title: Activation of nicotinic acetylcholine receptor prevents the production of reactive oxygen species in fibrillar beta amyloid peptide (1-42)-stimulated microglia.
abstract: Recent studies have reported that the cholinergic anti-inflammatory pathway regulates peripheral inflammatory responses via alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) and that acetylcholine and nicotine regulate the expression of proinflammatory mediators such as TNF-alpha and prostaglandin E2 in microglial cultures. In a previous study we showed that ATP released by beta-amyloid-stimulated microglia induced reactive oxygen species (ROS) production, in a process involving the P2X(7) receptor (P2X(7)R), in an autocrine fashion. These observations led us to investigate whether stimulation by nicotine could regulate fibrillar beta amyloid peptide (1-42) (fAbeta1-42)-induced ROS production by modulating ATP efflux-mediated Ca(2+) influx through P2X(7)R. Nicotine inhibited ROS generation in fAbeta(1-42)-stimulated microglial cells, and this inhibition was blocked by mecamylamine, a non-selective nAChR antagonist, and a-bungarotoxin, a selective alpha7 nAChR antagonist. Nicotine inhibited NADPH oxidase activation and completely blocked Ca(2+) influx in fAbeta(1-42)-stimulated microglia. Moreover, ATP release from fAbeta(1-42)-stimulated microglia was significantly suppressed by nicotine treatment. In contrast, nicotine did not inhibit 2',3'-O-(4-benzoyl)-benzoyl ATP (BzATP)-induced Ca(2+) influx, but inhibited ROS generation in BzATP-stimulated microglia, indicating an inhibitory effect of nicotine on a signaling process downstream of P2X(7)R. Taken together, these results suggest that the inhibitory effect of nicotine on ROS production in fAbeta1-42-stimulated microglia is mediated by indirect blockage of ATP release and by directly altering the signaling process downstream from P2X(7)R.
authors.affiliation: Neuroscience Graduate Program, Ajou University, School of Medicine, Suwon 443-721, Korea.
authors.forename: Ju Hyun
authors.initials: JH
authors.lastname: Moon
authors.forename: Soo Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Hwan Goo
authors.initials: HG
authors.lastname: Lee
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.forename: Yong Beom
authors.initials: YB
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D011978:Receptors, Nicotinic; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C075222:amyloid beta-protein (1-42); C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D009538:Nicotine; D000255:Adenosine Triphosphate; D019255:NADPH Oxidases; D002118:Calcium