Galantamine and carbon monoxide protect brain microvascular endothelial cells by heme oxygenase-1 induction

Atsunori Nakao, David J. Kaczorowski, Brian S. Zuckerbraun, Jing Lei, Gaetano Faleo, Kentaro Deguchi, Kenneth R. McCurry, Timothy R. Billiar, Shinichi Kanno

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 H2O2-induced cell death of mvECs in association with HO-1 induction. These protective effects were completely reversed by nuclear factor-κB (NF-κB) 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-κB 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.

Original languageEnglish
Pages (from-to)674-679
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume367
Issue number3
DOIs
Publication statusPublished - Mar 14 2008
Externally publishedYes

Keywords

  • Alzheimer disease
  • Carbon monoxide
  • Galantamine
  • Heme oxygenase
  • Inducible nitric oxide synthase
  • Nuclear factor-κB
  • Vascular dementia
  • Vascular endothelial cells

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Nakao, A., Kaczorowski, D. J., Zuckerbraun, B. S., Lei, J., Faleo, G., Deguchi, K., McCurry, K. R., Billiar, T. R., & Kanno, S. (2008). Galantamine and carbon monoxide protect brain microvascular endothelial cells by heme oxygenase-1 induction. Biochemical and Biophysical Research Communications, 367(3), 674-679. https://doi.org/10.1016/j.bbrc.2007.12.152