传递,突触可塑性和递质的调节。谷氨酸的NMDA受体参与前脑相关的学习及功能。在这篇综述中,我们提出前脑的NMDA受体通过增强谷氨酸性突触传递导致长期性的炎痛。具有增强NMDA受体功能的小鼠会产生更多的慢性痛。NMDA NR2B受体抑制剂在未来可能被用来控制人类的慢性痛。     

Antinociceptive effect of amitriptyline in mice of acute pain models

Tricyclic antidepressant drugs induce antinociceptive effect and suggest that their analgesic action could be related to the monoaminergic activity of the drugs. The analgesic activity of amitriptyline was observed in mouse models of acute pain. Mice were divided into different groups and were given amitriptyline in different doses alone and in combination with morphine. Reaction time in Hot-Plate and Tail-Flick tests was observed. Results showed that amitriptyline had antinociceptive effect in acute pain state in experimental models. Amitriptyline in combination with morphine had better analgesic effect than the morphine alone in Hot-Plate test.     

Antinociceptive and anti-inflammatory activities of butein in different nociceptive and inflammatory mice models

BackgroundAround 30% world population affected by acute and chronic pain due to inflammation and accidental injuries. Pain is a uncomfortable sensation and it reduce the patients’ life quality.ObjectiveThe present exploration focuses to explore the beneficial effects of butein on the different chemical and thermal-provoked nociceptive and inflammatory mice models.MethodologyThe nociception was induced to the Swiss mice using different chemical (formalin, acetic acid, glutamate, and capsaicin) and thermal (hot plate and tail immersion) methods. the mice were supplemented with 10, 15, and 20 mg/kg of butein and respective standard drugs like morphine, diclofenac sodium, and dexamethasone. The anti-inflammatory effects of butein was studied using carrageenan-provoked inflammation in mice.ResultsThe present findings clearly demonstrated that the butein was substantially lessened the different thermal and chemical provoked nociception in mice. The carrageenan-triggered paw edema and inflammatory cell infiltrations were appreciably suppressed by the butein treatment. The TNF-α, IL-1β, and IL-6 levels in the carrageenan-induced mice were effectively depleted by the butein.ConclusionAltogether, the present findings evidenced the potent antinociceptive and anti-inflammatory properties of the butein in different nociceptive mice models.     

Magnolia dealbata Zucc and its active principles honokiol and magnolol stimulate glucose uptake in murine and human adipocytes using the insulin-signaling pathway

Some Magnolia (Magnoliaceae) species are used for the empirical treatment of diabetes mellitus, but the antidiabetic properties of Magnolia dealbata have not yet been experimentally validated. Here we report that an ethanolic extract of Magnolia dealbata seeds (MDE) and its active principles honokiol (HK) and magnolol (MG) induced the concentration-dependent 2-NBDG uptake in murine 3T3-F442A and human subcutaneous adipocytes. In insulin-sensitive adipocytes, MDE 50 μg/ml induced the 2-NBDG uptake by 30% respect to insulin, while HK and MG, 30 μM each, did it by 50% (murine) and 40% (human). The simultaneous application of HK and MG stimulated 2-NBDG uptake by 70% in hormone-sensitive cells, on which Magnolia preparations exerted synergic effects with insulin. In insulin-resistant adipocytes, MDE, HK and MG induced 2-NBDG uptake by 57%, 80% and 96% respect to Rosiglitazone (RGZ), whereas HK and MG simultaneously applied stimulated 2-NBDG uptake more efficiently than RGZ (120%) in both murine and human adipocytes. Inhibitors of the insulin-signaling pathway abolished the glucose uptake induced by Magnolia dealbata preparations, suggesting that their antidiabetic effects are mediated by this signaling pathway. In addition, MDE, HK and MG exerted only mild to moderate proadipogenic effects on 3T3-F442A and human preadipocytes, although the combined application of HK and MG markedly increased the lipid accumulation in both cell types. In summary, Magnolia dealbata and its active principles HK and MG stimulate glucose uptake in insulin-sensitive and insulin-resistant murine and human adipocytes using the insulin signaling pathway.