Statins prevent cholinesterase inhibitor blockade of sympathetic α7-nAChR-mediated currents in rat superior cervical ganglion neurons

Abstract

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 alpha7-neuronal acetylcholine nicotinic receptor (alpha7-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 alpha7-nAChRs located on perivascular postganglionic sympathetic nerve terminals releases norepinephrine, which then acts on presynaptic beta(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 alpha7-nAChR level. We examined effects of concurrent application of ChEIs and statins on alpha7-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 alpha7-nAChR function directly at the receptor level. Since alpha7-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 alpha7-nAChR function from ChEI inhibition by concurrent administration of statins may provide an alternative strategy in improving the efficacy of AD and VaD therapy.

Endogenous methyl palmitate modulates nicotinic receptor-mediated transmission in the superior cervical ganglion

“…Detailed methods are found in SI Text. SCG cell culture.Detailed methods of culturing SCG neuronal cells (10,32) are found in SI Text. Electrophysiology.…”

“…Electrophysiology. Detailed methods of patch-clamp technique to record whole-cell currents (10,32) of SCG neuronal cells and 2-electrode voltage clamp for ␣7-nAChR-expressing oocytes (27) are found in SI Text.…”

Methanandamide Allosterically Inhibits in Vivo the Function of Peripheral Nicotinic Acetylcholine Receptors Containing the α7-Subunit

“…These receptors may be localized as follows: 1) on the cell bodies of the postganglionic sympathetic nerves; 2) on postganglionic sympathetic nerve endings; and/or 3) in the adrenal medulla. In fact, norepinephrine release in response to activation of ␣7-subunit-containing nAChRs was demonstrated in vitro in rat intracardiac nerve fibers and superior cervical ganglia (Del Signore et al, 2004;Mozayan and Lee, 2007). However, we can exclude that catecholamines released from the adrenal medulla contributed significantly to the NIC-induced tachycardia because the increase in HR elicited by NIC did not differ between adrenalectomized rats and animals with intact adrenals (Malinowska et al, 2001b).…”

“…Such receptors are expressed in autonomic ganglia and on postganglionic sympathetic nerve fibers of the rat (Franceschini et al, 2000;Skok, 2002;Wang et al, 2002;Del Signore, 2004;Lips et al, 2006;Mozayan and Lee, 2007), including those innervating the heart (Franceschini et al, 2000;Del Signore et al, 2004). The receptors under consideration comprise not only homopentameric ␣7-nAChRs, but also heteropentamers containing the ␣7 plus another subunit such as ␣5 and ␣10 (Girod et al, 1999;Lips et al, 2006).…”

L‐type calcium channels in sympathetic α3β2‐nAChR‐mediated cerebral nitrergic neurogenic vasodilation

“…Furthermore, nicotineinduced axo-axonal interaction-mediated dilation of isolated porcine basilar arteries is blocked by b-amyloid peptides (Si & Lee 2002, Si et al 2005, cholinesterase inhibitors (Mozayan et al 2006) and monoamine uptake inhibitors (Long et al 2006) and diminishes in hypertension (Chang et al 2012). All blockade by these different substances and inhibitors in normal animals is due to inhibition of nAChRs and is prevented by statins (Si et al 2005, Mozayan et al 2006, Mozayan & Lee 2007) and oestrogen (Si et al 2011) but not by testosterone (Lee et al 2011b). The blockade by b-amyloid peptides, however, is dependent on the subtypes of nAChR in that a7-nAChR but not a3b2-nAChR is sensitive to b-amyloid peptides (Si & Lee 2002, Lee et al 2011a, although both types of receptors are sensitive to cholinesterase inhibitors and mediate sympatheticparasympathetic interaction mechanism in inducing cerebral nitrergic vasodilation (Lee et al 2011b).…”