Exp Mol Med.  2008 Feb;40(1):11-18. 10.3858/emm.2008.40.1.11.

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

• KMID: 1103583
• DOI: http://doi.org/10.3858/emm.2008.40.1.11

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 P2X7 receptor (P2X7R), in an autocrine fashion. These observations led us to investigate whether stimulation by nicotine could regulate fibrillar beta amyloid peptide (1-42) (fA beta(1-42))-induced ROS production by modulating ATP efflux-mediated Ca2+ influx through P2X7R. Nicotine inhibited ROS generation in fA beta(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 Ca2+ influx in fA beta(1-42)-stimulated microglia. Moreover, ATP release from fA beta(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 Ca2+ influx, but inhibited ROS generation in BzATP-stimulated microglia, indicating an inhibitory effect of nicotine on a signaling process downstream of P2X7R. Taken together, these results suggest that the inhibitory effect of nicotine on ROS production in fA beta(1-42)-stimulated microglia is mediated by indirect blockage of ATP release and by directly altering the signaling process downstream from P2X7R.

Keyword

acetylcholine; adenosine triphosphate; amyloid beta-protein; microglia; NADPH oxidase; nicotine; reactive oxygen species; receptors, nicotinic; purinoceptor P2Z

MeSH Terms

Adenosine Triphosphate/analogs & derivatives/metabolism/pharmacology
Amyloid/*metabolism
Amyloid beta-Protein/*pharmacology
Animals
Calcium/metabolism
Enzyme Activation/drug effects
Microglia/cytology/*drug effects/enzymology/*metabolism
NADPH Oxidase/metabolism
Nicotine/pharmacology
Nicotinic Antagonists/pharmacology
Peptide Fragments/*pharmacology
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species/*metabolism
Receptors, Nicotinic/*metabolism
Receptors, Purinergic P2/metabolism