Cholinesterase inhibitor blockade and its prevention by statins of sympathetic alpha 7-nAChR-mediated cerebral nitrergic neurogenic vasodilation

Cholinesterase inhibitors (ChEIs) have been used to treat Alzheimer's disease (AD). The efficacy of these drugs, however, is less than satisfactory. The possibility that ChEIs may have effects unrelated to ChE activity, such as negatively modulate neuronal nicotinic acetylcholine receptors (nAChRs) was evaluated. Since alpha 7-nAChRs on cerebral perivascular sympathetic neurons mediate cerebral parasympathetic-nitrergic vasodilation, effects of physostigmine, neostigmine, and galantamine on alpha 7-nAChR-mediated dilation in isolated porcine basilar arterial rings denuded of endothelium was examined using in vitro tissue bath technique. The results indicated that these ChEIs blocked vasodilation induced by choline (0.3mmol/L), nicotine (0.1mmol/L), and transmural nerve stimulation (TNS). The ChEI inhibition of dilation induced by TNS but not by choline or nicotine was prevented by atropine (0.1 mu mol/L) pretreatment. Furthermore, using confocal microscopy, significant calcium influx induced by choline and nicotine in cultured porcine superior cervical ganglion (SCG) cells was attenuated by ChEIs. In alpha 7-nAChR-expressed Xenopus oocytes, nicotine-induced inward currents were attenuated by alpha -bungarotoxin and ChEIs. Moreover, ChEI inhibition of nicotine- and choline-induced dilation was prevented by pretreatment with mevastatin and lovastatin (10 mu mol/L), which did not affect ChEI inhibition of TNS-induced relaxation. These findings suggest that ChEIs inhibit the alpha 7-nAChRs located on postganglionic sympathetic nerve terminals of SCG origin, causing a decreased release of nitric oxide in the neighboring nitrergic nerves and cerebral vasodilation. Inhibition of alpha 7-nAChRs leading to a potential cerebral hypoperfusion may contribute to the limitation of ChEIs and question the validity of using a ChEI alone in treating AD. The efficacy of ChEIs may be improved by concurrent use of statins.Journal of Cerebral Blood Flow & Metabolism (2006) 26, 1562-1576. doi:10.1038/sj.jcbfm.9600310; published online 12 April 2006