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Research ArticleNEUROPHARMACOLOGY

Nicotinic Receptors Differentially Regulate N-Methyl-d-aspartate Damage in Acute Hippocampal Slices

P. A. Ferchmin, Dinely Perez, Vesna A. Eterovic and Jean de Vellis
Journal of Pharmacology and Experimental Therapeutics June 2003, 305 (3) 1071-1078; DOI: https://doi.org/10.1124/jpet.102.048173
P. A. Ferchmin
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Dinely Perez
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Vesna A. Eterovic
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Jean de Vellis
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Abstract

Although in neuronal cultures nicotine was reported to prevent early and delayed excitotoxic death, no studies with nicotinic drugs have been done with acute hippocampal slices. We investigated the effect of nicotine and methyllycaconitine (MLA) on the toxicity of N-methyl-d-aspartate (NMDA) in the CA1 area of hippocampal slices. The excitotoxic effect of NMDA was assessed as decreased recovery of the capability to produce synaptically evoked population spikes (PSs). Application of nicotine or MLA before NMDA application increased the recovery of PSs. This electrophysiological recovery was used as a measure of the early neuroprotective events. The neuroprotection conferred by both nicotine and MLA was inhibited by dihydro-β-erythroidine, showing mediation of neuroprotection by α4β2 neuronal nicotinic receptors (nAChRs). Because nicotine activates α4β2 and other nAChR subtypes, whereas 10 nM MLA inhibits the α7 subtype, we propose the involvement of a neuronal circuitry-dependent mechanism for nicotinic neuroprotection. The effect of nicotine downstream from the receptors was investigated using inhibitors of cell signaling. The results suggest that the effect of nicotine is mediated by tyrosine receptor kinases, 1,2-phosphatidylinositol-3 kinase, and the mitogen-activated extracellular signal-regulated kinases. Although nicotine neuroprotection is Ca2+-dependent, neither L-type Ca2+ channels nor calmodulin-dependent protein kinase is involved in the effect of nicotine. In summary, these results suggest that in acute slices nicotinic protection is initiated either by direct activation of α4β2 or indirectly by inhibition of α7 followed by signal transduction involving tyrosine kinases, phospholipid-dependent kinases, and mitogen-activated kinases.

Footnotes

  • This study was supported by National Institute of Neurological Disorders and Stroke and National Center for Research Resources-Specialized Neuroscience Research Program Grant NS39408 and partially by National Institutes of Health-Minority Biomedical Research Support S06GM50695 (to P.A.F.). Core facilities were supported by National Institutes of Health-Research Centers in Minority Institutions G-12RR03035.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.102.048173.

  • ABBREVIATIONS: PS, population spike; NMDA, N-methyl-d-aspartate; nAChR, nicotinic acetylcholine receptor; [Ca2+]i, intracellular calcium concentration; VGCC, voltage-gated Ca2+ channel; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; PI 3-kinase, phosphatidylinositol 3-kinase; αBtx, α-bungarotoxin; DHβE; dihydro-β-erythroidine; MLA, methyllycaconitine; ACSF, artificial cerebrospinal fluid; DMSO, dimethyl sulfoxide; CaM kinase, calmodulin-dependent protein kinase; SU6656, 2-oxo-3-(4,5,6,7-tetrahydro-1H-indol-2-ylmethylene)-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide; LY 294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; PD98059, 2′-amino-3′-methoxyflavonone, KN-62, 1-[N,O-bis(5-isoquinolinsulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine; K252a, (8R,9S,11S)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,910-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cyclo-octa(cde)trinden-1-one.

    • Received December 18, 2002.
    • Accepted March 11, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 3
1 Jun 2003
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Research ArticleNEUROPHARMACOLOGY

Nicotinic Receptors Differentially Regulate N-Methyl-d-aspartate Damage in Acute Hippocampal Slices

P. A. Ferchmin, Dinely Perez, Vesna A. Eterovic and Jean de Vellis
Journal of Pharmacology and Experimental Therapeutics June 1, 2003, 305 (3) 1071-1078; DOI: https://doi.org/10.1124/jpet.102.048173

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Research ArticleNEUROPHARMACOLOGY

Nicotinic Receptors Differentially Regulate N-Methyl-d-aspartate Damage in Acute Hippocampal Slices

P. A. Ferchmin, Dinely Perez, Vesna A. Eterovic and Jean de Vellis
Journal of Pharmacology and Experimental Therapeutics June 1, 2003, 305 (3) 1071-1078; DOI: https://doi.org/10.1124/jpet.102.048173
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