Review

Acta Pharmacologica Sinica (2006) 27, 1–26; doi:10.1111/j.1745-7254.2006.00255.x

Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine

Project supported in part by the grants from Ministry of Science and Technology of China (G1998051110, G1998051115, 2004CB518907) and the National Natural Science Foundation of China (No 39170860, 39770846, 3001161954, 30123005, 30271496, and 30572169).

Rui Wang, Han Yan and Xi-can Tang

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China

Correspondence: Prof Xi-can Tang, Fax: 86-21-5080-7088. E-mail: xctang@mail.shcnc.ac.cn

Received 5 October 2005; Accepted 20 October 2005.

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Abstract

Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase (AChE). Compared with tacrine, donepezil, and rivastigmine, HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. HupA has been found to improve cognitive deficits in a broad range of animal models. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53, and caspase-3, protect mitochondria, upregulate nerve growth factor and its receptors, and interfere with amyloid precursor protein metabolism. Antagonizing effects of HupA on N-methyl-D-aspartate receptors and potassium currents may also contribute to its neuroprotection as well. Pharmacokinetic studies in rodents, canines, and healthy human volunteers indicated that HupA was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate with the property of slow and prolonged release after oral administration. Animal and clinical safety tests showed that HupA had no unexpected toxicity, particularly the dose-limiting hepatotoxicity induced by tacrine. The phase IV clinical trials in China have demonstrated that HupA significantly improved memory deficits in elderly people with benign senescent forgetfulness, and patients with Alzheimer disease and vascular dementia, with minimal peripheral cholinergic side effects and no unexpected toxicity. HupA can also be used as a protective agent against organophosphate intoxication.

Keywords:

huperzine A, Alzheimer disease, acetylcholinesterase, cholinesterase inhibitors, cognitive enhancer, neuroprotect agents, oxidative stress, apoptosis

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