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This study investigated whether huperzine A, a natural acetylcholinesterase (AChE) inhibitor, has beneficial effects on long\u2010lasting inflammation as well as cognitive impairment in a rat model of cerebral hypoperfusion and how it plays these roles. Chronic cerebral hypoperfusion was induced by occlusion of bilateral common carotid arteries (two\u2010vessel occlusion; 2VO). Huperzine A was initially given 150 min after 2VO and daily for 3, 7, 14, and 28 days. Learning and memory dysfunction as tested by Morris water maze performance was observed in 2VO\u2010operated rats and was significantly improved by huperzine A treatment. WML and activation staining of immune cells were evaluated by Kl\u00fcver\u2010Barrera (KB) and immunohistochemistry, respectively. Myelin damage and increased immunostains were found in optic tract at all indicated days. Huperzine A treatment significantly ameliorated all these phenomena. Moreover, huperzine A also suppressed overexpression of the inflammatory factor tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) and overphosphorylation of JNK and p38 mitogen\u2010activated protein kinases (MAPKs) in a cell model of chronic hypoxia. Preincubation with mecamylamine (MEC), a nicotinic acetylcholine receptor (nAChR) antagonist, for 30 min before hypoxia notably reversed the effects of huperzine A on TNF\u2010\u03b1 production and MAPKs phosphorylation. In conclusion, delayed and chronic administration of huperzine A could protect against 2VO\u2010induced cognitive impairment, which might be related to its beneficial effects on WML, and the nAChR\u2010dependent cholinergic anti\u2010inflammation pathway plays an important role. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.22237","type":"journal-article","created":{"date-parts":[[2009,9,30]],"date-time":"2009-09-30T15:14:01Z","timestamp":1254323641000},"page":"807-815","source":"Crossref","is-referenced-by-count":82,"title":["Huperzine a improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion"],"prefix":"10.1002","volume":"88","author":[{"given":"Juan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi 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