4′-O-methylhonokiol increases levels of 2-arachidonoyl glycerol in mouse brain via selective inhibition of its COX-2-mediated oxygenation

Journal of Neuroinflammation

Jürg Gertsch¹  Roch-Philippe Charles¹  Wolfgang Schuehly²  Vanessa Petrucci¹  Maria Salomé Gachet¹  Andrea Chicca¹ 

[1]Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, Bern, CH-3012, Switzerland

[2]Institute of Zoology, Karl-Franzens-University Graz, Universitätsplatz 2, Graz, 8010, Austria

关键词: Magnolia grandiflora;    2-arachidonoyl glycerol;    Endocannabinoid system;    Partial agonist;    Polypharmacology;    CB2 receptor;    COX-2;    Endocannabinoids;    4′-O-methylhonokiol;   

Others  :  1227089
DOI  :  10.1186/s12974-015-0307-7

 received in 2015-02-06, accepted in 2015-04-24,  发布年份 2015

【 摘 要 】

Background and purpose

4′-O-methylhonokiol (MH) is a natural product showing anti-inflammatory, anti-osteoclastogenic, and neuroprotective effects. MH was reported to modulate cannabinoid CB2 receptors as an inverse agonist for cAMP production and an agonist for intracellular [Ca2+]. It was recently shown that MH inhibits cAMP formation via CB2 receptors. In this study, the exact modulation of MH on CB2 receptor activity was elucidated and its endocannabinoid substrate-specific inhibition (SSI) of cyclooxygenase-2 (COX-2) and CNS bioavailability are described for the first time.

Methods

CB2 receptor modulation ([35S]GTPγS, cAMP, and β-arrestin) by MH was measured in hCB2-transfected CHO-K1 cells and native conditions (HL60 cells and mouse spleen). The COX-2 SSI was investigated in RAW264.7 cells and in Swiss albino mice by targeted metabolomics using LC-MS/MS.

Results

MH is a CB2 receptor agonist and a potent COX-2 SSI. It induced partial agonism in both the [35S]GTPγS binding and β-arrestin recruitment assays while being a full agonist in the cAMP pathway. MH selectively inhibited PGE2 glycerol ester formation (over PGE2) in RAW264.7 cells and significantly increased the levels of 2-AG in mouse brain in a dose-dependent manner (3 to 20 mg kg⁻¹) without affecting other metabolites. After 7 h from intraperitoneal (i.p.) injection, MH was quantified in significant amounts in the brain (corresponding to 200 to 300 nM).

Conclusions

LC-MS/MS quantification shows that MH is bioavailable to the brain and under condition of inflammation exerts significant indirect effects on 2-AG levels. The biphenyl scaffold might serve as valuable source of dual CB2 receptor modulators and COX-2 SSIs as demonstrated by additional MH analogs that show similar effects. The combination of CB2 agonism and COX-2 SSI offers a yet unexplored polypharmacology with expected synergistic effects in neuroinflammatory diseases, thus providing a rationale for the diverse neuroprotective effects reported for MH in animal models.

