Generic placeholder image

Current Vascular Pharmacology

Editor-in-Chief

ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Research Article

MDMB-FUBINACA Influences Brain Angiogenesis and the Expression of VEGF, ANG-1, and ANG-2

Author(s): Laith AL-Eitan* and Mishael Alkhawaldeh

Volume 21, Issue 5, 2023

Published on: 13 September, 2023

Page: [356 - 365] Pages: 10

DOI: 10.2174/1570161121666230913093441

Price: $65

Abstract

Aim: This study aims to explore the impact of the synthetic cannabinoid methyl 2-(1-(4- fluorobenzyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (MDMB-FUBINACA) on the angiogenesis process in human brain microvascular endothelial cells.

Background: Synthetic cannabinoids (SCs) are substances that mimic the natural components found in the cannabis plant. SCs are considered prohibited substances that have a clear impact on the central nervous system (CNS).

Objectives: The purpose of this study is to explore how MDMB-FUBINACA influences angiogenesis in human brain microvascular endothelial cells and to clarify the pathways related to the cannabinoid receptors.

Methods: Human brain microvascular endothelial cells (hBMECs) were grown in the medium containing Dulbecco Modified Eagle Medium (DMEM/F12) using an endothelial cell growth kit. Endothelial cell viability was evaluated using the MTT test. Migration ability was measured using the Wound healing test. The angiogenic capability was measured using a Tube Formation assay. Real-time polymerase chain reaction (RT-PCR) was utilized to explore the mRNA concentrations following MDMBFUBINACA treatment. ELISA and Western blotting were also employed to measure the protein levels.

Results: MDMB-FUBINACA greatly increases tube formation, endothelial cell proliferation, and migration. Pro-angiogenic factors such as angiopoietins 1 and 2 (ANG-1 and 2) and vascular endothelial growth factor (VEGF) were shown to be increased at both the RNA and protein levels.

Conclusion: MDMB-FUBINACA induces the progression of the angiogenesis process by inducing the expression of pro-angiogenic factors. These findings aim toward developing novel treatments for angiogenesis- related disorders.

Keywords: MDMDB-FUBINACA, angiogenesis, brain endothelial cells, VEGF, ANG-1, ANG-2.

