CB1 receptor selective activation inhibits beta-amyloid-induced iNOS protein expression in C6 cells and subsequently blunts tau protein hyperphosphorylation in co-cultured neurons.
Among the wide range of neuro-inflammatory signalling molecules released by beta-amyloid-stimulated astroglial cells, nitric oxide (NO) plays a fundamental role in AD aethiopathogenesis since it directly promotes neuronal tau protein hyperphosphorylation leading to neurofibrillary tangle formation. Synthetic cannabinoids (CBs), via a selective CB1 receptor activation, negatively modulates both iNOS protein expression and NO production induced by pro-inflammatory stimuli. In this study we investigated the role of both the non-selective WIN 55,212-2 and the selective CB1 receptor agonist, ACEA, on: (i) NO production, (ii) iNOS protein expression in (1-42) beta-amyloid peptide (Abeta)-stimulated C6 rat glioma cells and (iii) tau protein hyperphosphorylation in co-cultured differentiated PC12 neurons. Our results demonstrated that synthetic CBs, by a selective CB1 effect, down-regulate iNOS protein expression and NO production in Abeta-stimulated C6 cells. This effect leads, in turn, to a significant and concentration-dependent inhibition of NO-dependent tau protein hyperphosphorylation in co-cultured PC12 neurons. The results of the present study extend our knowledge about the neuroprotective actions of synthetic CBs on Abeta-dependent neurotoxicity in vitro. Furthermore, our study allows us to identify, in the CB1-mediated inhibition of astroglial-derived NO, a new potential target to blunt tau hyperphosphorylation and the consequent related tauopathy in AD.
Esposito
Giuseppe
G
Department of Human Physiology and Pharmacology, Vittorio Espamer Faculty of Pharmacy, University of Rome La Sapienza Piazzale A. Moro 5, 00151 Roma, Italy.
De Filippis
Daniele
D
Steardo
Luca
L
Scuderi
Caterina
C
Savani
Claudia
C
Cuomo
Vincenzo
V
Iuvone
Teresa
T
D016229:Amyloid beta-Peptides / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005910:Glioma; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D010673:Pheochromocytoma; D010766:Phosphorylation; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D043884:Receptor, Cannabinoid, CB1; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II