【 授权许可】

   
2015 Chicca et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Schuehly W, Paredes JM, Kleyer J, Huefner A, Anavi-Goffer S, Raduner S, et al.: Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB (2) receptor inverse agonists. Chem Biol. 2011, 18:1053-64.
• [2]Lee YJ, Choi DY, Choi IS, Kim KH, Kim YH, Kim HM, et al.: Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models. J Neuroinflammation. 2012, 9:35. BioMed Central Full Text
• [3]Lee YJ, Choi DY, Lee YK, Lee YM, Han SB, Kim YH, et al.: 4-O-methylhonokiol prevents memory impairment in the Tg2576 transgenic mice model of Alzheimer’s disease via regulation of β-secretase activity. J Alzheimers Dis. 2012, 29:677-90.
• [4]Jung YY, Lee YJ, Choi DY, Hong JT: Amelioration of cognitive dysfunction in APP/ps1 double transgenic mice by long-term treatment of 4-O-Methylhonokiol. Biomol Ther (Seoul). 2014, 22:232-8.
• [5]Gertsch J, Anavi-Goffer S: Methylhonokiol attenuates neuroinflammation: a role for cannabinoid receptors? J Neuroinflammation. 2012, 9:135. BioMed Central Full Text
• [6]Kim HS, Ryu HS, Kim JS, Kim YG, Lee HK, Jung JK, et al. Validation of cyclooxygenase-2 as a direct anti-inflammatory target of 4-O-methylhonokiol in zymosan-induced animal models. Arch Pharm Res. 2014. In press.
• [7]Schühly W, Hüfner A, Pferschy-Wenzig EM, Prettner E, Adams M, Bodensieck A, et al.: Design and synthesis of ten biphenyl-neolignan derivatives and their in vitro inhibitory potency against cyclooxygenase-1/2 activity and 5-lipoxygenase-mediated LTB4-formation. Bioorg Med Chem. 2009, 17:4459-65.
• [8]Baur R, Schuehly W, Sigel E: Moderate concentrations of 4-O-methylhonokiol potentiate GABAA receptor currents stronger than honokiol. Biochim Biophys Acta. 2014, 1840:3017-21.
• [9]Fuchs A, Rempel V, Müller CE: The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists. PLoS One. 2013, 8:e77739.
• [10]Kozak KR, Crews BC, Morrow JD, Wang LH, Ma YH, Weinander R, et al.: Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides. J Biol Chem. 2002, 277:44877-85.
• [11]Kozak KR, Gupta RA, Moody JS, Ji C, Boeglin WE, DuBois RN, et al.: 15-Lipoxygenase metabolism of 2-arachidonylglycerol. Generation of a peroxisome proliferator-activated receptor alpha agonist. J Biol Chem 2002, 277:23278-86.
• [12]Snider NT, Walker VJ, Hollenberg PF: Oxidation of the endogenous cannabinoid arachidonoyl ethanolamide by the cytochrome P450 monooxygenases: physiological and pharmacological implications. Pharmacol Rev. 2010, 62:136-54.
• [13]Weber A, Ni J, Ling KH, Acheampong A, Tang-Liu DD, Burk R, et al.: Formation of prostamides from anandamide in FAAH knockout mice analyzed by HPLC with tandem mass spectrometry. J Lipid Res. 2004, 45:757-63.
• [14]Duggan KC, Hermanson DJ, Musee J, Prusakiewicz JJ, Scheib JL, Carter BD, et al.: (R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2. Nat Chem Biol 2011, 7:803-9.
• [15]Gatta L, Piscitelli F, Giordano C, Boccella S, Lichtman A, Maione S, et al.: Discovery of prostamide F2α and its role in inflammatory pain and dorsal horn nociceptive neuron hyperexcitability. PLoS One. 2012, 7:e31111.
• [16]Kaufmann WE, Worley PF, Pegg J, Bremer M, Isakson P: COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci U S A. 1996, 93:2317-21.
• [17]Yoshikawa K, Takei S, Hasegawa-Ishii S, Chiba Y, Furukawa A, Kawamura N, et al.: Preferential localization of prostamide/prostaglandin F synthase in myelin sheaths of the central nervous system. Brain Res. 2011, 1367:22-32.
• [18]Ritter JK, Li C, Xia M, Poklis JL, Lichtman AH, Abdullah RA, et al.: Production and actions of the anandamide metabolite prostamide E2 in the renal medulla. J Pharmacol Exp Ther. 2012, 342:770-9.
• [19]Liang Y, Woodward DF, Guzman VM, Li C, Scott DF, Wang JW, et al.: Identification and pharmacological characterization of the prostaglandin FP receptor and FP receptor variant complexes. Br J Pharmacol. 2008, 154:1079-93.
• [20]Ligresti A, Martos J, Wang J, Guida F, Allarà M, Palmieri V, et al.: Prostamide F (2) α receptor antagonism combined with inhibition of FAAH may block the pro-inflammatory mediators formed following selective FAAH inhibition. Br J Pharmacol. 2014, 171:1408-19.
• [21]Hermanson DJ, Hartley ND, Gamble-George J, Brown N, Shonesy BC, Kingsley PJ, et al.: Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation. Nat Neurosci. 2013, 16:1291-8.
• [22]Chicca A, Caprioglio D, Minassi A, Petrucci V, Appendino G, Taglialatela-Scafati O, et al.: Functionalization of β-caryophyllene generates novel polypharmacology in the endocannabinoid system. ACS Chem Biol. 2014, 9:1499-507.
• [23]Chicca A, Marazzi J, Gertsch J: The antinociceptive triterpene β-amyrin inhibits 2-arachidonoylglycerol (2-AG) hydrolysis without directly targeting cannabinoid receptors. Br J Pharmacol. 2002, 167:1596-608.
• [24]Rosati O, Messina F, Pelosi A, Curini M, Petrucci V, Gertsch J, et al.: One-pot heterogeneous synthesis of Δ (3)-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB (1) and CB (2) receptors. Eur J Med Chem. 2014, 85:77-86.
• [25]Gachet MS, Rhyn P, Bosch OG, Quednow BB, Gertsch J: A quantitiative LC-MS/MS method for the measurement of arachidonic acid, prostanoids, endocannabinoids, N-acylethanolamines and steroids in human plasma. J Chromatogr, B. 2015, 976–977:6-18.
• [26]Seifert R, Wenzel-Seifert K, Gether U, Kobilka BK: Functional differences between full and partial agonists: evidence for ligand-specific receptor conformations. J Pharmacol Exp Ther. 2001, 297:1218-26.
• [27]Munro S, Thomas KL, Abu-Shaar M: Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993, 365:61-5.
• [28]Marini P, Cascio MG, King A, Pertwee RG, Ross RA: Characterization of cannabinoid receptor ligands in tissues natively expressing cannabinoid CB2 receptors. Br J Pharmacol. 2013, 169:887-99.
• [29]Kenakin T: Functional selectivity through protean and biased agonism: who steers the ship? Mol Pharmacol. 2007, 72:1393-13401.
• [30]Mancini I, Brusa R, Quadrato G, Foglia C, Scandroglio P, Silverman LS, et al.: Constitutive activity of cannabinoid-2 (CB2) receptors plays an essential role in the protean agonism of (+) AM1241 and L768242. Br J Pharmacol. 2009, 158:382-91.
• [31]Yao BB, Mukherjee S, Fan Y, Garrison TR, Daza AV, Grayson GK, et al.: In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB2 receptor? Br J Pharmacol. 2006, 149:145-54.
• [32]Bolognini D, Cascio MG, Parolaro D, Pertwee RG: AM630 behaves as a protean ligand at the human cannabinoid CB2 receptor. Br J Pharmacol. 2012, 165:2561-74.
• [33]Silvestri C, Martella A, Poloso NJ, Piscitelli F, Capasso R, Izzo A, et al.: Anandamide-derived prostamide F2α negatively regulates adipogenesis. J Biol Chem. 2014, 288:23307-21.
• [34]Nomura DK, Morrison BE, Blankman JL, Long JZ, Kinsey SG, Marcondes MC, et al.: Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science. 2011, 334:809-13.
• [35]Cabrera R, Korte SM, Lentjes EG, Romijn F, Schönbaum E, De Nicola A, et al.: The amount of free corticosterone is increased during lipopolysaccharide-induced fever. Life Sci. 2002, 66:553-62.
• [36]Lee YK, Choi IS, Ban JO, Lee HJ, Lee US, Han SB, et al.: 4-O-methylhonokiol attenuated β-amyloid-induced memory impairment through reduction of oxidative damages via inactivation of p38 MAP kinase. J Nutr Biochem. 2011, 22:476-86.
• [37]Chicca A, Marazzi J, Nicolussi S, Gertsch J: Evidence for bidirectional endocannabinoid transport across cell membranes. J Biol Chem. 2012, 287:34660-82.
• [38]Zaki PA, Keith DE Jr, Brine GA, Carroll FI, Evans CJ: Ligand-induced changes in surface mu-opioid receptor number: relationship to G protein activation? J Pharmacol Exp Ther. 2000, 292:1127-34.
• [39]Felder CC, Joyce KE, Briley EM, Glass M, Mackie KP, Fahey KJ, et al.: LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. J Pharmacol Exp Ther. 1998, 284:291-7.
• [40]Bauer M, Chicca A, Tamborrini M, Eisen D, Lerner R, Lutz B, et al.: Identification and quantification of a new family of peptide endocannabinoids (Pepcans) showing negative allosteric modulation at CB1 receptors. J Biol Chem. 2012, 287:36944-9667.
• [41]Lauckner JE, Hille B, Mackie K: The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc Natl Acad Sci U S A. 2005, 102:19144-9.
