Nicotine exposure reduces N-methyl-D-aspartate toxicity in the hippocampus: relation to distribution of the α7 nicotinic acetylcholine receptor subunit
Mark A. Prendergast, Barton R. Harris, Sveta Mayer, Robert C. Holley, James R. Pauly, John M. Littleton
Med Sci Monit 2001; 7(6): BR1153-1160
Background: Exposure to nicotine has been shown to promote neuronal survival after excitotoxic insult to the brain. The role of specific nicotinic acetylcholine receptors (nAChRs) subtypes in mediating this effect is not well understood, however. Examination of distinct receptor subtypes in promoting neuronal survival is of importance not only in understanding the regulation of necrotic cell death but potentially in the development of novel pharmacological therapies that may reduce this form of neurodegeneration.
Material and methods: The present studies examined the relationship between distribution of α7 subunit-bearing nAChRs, using autoradiographic imaging of [125I]α-bungarotoxin binding, and protective effects of nicotine against excitotoxic damage. Organotypic cultures of rat hippocampus were exposed to N-methyl-D-aspartate (NMDA; 200 μM) for 1 hour with or without (–)-nicotine (0.1-10 μM) and the α7 nAChR antagonist methyllycaconitine (MLA; 100 nM). Neuronal damage was assayed 24 hours later by observation of uptake of the non-vital fluorescent marker propidium iodide.
Results: NMDA exposure produced significant neurotoxicity, particularly in pyramidal cell layers of CA3 and CA1, that was prevented by co-exposure to MK-801 (10 μM). Localization of the α7 subunit was varied with no binding observed in the dentate gyrus, low density in the CA3 and CA1 regions, and dense binding in the hilus. In all regions, co-exposure to (–)-nicotine (0.1-10.0 mM) significantly reduced (>30%) the cytotoxic consequences of NMDA insult. This protective effect was inhibited by co-exposure to MLA in the dentate and CA3, and to a lesser extent, CA1 regions.
Conclusion: The neuroprotective effect of nicotine against excitotoxicity, then, is not directly related to α7 subunit localization in the hippocampus.
Keywords: Acetylcholine, Glutamate, neuroprotection, NMDA, bungarotoxin, Hippocampus