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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/H1737    most recent 00269.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Mozayan, M. Articles by Lee, T. J. F. Search for Related Content PubMed PubMed Citation Articles by Mozayan, M. Articles by Lee, T. J. F.

Statins prevent cholinesterase inhibitor blockade of sympathetic 7-nAChR-mediated currents in rat superior cervical ganglion neurons

¹Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois; and ²Tzu Chi University Center for Vascular Medicine, College of Life Sciences, Neuro-Medical Scientific Center, Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan

Submitted 5 March 2007 ; accepted in final form 4 June 2007

Statins are reported to be beneficial in treating a multitude of disorders including dementia due to Alzheimer disease (AD) and vascular dementia (VaD) with varying, yet-to-be determined mechanisms of actions. Although cholinesterase inhibitors (ChEIs) are still recommended as the primary drug of choice for AD and related diseases, their efficacy is frequently questioned. We recently reported that 7-neuronal acetylcholine nicotinic receptor (7-nAChR)-mediated neurogenic vasodilation of porcine cerebral arteries was blocked by ChEIs, and this blockade was prevented by statin pretreatment. The exact mechanism of interaction between ChEIs and statins remains unclear. Activation of 7-nAChRs located on perivascular postganglionic sympathetic nerve terminals releases norepinephrine, which then acts on presynaptic ₂-adrenoceptors located on neighboring nitrergic nerve terminals, resulting in nitric oxide release and vasodilation. The present study, therefore, was designed to determine whether interaction of ChEIs and statins occurs at the 7-nAChR level. We examined effects of concurrent application of ChEIs and statins on 7-nAChR-mediated inward currents in primary neuronal cultures of rat superior cervical ganglion cells, the origin of the perivascular sympathetic innervation to the cerebral arteries. The results indicated that physostigmine, neostigmine, and galantamine inhibited choline- and nicotine-induced whole cell currents in a concentration-dependent manner. This inhibition, which was noncompetitive in nature, was prevented by concurrent application of mevastatin and lovastatin in a concentration-dependent manner. These results suggest that statins protect 7-nAChR function directly at the receptor level. Since 7-nAChR is neuroprotective, having beneficial effects on memory and cerebral vascular function, its functional inhibition by ChEIs may explain in part the limitation of its effectiveness in AD and VaD therapy. Protection of 7-nAChR function from ChEI inhibition by concurrent administration of statins may provide an alternative strategy in improving the efficacy of AD and VaD therapy.

vascular dementia; galantamine; lovastatin

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