Nakao Atsunori, Kaczorowski David J, Zuckerbraun Brian S, Lei Jing, Faleo Gaetano, Deguchi Kentaro, McCurry Kenneth R, Billiar Timothy R, Kanno Shinichi
Department of Surgery, University of Pittsburgh Medical Center, E1551-BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
Biochem Biophys Res Commun. 2008 Mar 14;367(3):674-9. doi: 10.1016/j.bbrc.2007.12.152. Epub 2008 Jan 2.
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.
加兰他敏是一种乙酰胆碱酯酶（AChE）的可逆抑制剂，是治疗轻至中度阿尔茨海默病和血管性痴呆的新型药物。有趣的是，有人提出，与其他AChE抑制剂相比，加兰他敏治疗对轻至中度阿尔茨海默病患者具有更多的临床益处。我们推测，加兰他敏的保护作用除了增强胆碱能系统外，还涉及诱导保护性基因血红素加氧酶-1（HO-1）。从自发性高血压大鼠中分离出脑微血管内皮细胞（mvECs）。加兰他敏与HO-1的诱导相关，显著降低了H2O2诱导的mvECs细胞死亡。这些保护作用被核因子-κB（NF-κB）抑制或HO抑制完全逆转。此外，加兰他敏未能在缺乏诱导型一氧化氮合酶（iNOS）的mvECs中诱导HO-1，在iNOS缺陷的mvECs上补充一氧化氮（NO）供体或进行iNOS基因转染可导致加兰他敏诱导HO-1。这些数据表明，加兰他敏的保护作用除了需要HO-1外，还需要NF-κB激活和iNOS表达。同样，HO的副产物之一一氧化碳（CO）以类似的方式上调HO-1并保护mvECs免受氧化应激。我们的数据表明，加兰他敏通过诱导HO-1介导对mvECs的细胞保护作用。加兰他敏的这种药理作用可能至少部分解释了其在血管性痴呆和阿尔茨海默病中卓越的临床疗效。
