Huperzine a improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion.
Chronic cerebral hypoperfusion has been suggested to contribute to the progression of dementia. Inflammation and white matter lesion (WML) are involved in the pathologic process. This study investigated whether huperzine A, a natural acetylcholinesterase (AChE) inhibitor, has beneficial effects on long-lasting 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-vessel 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-operated rats and was significantly improved by huperzine A treatment. WML and activation staining of immune cells were evaluated by Klüver-Barrera (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-alpha (TNF-alpha) and overphosphorylation of JNK and p38 mitogen-activated 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-alpha production and MAPKs phosphorylation. In conclusion, delayed and chronic administration of huperzine A could protect against 2VO-induced cognitive impairment, which might be related to its beneficial effects on WML, and the nAChR-dependent cholinergic anti-inflammation pathway plays an important role.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
Juan
J
Wang
Hai Yan
HY
Zhang
Xi Can
XC
Tang
D000470:Alkaloids; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000150:complications* / Q000473:pathology* / Q000628:therapy; D015687:Cell Hypoxia / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology*; D003072:Cognition Disorders / Q000188:drug therapy*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000627:therapeutic use*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000470:Alkaloids; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; C050426:huperzine A; D020929:Mitogen-Activated Protein Kinase Kinases