title: Cannabinoid effects on β amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro.
abstract: Cannabinoid (CB) ligands have demonstrated neuroprotective properties. In this study we compared the effects of a diverse set of CB ligands against β amyloid-mediated neuronal toxicity and activated microglial-conditioned media-based neurotoxicity in vitro, and compared this with a capacity to directly alter β amyloid (Aβ) fibril or aggregate formation. Neuroblastoma (SH-SY5Y) cells were exposed to Aβ1-42 directly or microglial (BV-2 cells) conditioned media activated with lipopolysaccharide (LPS) in the presence of the CB1 receptor-selective agonist ACEA, CB2 receptor-selective agonist JWH-015, phytocannabinoids Δ(9)-THC and cannabidiol (CBD), the endocannabinoids 2-arachidonoyl glycerol (2-AG) and anandamide or putative GPR18/GPR55 ligands O-1602 and abnormal-cannabidiol (Abn-CBD). TNF-α and nitrite production was measured in BV-2 cells to compare activation via LPS or albumin with Aβ1-42. Aβ1-42 evoked a concentration-dependent loss of cell viability in SH-SY5Y cells but negligible TNF-α and nitrite production in BV-2 cells compared to albumin or LPS. Both albumin and LPS-activated BV-2 conditioned media significantly reduced neuronal cell viability but were directly innocuous to SH-SY5Y cells. Of those CB ligands tested, only 2-AG and CBD were directly protective against Aβ-evoked SH-SY5Y cell viability, whereas JWH-015, THC, CBD, Abn-CBD and O-1602 all protected SH-SY5Y cells from BV-2 conditioned media activated via LPS. While CB ligands variably altered the morphology of Aβ fibrils and aggregates, there was no clear correlation between effects on Aβ morphology and neuroprotective actions. These findings indicate a neuroprotective action of CB ligands via actions at microglial and neuronal cells.
authors.affiliation: Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
authors.forename: Emelie
authors.initials: E
authors.lastname: Janefjord
authors.forename: Jesper L V
authors.initials: JL
authors.lastname: Mååg
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Harvey
authors.forename: Scott D
authors.initials: SD
authors.lastname: Smid
mesh_terms: D000418:Albumins / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity* / Q000648:ultrastructure; D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D020836:Protein Structure, Quaternary / Q000187:drug effects*
chemical_list: D000418:Albumins; D016229:Amyloid beta-Peptides; D002186:Cannabinoids; D017077:Culture Media, Conditioned; D008024:Ligands; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents
references.citation: Glia. 2009 Feb;57(3):286-94
references.pmid: 18837048
references.citation: J Cereb Blood Flow Metab. 2005 Apr;25(4):477-84
references.pmid: 15729296
references.citation: Br J Pharmacol. 2007 Aug;151(8):1272-9
references.pmid: 17592514
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7710-5
references.pmid: 20385841
references.citation: Br J Pharmacol. 2007 Nov;152(5):734-43
references.pmid: 17906680
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20324-9
references.pmid: 19910533
references.citation: Neurosci Lett. 2006 May 15;399(1-2):91-5
references.pmid: 16490313
references.citation: Mol Pharmacol. 2008 Feb;73(2):441-50
references.pmid: 17965195
references.citation: J Neuroimmune Pharmacol. 2011 Dec;6(4):566-77
references.pmid: 21735070
references.citation: J Neurochem. 2009 May;109(3):694-705
references.pmid: 19187440
references.citation: J Pharm Biomed Anal. 1990;8(4):353-6
references.pmid: 1966044
references.citation: BMC Neurosci. 2010 Mar 26;11:44
references.pmid: 20346144
references.citation: Cell Rep. 2012 Jun 28;1(6):617-23
references.pmid: 22813736
references.citation: Brain. 2006 Nov;129(Pt 11):3006-19
references.pmid: 16984903
references.citation: J Biol Chem. 2010 Jul 30;285(31):24228-37
references.pmid: 20511235
references.citation: FEBS J. 2009 Oct;276(20):5960-72
references.pmid: 19754881
references.citation: Curr Pharm Des. 2008;14(23):2299-3305
references.pmid: 18781980
references.citation: Br J Clin Pharmacol. 2013 Feb;75(2):323-33
references.pmid: 22625422
references.citation: Neuroscience. 2011 Mar 31;178:159-68
references.pmid: 21256197
references.citation: J Alzheimers Dis. 2008 Nov;15(3):495-504
references.pmid: 18997302
references.citation: J Neurosci. 2007 Sep 5;27(36):9537-44
references.pmid: 17804615
references.citation: J Struct Biol. 2005 Sep;151(3):229-38
references.pmid: 16125973
references.citation: Neuropharmacology. 2009;56 Suppl 1:244-53
references.pmid: 18722389
references.citation: J Neurosci. 2004 Dec 1;24(48):10908-17
references.pmid: 15574741
references.citation: Neurotoxicology. 2012 Jan;33(1):138-46
references.pmid: 22233683
references.citation: Inflamm Bowel Dis. 2011 Aug;17(8):1651-64
references.pmid: 21744421
references.citation: Mol Neurodegener. 2011 Jun 30;6:45
references.pmid: 21718498
references.citation: Biochem J. 2003 Mar 1;370(Pt 2):459-67
references.pmid: 12429020
references.citation: Int J Biochem Cell Biol. 2012 Nov;44(11):2085-93
references.pmid: 22903022
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8268-73
references.pmid: 9653176
references.citation: Neurosci Lett. 2002 Oct 31;332(2):127-30
references.pmid: 12384227
references.citation: J Neurosci. 2005 Feb 23;25(8):1904-13
references.pmid: 15728830
references.citation: Expert Opin Ther Targets. 2012 Apr;16(4):407-20
references.pmid: 22448595
references.citation: Cell Rep. 2012 Nov 29;2(5):1329-39
references.pmid: 23122958
references.citation: Cent Nerv Syst Agents Med Chem. 2012 Sep;12(3):233-9
references.pmid: 22831390
references.citation: Neurochem Res. 2008 Dec;33(12):2516-31
references.pmid: 18307032
references.citation: Expert Opin Ther Targets. 2010 Apr;14(4):387-404
references.pmid: 20230193
references.citation: J Neurosci. 2009 Feb 18;29(7):2053-63
references.pmid: 19228959
references.citation: J Mol Med (Berl). 2008 Feb;86(2):197-209
references.pmid: 17885746
references.citation: Ann Neurol. 2011 Oct;70(4):532-40
references.pmid: 22028219
references.citation: J Neurochem. 2004 Apr;89(1):134-41
references.pmid: 15030397
references.citation: J Neurosci. 2011 Oct 12;31(41):14488-95
references.pmid: 21994365
references.citation: Pharmacol Rev. 2010 Dec;62(4):588-631
references.pmid: 21079038
references.citation: PLoS One. 2010 Mar 03;5(3):e9505
references.pmid: 20209079
references.citation: PLoS One. 2011;6(12):e28668
references.pmid: 22163051
references.citation: Br J Pharmacol. 2013 Jun;169(4):808-19
references.pmid: 23043675