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4'-O-methylhonokiol increases levels of 2-arachidonoyl glycerol in mouse brain via selective inhibition of its COX-2-mediated oxygenation.
J Neuroinflammation. 2015 May 13; 12:89.JN

Abstract

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.

Authors+Show Affiliations

Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, CH-3012, Bern, Switzerland. chicca@ibmm.unibe.ch.Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, CH-3012, Bern, Switzerland. gachet@ibmm.unibe.ch.Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, CH-3012, Bern, Switzerland. petrucci@ibmm.unibe.ch.Institute of Zoology, Karl-Franzens-University Graz, Universitätsplatz 2, 8010, Graz, Austria. wolfgang.schuehly@uni-graz.at.Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, CH-3012, Bern, Switzerland. charles@ibmm.unibe.ch.Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, CH-3012, Bern, Switzerland. gertsch@ibmm.unibe.ch.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25962384

Citation

Chicca, Andrea, et al. "4'-O-methylhonokiol Increases Levels of 2-arachidonoyl Glycerol in Mouse Brain Via Selective Inhibition of Its COX-2-mediated Oxygenation." Journal of Neuroinflammation, vol. 12, 2015, p. 89.
Chicca A, Gachet MS, Petrucci V, et al. 4'-O-methylhonokiol increases levels of 2-arachidonoyl glycerol in mouse brain via selective inhibition of its COX-2-mediated oxygenation. J Neuroinflammation. 2015;12:89.
Chicca, A., Gachet, M. S., Petrucci, V., Schuehly, W., Charles, R. P., & Gertsch, J. (2015). 4'-O-methylhonokiol increases levels of 2-arachidonoyl glycerol in mouse brain via selective inhibition of its COX-2-mediated oxygenation. Journal of Neuroinflammation, 12, 89. https://doi.org/10.1186/s12974-015-0307-7
Chicca A, et al. 4'-O-methylhonokiol Increases Levels of 2-arachidonoyl Glycerol in Mouse Brain Via Selective Inhibition of Its COX-2-mediated Oxygenation. J Neuroinflammation. 2015 May 13;12:89. PubMed PMID: 25962384.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 4'-O-methylhonokiol increases levels of 2-arachidonoyl glycerol in mouse brain via selective inhibition of its COX-2-mediated oxygenation. AU - Chicca,Andrea, AU - Gachet,Maria Salomé, AU - Petrucci,Vanessa, AU - Schuehly,Wolfgang, AU - Charles,Roch-Philippe, AU - Gertsch,Jürg, Y1 - 2015/05/13/ PY - 2015/02/06/received PY - 2015/04/24/accepted PY - 2015/5/13/entrez PY - 2015/5/13/pubmed PY - 2016/8/9/medline SP - 89 EP - 89 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 12 N2 - 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. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/25962384/4'_O_methylhonokiol_increases_levels_of_2_arachidonoyl_glycerol_in_mouse_brain_via_selective_inhibition_of_its_COX_2_mediated_oxygenation_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-015-0307-7 DB - PRIME DP - Unbound Medicine ER -