Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine1

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, 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 intoxication.

Polygalasaponin XXXII from Polygala tenuifolia root improves hippocampal-dependent learning and memory

“…However, the swimming time in the target quadrant was greatly pro- npg longed in the probe trial in this group; this may suggest that the sample size for behavioral testing should be increased and that further refinements to the dosages need to be considered. Huperzine A (HupA), a lycopodium alkaloid isolated from Huperzia serrata (Qian Ceng Ta), has been widely used for AD (Alzheimer's disease) therapy in China and has been shown to enhance memory, cognitive skills and daily life capabilities in both AD and VD (vascular dementia) patients [22] . Using HupA as a positive control, we discovered that the action of PGS32 on the cognitive function of scopolamine-treated mice was comparably good; this suggested that PGS32 has as much promise as a potential cognition-enhancing therapeutic drug Figure 4.…”

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

“…Previous reports have suggested that huperzine A can improve mitochondrial dysfunction [90] and regulate anti-oxidative enzyme activities and apoptotic gene expressions [91] in ischemic animal models. Whether these effects contribute to VaD therapy and reflect responsible cellular targets remain open questions.…”

New insights into huperzine A for the treatment of Alzheimer's disease

“…Multiple lines of evidences proved that huperzine A is a mixed-competitive and reversible AChE inhibitor, which shows higher potency and selectivity of AChE inhibition both in vitro and in vivo as compared with galanthamine, donepezil, tacrine, and rivastigmine (reviewed by [2] ). The potent inhibitory effect on AChE could in turn markedly enhance the synaptic ACh release and consequently cholinergic neurotransmission.…”

“…Since then, large amount of clinical studies have shown that huperzine A administration can significantly improve the memory, cognitive skills, and daily life abilities of AD patients with no severe side effects. Besides being indicated for AD, huperzine A is also used in treating memory impairment in vascular dementia (VaD) patients, schizophrenia patients and sleep disorder in insomniacs (reviewed by [2] ).…”

“…Huperzine A is widely proved to be a potent, selective and well-tolerated inhibitor of acetylcholinesterase (AChE) (reviewed by [2] ). This effect was accidentally discovered in the 1970s while herbal extraction of Huperzine serrata was used to treat schizophrenia and found with significant cholinergic side effects.…”