• [42]Chen R, Zhang J, Fan N, Teng ZQ, Wu Y, Yang H, et al.: Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling. Cell. 2014, 155:1154-65.
• [43]Reiter E, Ahn S, Shukla AK, Lefkowitz RJ: Molecular mechanism of β-arrestin-biased agonism at seven-transmembrane receptors. Annu Rev Pharmacol Toxicol. 2012, 52:179-97.
• [44]Kenakin T, Christopoulos A: Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat Rev Drug Discov. 2013, 12:205-16.
• [45]Kleyer J, Nicolussi S, Taylor P, Simonelli D, Furger E, Anderle P, et al.: Cannabinoid receptor trafficking in peripheral cells is dynamically regulated by a binary biochemical switch. Biochem Pharmacol. 2012, 83:1393-412.
• [46]Marazzi J, Kleyer J, Paredes JM, Gertsch J: Endocannabinoid content in fetal bovine sera - unexpected effects on mononuclear cells and osteoclastogenesis. J Immunol Methods. 2011, 373:219-28.
• [47]Kozak KR, Crews BC, Ray JL, Tai HH, Morrow JD, Marnett LJ: Metabolism of prostaglandin glycerol esters and prostaglandin ethanolamides in vitro and in vivo. J Biol Chem. 2001, 276:36993-8.
• [48]Savinainen JR, Kansanen E, Pantsar T, Navia-Paldanius D, Parkkari T, Lehtonen M, et al.: Robust hydrolysis of prostaglandin glycerol esters by human monoacylglycerol lipase (MAGL). Mol Pharmacol. 2014, 86:522-35.
• [49]Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, et al.: Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol. 2009, 5:37-44.
• [50]Marrs WR, Blankman JL, Horne EA, Thomazeau A, Lin YH, Coy J, et al.: The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nat Neurosci. 2010, 13:951-7.
• [51]Du H, Chen X, Zhang J, Chen C: Inhibition of COX-2 expression by endocannabinoid 2-arachidonoylglycerol is mediated via PPAR-γ. Br J Pharmacol. 2011, 163:1533-49.
• [52]Font-Nieves M, Sans-Fons MG, Gorina R, Bonfill-Teixidor E, Salas-Pérdomo A, Márquez-Kisinousky L, et al.: Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 production in astrocytes. J Biol Chem. 2012, 287:6454-68.
• [53]Woodward DF, Carling RW, Cornell CL, Fliri HG, Martos JL, Pettit SN, et al.: The pharmacology and therapeutic relevance of endocannabinoid derived cyclo-oxygenase (COX)-2 products. Pharmacol Ther. 2008, 120:71-80.
• [54]Kim J, Alger BE: Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus. Nat Neurosci. 2004, 7:697-8.
• [55]Straiker A, Wager-Miller J, Hu SS, Blankman JL, Cravatt BF, Mackie K: COX-2 and fatty acid amide hydrolase can regulate the time course of depolarization-induced suppression of excitation. Br J Pharmacol. 2011, 164:1672-83.
• [56]Han H, Jung JK, Han SB, Nam SY, Oh KW, Hong JT: Anxiolytic-like effects of 4-O-methylhonokiol isolated from Magnolia officinalis through enhancement of GABAergic transmission and chloride influx. J Med Food. 2011, 14:724-31.
• [57]Yu HE, Oh SJ, Ryu JK, Kang JS, Hong JT, Jung JK, et al.: Pharmacokinetics and metabolism of 4-O-methylhonokiol in rats. Phytother Res. 2014, 28:568-78.
• [58]Ashton JC, Glass M: The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Curr Neuropharmacol 2007, 5(2):73-80.
• [59]Zotova E, Nicoll JA, Kalaria R, Holmes C, Boche D: Inflammation in Alzheimer’s disease: relevance to pathogenesis and therapy. Alzheimers Res Ther 2010, 2(1):1.
• [60]Rom S, Persidsky Y: Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation. J Neuroimmune Pharmacol. 2013, 8:608-20.
• [61]Gowran A, Noonan J, Campbell VA: The multiplicity of action of cannabinoids: implications for treating neurodegeneration. CNS Neurosci Ther. 2011, 17:637-44.
• [62]Aso E, Juvés S, Maldonado R, Ferrer I: CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AβPP/PS1 mice. J Alzheimers Dis 2013, 35(4):847-58.
• [63]Carreras I, McKee AC, Choi JK, Aytan N, Kowall NW, Jenkins BG, et al.: R-flurbiprofen improves tau, but not Aß pathology in a triple transgenic model of Alzheimer’s disease. Brain Res. 2013, 1541:115-27.
• [64]Kukar T, Prescott S, Eriksen JL, Holloway V, Murphy MP, Koo EH, et al.: Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci. 2007, 8:54. BioMed Central Full Text
• [65]Schmitz K, de Bruin N, Bishay P, Männich J, Häussler A, Altmann C, et al.: R-flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice. EMBO Mol Med. 2014, 6:1398-422.