Nicotine-induced inhibition of neuronal phospholipase A2.
A protective effect of nicotine against glutamate-induced neurotoxicity has previously been reported in cultured striatal and cortical neurons. The aim of this study was to investigate whether nicotine also inhibits glutamate-evoked arachidonic acid release from cultured striatal neurons. (-)-Nicotine selectively inhibited the release of [3H]-arachidonic acid induced by the joint stimulation of alpha-amino-3-isoxazol-5-propionic acid and metabotropic receptors, whereas the response evoked by the sole activation of N-methyl-D-aspartate receptors remained unchanged. The inhibitory effect of (-)-nicotine was not mediated by nicotinic receptors because it was neither reproduced by acetylcholine (in the presence of atropine) or 1,1-dimethyl-4-phenyl piperazinium, nor reversed by dihydro-beta-erythroidine or hexamethonium, two central nicotinic receptor antagonists. (-)-Nicotine, which induced rapidly desensitizing inward currents in 17% of striatal neurons, did not alter the alpha-amino-3-isoxazol-5-propionic acid-evoked currents. Moreover, (-)-nicotine did not inhibit the accumulation of inositol phosphate derivatives induced by agonists of glutamate metabotropic receptors. In fact, using the fluorogenic phospholipase A2 substrate 1,2-bis-(1-pyrenedecanoyl)-sn-glycero-3-phosphocholine, (-)-nicotine was found to inhibit both particulate and soluble phospholipase A2 activities from striatal neurons. Therefore, (-)-nicotine can modulate a neuronal response (arachidonic acid release) evoked by glutamate but this process is not involved in the neuroprotective effect of the drug on glutamate-induced neurotoxicity.
Marin
P
P
INSERM U114, Chaire de Neuropharmacologie, College de France, Paris.
Hamon
B
B
Glowinski
J
J
Premont
J
J
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D018091:Receptors, AMPA / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000378:metabolism; D014316:Tritium
D007295:Inositol Phosphates; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D011978:Receptors, Nicotinic; D014316:Tritium; D016718:Arachidonic Acid; D009538:Nicotine; D010741:Phospholipases A; D054467:Phospholipases A2