Nicotine-Induced Inhibition of Neuronal Phospholipase A21
- INSERM U114, Chaire de Neuropharmacologie, Collège de France, 11, Place Marcelin Berthelot, 75231 Paris Cedex 05, France
Abstract
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 α-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-β-erythroidine or hexamethonium, two central nicotinic receptor antagonists. (−)-Nicotine, which induced rapidly desensitizing inward currents in 17% of striatal neurons, did not alter the α-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.
Footnotes
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Send reprint requests to: Dr. Philippe Marin, INSERM U114, Chaire de Neuropharmacologie, Collège de France, 11, Place Marcelin Berthelot, 75231 Paris Cedex 05, France.
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↵1 This research was supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), Direction des Recherches, Etudes et Techniques (DRET, Contract 94/158), Rhône Poulenc Rorer and Philip Morris Europe.
- Abbreviations:
- trans-ACPD
- (1S-3R)-1-aminocyclopentane-1,3-dicarboxylic acid
- AMPA
- α-amino-3-isoxazol-5-propionic acid
- DHBE
- dihydro-β-erythroidine
- DMPP
- 1,1-dimethyl-4-phenyl piperazinium
- GPT
- glutamate-pyruvate transaminase
- MK-801
- (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate
- NMDA
- N-methyl-d-aspartate
- p-BPB
- p-bromophenacyl bromide
- PLA2
- phospholipase A2
- PPC
- 1,2-bis-(1-pyrenedecanoyl)-sn-glycero-3-phosphocholine
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- Received June 24, 1996.
- Accepted November 18, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
