title: Contrasting protective effects of cannabinoids against oxidative stress and amyloid-β evoked neurotoxicity in vitro.
abstract: Cannabinoids have been widely reported to have neuroprotective properties in vitro and in vivo. In this study we compared the effects of CB1 and CB2 receptor-selective ligands, the endocannabinoid anandamide and the phytocannabinoid cannabidiol, against oxidative stress and the toxic hallmark Alzheimer's protein, β-amyloid (Aβ) in neuronal cell lines. PC12 or SH-SY5Y cells were selectively exposed to either hydrogen peroxide, tert-butyl hydroperoxide or Aβ, alone or in the presence of the CB1 specific agonist arachidonyl-2'-chloroethylamide (ACEA), CB2 specific agonist JWH-015, anandamide or cannabidiol. Cannabidiol improved cell viability in response to tert-butyl hydroperoxide in PC12 and SH-SY5Y cells, while hydrogen peroxide-mediated toxicity was unaffected by cannabidiol pretreatment. Aβ exposure evoked a loss of cell viability in PC12 cells. Of the cannabinoids tested, only anandamide was able to inhibit Aβ-evoked neurotoxicity. ACEA had no effect on Aβ-evoked neurotoxicity, suggesting a CB1 receptor-independent effect of anandamide. JWH-015 pretreatment was also without protective influence on PC12 cells from either pro-oxidant or Aβ exposure. None of the cannabinoids directly inhibited or disrupted preformed Aβ fibrils and aggregates. In conclusion, the endocannabinoid anandamide protects neuronal cells from Aβ exposure via a pathway unrelated to CB1 or CB2 receptor activation. The protective effect of cannabidiol against oxidative stress does not confer protection against Aβ exposure, suggesting divergent pathways for neuroprotection of these two cannabinoids.
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, The University of Adelaide, SA, Australia.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Harvey
authors.forename: Katharina S
authors.initials: KS
authors.lastname: Ohlsson
authors.forename: Jesper L V
authors.initials: JL
authors.lastname: Mååg
authors.forename: Ian F
authors.initials: IF
authors.lastname: Musgrave
authors.forename: Scott D
authors.initials: SD
authors.lastname: Smid
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology* / Q000648:ultrastructure; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology; D052160:Benzothiazoles; D002186:Cannabinoids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D001095:Arachidonic Acids; D052160:Benzothiazoles; D002186:Cannabinoids; D002839:Chromans; D007211:Indoles; D010446:Peptide Fragments; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C119325:arachidonyl-2-chloroethylamide; C009462:thioflavin T; D006861:Hydrogen Peroxide; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; C402944:JHW 015