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

Rui Wang, Han Yan, Xi-can Tang


Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia
, 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, β-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