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Activation of nicotinic acetylcholine receptor prevents the production of reactive oxygen species in fibrillar beta amyloid peptide (1-42)-stimulated microglia.

Moon, JH; Kim, SY; Lee, HG; Kim, SU; Lee, YB
Experimental & molecular medicine, 40(1):11-18, 2008
Journal Title
Experimental & molecular medicine
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.
MeSH terms
Adenosine Triphosphate/analogs & derivativesAdenosine Triphosphate/metabolismAdenosine Triphosphate/pharmacologyAmyloid/metabolism*Amyloid beta-Peptides/pharmacology*AnimalsCalcium/metabolismEnzyme Activation/drug effectsMicroglia/cytologyMicroglia/drug effects*Microglia/enzymologyMicroglia/metabolism*NADPH Oxidase/metabolismNicotine/pharmacologyNicotinic Antagonists/pharmacologyPeptide Fragments/pharmacology*RatsRats, Sprague-DawleyReactive Oxygen Species/metabolism*Receptors, Nicotinic/metabolism*Receptors, Purinergic P2/metabolismReceptors, Purinergic P2X7
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