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

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-␤-erythroidine, showing mediation of neuroprotection by ␣4␤2 neuronal nicotinic receptors (nAChRs). Because nicotine activates ␣4␤2 and other nAChR subtypes, whereas 10 nM MLA inhibits the ␣7 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 Ca 2ϩ -dependent, neither L-type Ca 2ϩ 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 ␣4␤2 or indirectly by inhibition of ␣7 followed by signal transduction involving tyrosine kinases, phospholipid-dependent kinases, and mitogen-activated kinases.

Mice lacking neuronal nicotinic acetylcholine receptor β4-subunit and mice lacking both α5- and β4-subunits are highly resistant to nicotine-induced seizures

“…Additionally, it was shown that nicotine could exert a neuroprotective effect via ␣7-nAChRs and ␣4␤2-nAChRs (12,21,32). Although there is no published data, thus far, linking receptors containing ␣5-or ␤4-subunits to neuronal death or neuroprotection, it might be possible that absence of these subunits may lead to neuronal cell death and to decreased ␣3 expression.…”

Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system

“…The nAChRmediated neuroprotection against excitotoxicity is calciumdependent [82][83][84] and does not involve blockade of glutamate receptor function [83][84][85] . Excessive activation of the N-methyl-D-aspartate (NMDA) receptor is thought to play a prominent role in a variety of acute and chronic neurological injuries [86,87] .…”

“…Excessive activation of the N-methyl-D-aspartate (NMDA) receptor is thought to play a prominent role in a variety of acute and chronic neurological injuries [86,87] . In hippocampal slices, nicotine-mediated protection against acute NMDA excitotoxicity is mediated by the activation of phosphatidylinositol 3-kinase (PI 3 K) and the ERK/MAPK pathway [84] . These signalling molecules could increase the expression of calcium buffering proteins such as calbindin-D28K, which have been implicated in the nAChR-dependent amelioration of excitotoxic insults [85] .…”

Comments on “Memantine Blocks α7* Nicotinic Acetylcholine Receptors More Potently Than N-Methyl-d-aspartate Receptors in Rat Hippocampal Neurons”

“…In the rodent hippocampal tissue, both ␣7 nAChR agonists and antagonists were found to be neuroprotective against N-methyl-D-aspartate (Ferchmin et al, 2003). Furthermore, there have been many studies that have shown that activation of ␣7 nAChRs may be involved in processes that contribute to AD pathophysiology and neuropathology.…”

“…Although it has been shown that ␣7 nAChR agonists enhance cognition and are neuroprotective, it is not clear whether these effects are the result of receptor activation per se or activationinduced receptor desensitization, because ␣7 nAChRs are known to rapidly desensitize following activation (Quick and Lester, 2002). Furthermore, some effects of ␣7 nAChR agonists can be mimicked by selective ␣7 nAChR antagonists (Fujii and Sumikawa, 2000;Ferchmin et al, 2003). Thus, although the authors demonstrate that memantine inhibits ␣7 nAChR-mediated currents in rat hippocampal neurons, the statement drawn from these data are not supported either by the current state of the field or recent clinical experience.…”