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Abstract
Memantine, an NMDA receptor antagonist used for treatment of Alzheimer’s disease (AD), is known to block the nicotinic acetylcholine receptors (nAChRs) in the central nervous system (CNS). In the present study, we examined by wire myography if memantine inhibited α3β2-nAChRs located on cerebral perivascular sympathetic nerve terminals originating in the superior cervical ganglion (SCG), thus, leading to inhibition of nicotine-induced nitrergic neurogenic dilation of isolated porcine basilar arteries. Memantine concentration-dependently blocked nicotine-induced neurogenic dilation of endothelium-denuded basilar arteries without affecting that induced by transmural nerve stimulation, sodium nitroprusside, or isoproterenol. Furthermore, memantine significantly inhibited nicotine-elicited inward currents in Xenopous oocytes expressing α3β2-, α7- or α4β2-nAChR, and nicotine-induced calcium influx in cultured rat SCG neurons. These results suggest that memantine is a non-specific antagonist for nAChR. By directly inhibiting α3β2-nAChRs located on the sympathetic nerve terminals, memantine blocks nicotine-induced neurogenic vasodilation of the porcine basilar arteries. This effect of memantine is expected to reduce the blood supply to the brain stem and possibly other brain regions, thus, decreasing its clinical efficacy in the treatment of Alzheimer’s disease.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegeneration disease
The major findings of the present study are that 1) in the endothelium-denuded cerebral arterial rings of the pigs crossbreed among Landrace, Yorkshire and Duroc (LYD), memantine in a concentration-dependent manner inhibits nicotine-induced vasorelaxation without affecting that induced by Transmural Nerve Stimulation (TNS), ISO- or Sodium Nitroprusside (SNP), 2) in oocytes expressing a7, a4b2, and a3b2-nicotinic acetylcholine receptors (nAChRs), memantine in a concentration-dependent manner inhibits nicotine-induced inward currents mediated by all subtypes, and 3) in cultured rat superior cervical ganglion (SCG) neurons, memantine in a concentration-dependent manner inhibits nicotine-induced calcium influx
These results suggest that memantine directly inhibits nAChRs, and, the a3b2nAChR located on the sympathetic nerve terminals innervating the basilar arteries of the LYD pigs, leading to blockade of nicotine-induced neurogenic nitrergic dilation of these arteries
Summary
Alzheimer’s disease (AD) is a progressive neurodegeneration disease. The beta-amyloid peptide (Ab) and the hyperphosphorylated microtubular protein tau are the key causative factors in pathogenesis of AD [1]. The oxidation of Ab and hyperphosphorylated protein tau further triggers lipid peroxidation and inflammation, leading to irreversible loss of neurons [2], in the hippocampus and cortex in AD. An N-methyl-D-aspartate receptor (NMDA) antagonist [5,6], via inhibition of the NMDA receptor on neurons, prevents neuronal cell death triggered by excessive extracellular calcium influx induced by NMDA over stimulation, improving the cognitive impairments in AD patients [4,6,7]. Inhibition of nAChR-mediated basilar arterial neurogenic vasodilation by memantine may become an important side effect of its clinical sue. Effects of memantine on the nAChR-mediated neurogenic nitrergic vasodilation in the basilar artery were examined. Our results indicated that memantine inhibited nicotine-induced a3b2-nAChR-mediated neurogenic nitrergic dilation of isolated basilar arteries
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