title: Galantamine and carbon monoxide protect brain microvascular endothelial cells by heme oxygenase-1 induction.
abstract: Galantamine, a reversible inhibitor of acetylcholine esterase (AChE), is a novel drug treatment for mild to moderate Alzheimer's disease and vascular dementia. Interestingly, it has been suggested that galantamine treatment is associated with more clinical benefit in patients with mild-to-moderate Alzheimer disease compared to other AChE inhibitors. We hypothesized that the protective effects of galantamine would involve induction of the protective gene, heme oxygenase-1 (HO-1), in addition to enhancement of the cholinergic system. Brain microvascular endothelial cells (mvECs) were isolated from spontaneous hypertensive rats. Galantamine significantly reduced H(2)O(2)-induced cell death of mvECs in association with HO-1 induction. These protective effects were completely reversed by nuclear factor-kappaB (NF-kappaB) inhibition or HO inhibition. Furthermore, galantamine failed to induce HO-1 in mvECs which lack inducible nitric oxide synthase (iNOS), supplementation of a nitric oxide (NO) donor or iNOS gene transfection on iNOS-deficient mvECs resulted in HO-1 induction with galantamine. These data suggest that the protective effects of galantamine require NF-kappaB activation and iNOS expression, in addition to HO-1. Likewise, carbon monoxide (CO), one of the byproducts of HO, up-regulated HO-1 and protected mvECs from oxidative stress in a similar manner. Our data demonstrate that galantamine mediates cytoprotective effects on mvECs through induction HO-1. This pharmacological action of galantamine may, at least in part, account for the superior clinical efficacy of galantamine in vascular dementia and Alzheimer disease.
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, E1551-BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nakao
authors.forename: David J
authors.initials: DJ
authors.lastname: Kaczorowski
authors.forename: Brian S
authors.initials: BS
authors.lastname: Zuckerbraun
authors.forename: Jing
authors.initials: J
authors.lastname: Lei
authors.forename: Gaetano
authors.initials: G
authors.lastname: Faleo
authors.forename: Kentaro
authors.initials: K
authors.lastname: Deguchi
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: McCurry
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kanno
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply*; D002248:Carbon Monoxide / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005702:Galantamine / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D016328:NF-kappa B; D018696:Neuroprotective Agents; D016877:Oxidants; D005702:Galantamine; D002248:Carbon Monoxide; D006861:Hydrogen Peroxide; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D001616:beta-Galactosidase