« Previous
Graphical Abstract
[1]
Gunderson EW, Haughey HM, Ait-Daoud N, Joshi AS, Hart CL. “Spice” and “K2” herbal highs: A case series and systematic review of the clinical effects and biopsychosocial implications of synthetic cannabinoid use in humans. Am J Addict 2012; 21(4): 320-6.
[http://dx.doi.org/10.1111/j.1521-0391.2012.00240.x] [PMID: 22691010]
[2]
Järbe TUC, Gifford RS. “Herbal incense”: Designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays. Life Sci 2014; 97(1): 64-71.
[http://dx.doi.org/10.1016/j.lfs.2013.07.011] [PMID: 23891559]
[3]
Bonar EE, Ashrafioun L, Ilgen MA. Synthetic cannabinoid use among patients in residential substance use disorder treatment: Prevalence, motives, and correlates. Drug Alcohol Depend 2014; 143: 268-71.
[http://dx.doi.org/10.1016/j.drugalcdep.2014.07.009] [PMID: 25096272]
[4]
a) Vandrey R, Dunn KE, Fry JA, Girling ER. A survey study to characterize use of Spice products (synthetic cannabinoids). Drug Alcohol Depend 2012; 120(1-3): 238-41.
[http://dx.doi.org/10.1016/j.drugalcdep.2011.07.011] [PMID: 21835562];
b) Laith NA-E, Saif ZA, Mohd FME-M, Mansour AA. The synthetic cannabinoid 5F-MDMB-PICA enhances the metabolic activity and angiogenesis in human brain microvascular endothelial cells by upregulation of VEGF, ANG-1, and ANG-2. Toxicol Res 2023; tfad068.
[http://dx.doi.org/10.1093/toxres/tfad068]
[5]
Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997; 74(2): 129-80.
[http://dx.doi.org/10.1016/S0163-7258(97)82001-3] [PMID: 9336020]
[6]
a) Castaneto MS, Gorelick DA, Desrosiers NA, Hartman RL, Pirard S, Huestis MA. Synthetic cannabinoids: Epidemiology, pharmacodynam-ics, and clinical implications. Drug Alcohol Depend 2014; 144: 12-41.
[http://dx.doi.org/10.1016/j.drugalcdep.2014.08.005] [PMID: 25220897];
b) Laith A-E and, Hana AK. The effect of the synthetic cannabinoid AB-CHMINACA on the roles of vascular endothelial growth factor, an-giopoietin-1, and angiopoietin-2 in brain angiogenesis. Appl In Vitro Toxicol 2023.
[http://dx.doi.org/10.1089/aivt.2023.0003]
[7]
Matsumoto T, Bohman S, Dixelius J, et al. VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis. EMBO J 2005; 24(13): 2342-53.
[http://dx.doi.org/10.1038/sj.emboj.7600709] [PMID: 15962004]
[8]
Lamalice L, Le Boeuf F, Huot J. Endothelial cell migration during angiogenesis. Circ Res 2007; 100(6): 782-94.
[http://dx.doi.org/10.1161/01.RES.0000259593.07661.1e] [PMID: 17395884]
[9]
Vendel E, de Lange ECM. Functions of the CB1 and CB 2 receptors in neuroprotection at the level of the blood-brain barrier. Neuromolecular Med 2014; 16(3): 620-42.
[http://dx.doi.org/10.1007/s12017-014-8314-x] [PMID: 24929655]
[10]
Davis S, Aldrich TH, Jones PF, et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 1996; 87(7): 1161-9.
[http://dx.doi.org/10.1016/S0092-8674(00)81812-7] [PMID: 8980223]
[11]
Teichert-Kuliszewska K, Maisonpierre PC, Jones N, et al. Biological action of angiopoietin-2 in a fibrin matrix model of angiogenesis is asso-ciated with activation of Tie2. Cardiovasc Res 2001; 49(3): 659-70.
[http://dx.doi.org/10.1016/S0008-6363(00)00231-5] [PMID: 11166279]
[12]
Mochizuki Y, Nakamura T, Kanetake H, Kanda S. Angiopoietin 2 stimulates migration and tube-like structure formation of murine brain capillary endothelial cells through c-Fes and c-Fyn. J Cell Sci 2002; 115(1): 175-83.
[http://dx.doi.org/10.1242/jcs.115.1.175] [PMID: 11801735]
[13]
Witzenbichler B, Maisonpierre PC, Jones P, Yancopoulos GD, Isner JM. Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. J Biol Chem 1998; 273(29): 18514-21.
[http://dx.doi.org/10.1074/jbc.273.29.18514] [PMID: 9660821]
[14]
AL-Eitan L Alhusban A, Alahmad S. Effects of the synthetic cannabinoid XLR-11 on the viability and migration rates of human brain microvascular endothelial cells in a clinically-relevant model. Pharmacol Rep 2020; 72(6): 1717-24.
[http://dx.doi.org/10.1007/s43440-020-00123-0] [PMID: 32632915]
[15]
a) Xiang Y, Yao X, Wang X, et al. Houshiheisan promotes angiogenesis via HIF-1α/VEGF and SDF-1/CXCR4 pathways: In vivo and in vitro. Biosci Rep 2019; 39(10)BSR20191006
[http://dx.doi.org/10.1042/BSR20191006] [PMID: 31652450];
b) Al-Eitan LN, Alahmad SZ. The expression analyses of GSK3B, VEGF, ANG1, and ANG2 in human brain microvascular endothelial cells treated with the synthetic cannabinoid XLR-11. Gene 2023; 878147585
[16]
Gamage TF, Farquhar CE, Lefever TW, et al. Molecular and behavioral pharmacological characterization of abused synthetic cannabinoids MMB-and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA. J Pharmacol Exp Ther 2018; 365(2): 437-46.
[http://dx.doi.org/10.1124/jpet.117.246983] [PMID: 29549157]
[17]
Lee JH, Park HN, Leem TS, et al. Identification of new synthetic cannabinoid analogue APINAC (adamantan-1-yl 1-pentyl-1H-indazole-3-carboxylate) with other synthetic cannabinoid MDMB(N)-Bz-F in illegal products. Forensic Toxicol 2017; 35(1): 45-55.
[http://dx.doi.org/10.1007/s11419-016-0331-z]
[18]
Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999; 13(1): 9-22.
[http://dx.doi.org/10.1096/fasebj.13.1.9] [PMID: 9872925]
[19]
Melincovici CS, Boşca AB, Şuşman S, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol 2018; 59(2): 455-67.
[PMID: 30173249]
[20]
Han H, Yang Y, Wu Z, et al. Capilliposide B blocks VEGF-induced angiogenesis in vitro in primary human retinal microvascular endothelial cells. Biomed Pharmacother 2021; 133110999
[http://dx.doi.org/10.1016/j.biopha.2020.110999] [PMID: 33227710]
[21]
Kim I, Kim JH, Moon SO, Kwak HJ, Kim NG, Koh GY. Angiopoietin-2 at high concentration can enhance endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Oncogene 2000; 19(39): 4549-52.
[http://dx.doi.org/10.1038/sj.onc.1203800] [PMID: 11002428]
[22]
Zhang Z, Chopp M. Vascular endothelial growth factor and angiopoietins in focal cerebral ischemia. Trends Cardiovasc Med 2002; 12(2): 62-6.
[http://dx.doi.org/10.1016/S1050-1738(01)00149-9] [PMID: 11852252]
[23]
Zhang YJ, Xu YF, Liu YH, Yin J, Wang JZ. Nitric oxide induces tau hyperphosphorylation via glycogen synthase kinase-3β activation. FEBS Lett 2005; 579(27): 6230-6.
[http://dx.doi.org/10.1016/j.febslet.2005.09.095] [PMID: 16253246]
[24]
Flügel D, Görlach A, Michiels C, Kietzmann T. Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1α and mediates its destabilization in a VHL-independent manner. Mol Cell Biol 2007; 27(9): 3253-65.
[http://dx.doi.org/10.1128/MCB.00015-07] [PMID: 17325032]
[25]
Mottet D, Dumont V, Deccache Y, et al. Regulation of hypoxia-inducible factor-1α protein level during hypoxic conditions by the phosphati-dylinositol 3-kinase/Akt/glycogen synthase kinase 3β pathway in HepG2 cells. J Biol Chem 2003; 278(33): 31277-85.
[http://dx.doi.org/10.1074/jbc.M300763200] [PMID: 12764143]
[26]
Flügel D, Görlach A, Kietzmann T. GSK-3β regulates cell growth, migration, and angiogenesis via Fbw7 and USP28-dependent degradation of HIF-1α. Blood 2012; 119(5): 1292-301.
[http://dx.doi.org/10.1182/blood-2011-08-375014] [PMID: 22144179]
[27]
Cassavaugh JM, Hale SA, Wellman TL, Howe AK, Wong C, Lounsbury KM. Negative regulation of HIF-1α by an FBW7-mediated degradation pathway during hypoxia. J Cell Biochem 2011; 112(12): 3882-90.
[http://dx.doi.org/10.1002/jcb.23321] [PMID: 21964756]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy