title: Arecoline, a major alkaloid of the areca nut, causes neurotoxicity through enhancement of oxidative stress and suppression of the antioxidant protective system.
abstract: Arecoline, an areca nut alkaloid, has been noted for its potential cognition-enhancing effects in patients with Alzheimer dementia. However, it has been confirmed that areca nut use is associated with oral and pharyngeal cancers. In addition, arecoline is genotoxic and cytotoxic both in vitro and in vivo through oxidative stress-dependent mechanisms. The aim of this study was to investigate whether arecoline would interfere with the antioxidant defense system and induce cytotoxicity in rat primary cortical neurons. Results indicate that arecoline (50-200 μM) induces neuronal cell death, and catalase, NADPH oxidase inhibitors (diphenyleneiodonium chloride and apocynin), and a caspase inhibitor (z-VAD-fmk) can prevent arecoline-induced cell death. Furthermore, arecoline increased reactive oxygen species production and upregulated protein expression and mRNA levels of NADPH oxidase 2, which could be attenuated by catalase and NADPH oxidase inhibitors. Arecoline also attenuated neuronal antioxidant defense by decreasing glutathione (GSH) level and superoxide dismutase activity. In addition, arecoline enhanced the expression of proapoptotic proteins (cytochrome c, Bax, caspase-9, and caspase-3) and attenuated the expression of the antiapoptotic protein Bcl-2. Moreover, NADPH oxidase inhibitors could attenuate the arecoline-induced GSH depletion and reverse arecoline-induced changes in proapoptotic and antiapoptotic proteins. In conclusion, the results indicate that arecoline could induce neuronal apoptotic death by attenuating antioxidant defense and enhancing oxidative stress.
authors.affiliation: Graduate Institute of Natural Products, School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Shih
authors.forename: Po See
authors.initials: PS
authors.lastname: Chen
authors.forename: Chi-Han
authors.initials: CH
authors.lastname: Wu
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Tseng
authors.forename: Yang-Chang
authors.initials: YC
authors.lastname: Wu
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Lo
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001114:Areca / Q000009:adverse effects; D001115:Arecoline / Q000633:toxicity*; D020169:Caspases / Q000096:biosynthesis; D016923:Cell Death / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000037:antagonists & inhibitors; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors
chemical_list: D000975:Antioxidants; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D001115:Arecoline; D045304:Cytochromes c; D013482:Superoxide Dismutase; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020169:Caspases; D005978:Glutathione