Review
Huperzine A from Huperzia species—An ethnopharmacolgical review

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Abstract

Huperzine A (HupA), isolated originally from a traditional Chinese medicine Qiang Ceng Ta, whole plant of Huperzia serrata (Thunb. ex Murray) Trev., a member of the Huperziaceae family, has attracted intense attention since its marked anticholinesterase activity was discovered by Chinese scientists. Several members of the Huperziaceae (Huperzia and Phlegmariurus species) have been used as medicines in China for contusions, strains, swellings, schizophrenia, myasthenia gravis and organophosphate poisoning. HupA has been marketed in China as a new drug for Alzheimer's disease (AD) treatment and its derivative ZT-1 is being developed as anti-AD new drug candidate both in China and in Europe. A review of the chemistry, bioactivities, toxicology, clinical trials and natural resources of HupA source plants is presented.

Introduction

Qian Ceng Ta, a traditional Chinese medicine produced from the whole plant of the club moss Huperzia serrata (Thunb. ex Murray) Trev. (synonym Lycopodium serratum Thunb. ex Murray, a member of Huperziaceae), has been used for over 1000 years in China for treatment of a number of ailments, including contusions, strains, swellings, schizophrenia, myasthenia gravis and now organophosphate poisoning (College, 1985, Ma, 1997). It has become known worldwide as a medicinal plant since Chinese scientists discovered huperzine A (HupA) (Fig. 1) from it in the 1980s (Liu et al., 1986a, Liu et al., 1986b).

The earliest record of medicinal usage of Qian Ceng Ta can be traced back to an ancient Chinese pharmacopeia “Ben Cao Shi Yi”, which was written by Zangqi Chen in 739 (during the Tang Dynasty). The herb was named Shi Song in this book and it was prescribed for relieving rheumatism and colds, to relax muscles and tendons and to promote blood circulation. The same herb with different names but similar usage prescriptions can be found in “Ben Cao Gang Mu” by Shizhen Li in 1578 (during the Ming Dynasty) and “Zhi Wu Ming Shi Tu Kao” by Qijun Wu in 1848 (during the Qing Dynasty). In fact, Shi Song was a confusing name for the medicinal herb in the ancient times because this name was used to describe several different medicinal herbs. Qian Ceng Ta is one of these Shi Song herbs and was popularly used in southern China. However, all of the Shi Song herbs are members of the genus Lycopodium (sensu latu) (e.g. Lycopodium japonicum Thunb., Lycopodium annotinum L., Lycopodium obscurum L., Diphasiastrum complanaatum (L.) Holub, Phalhinhaea cernua (L.) A. Franco et Vasc., and Huperzia serrata) (Ma, 1997).

In the early 1980s, Chinese scientists searched for new drugs for myasthenia gravis treatment. Lycopodium alkaloids extracted from Lycopodium (s.l.) species were lead drug targets based on the traditional use the herbs that contain them (Cheng et al., 1986). In vitro and in vivo pharmacological studies have demonstrated that Lycopodium alkaloids produce definite effects in the treatment of diseases that affect the cardiovascular or neuromuscular systems, or that are related to cholinesterase activity. These alkaloids have been shown to have positive effects on learning and memory (Liu et al., 1986b, Tang et al., 1986, Zhu and Tang, 1987). Of these, HupA, which was isolated from Qian Ceng Ta (Huperzia serrata) by Chinese scientist Liu and co-workers (Liu et al., 1986b) is the most well known, and appears to be the most potent. HupA has been extensively evaluated by the Chinese for bioactivity, especially for activity toward cholinesterases and for treatment of Alzheimer's disease (AD).

HupA has been proven to be a powerful, highly specific, and reversible inhibitor of acetylcholinesterase (AChE) (Tang et al., 1986, Tang et al., 1989, Cheng et al., 1996). Shuangyiping, a tablet form of HupA produced from extracts of Huperzia serrata, was developed in 1996 (by one of the authors, Zhu) as a new drug for symptomatic treatment of AD in China (Tang, 1996). HupA is also marketed in the USA as a dietary supplement (as powdered Huperzia serrata in tablet or capsule form). As the world's population lives longer, increasing numbers of people, especially in the developed world suffer from AD and other types of dementia. AD is the most common form of dementia, and is characterized by the loss of memory, motor ability and eventually muscle control. Phase IV clinical trials in China have demonstrated that HupA significantly improves memory deficits in elderly people with benign senescent forgetfulness and in patients with AD or vascular dementia (VD), with minimal peripheral cholinergic side effects and no unexpected toxicity (Xu et al., 1995, Xu et al., 1999, Zhang et al., 2002b). Several new drugs for treatment of AD symptoms have been approved by the U.S. Food and Drug Administration (FDA) in recent years, all of which are AChE inhibitors (AChEIs). These include tacrine (trade name: Cognex) in 1993, donepezil (trade name: Aricept) in 1996, rivastigmine (trade name: Exelon) in 2000, and galanthamine (trade name: Reminyl) in 2001. Tacrine produces some serious side effects (including liver toxicity) among >29% of patients, and has removed from the market. Donepezil appears to have better properties, both greater effect and lower toxicity, than tacrine. Rivastigmine also appears to have better properties than tacrine, in that it does not appear to cause liver damage. However, it can produce stomach-related side-effects such as nausea and vomiting. Galanthamine, unlike the other three FDA-approved AChEIs, is a natural plant alkaloid, produced by Galanthus nivalis L. and related plants (Amaryllidaceae family) (Heinrich and Lee Teoh, 2004). It has also been used to treat symptoms of other forms of dementia, such as VD (Farlow, 2003). Compared with the above acetylcholinesterase inhibitors (AChEIs), including galanthamine, HupA has better penetration through the blood–brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action (Wang et al., 2006a). Most of these clinical trials have been performed in China, where an estimated 100,000 people have been treated with HupA (Chiu and Zhang, 2000). Results of these studies indicate that HupA is an effective and safe drug that alleviates AD and improves cognitive function. In addition, HupA can also be used as a protective (prophylactive) agent against organophosphate (OP) poisoning (Saxena et al., 1994, Rocha et al., 1998, Lallement et al., 2002b, Gordon et al., 2005, Liu and Sun, 2005, Eckert et al., 2006).

ZT-1 (Fig. 1), a semi-synthetic derivative of HupA, was originally synthesised by Zhu and coworkers at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences (Ma and Gang, 2004). Experimental data demonstrated that ZT-1 possesses AChEI activity similar to HupA. However, it is more selective and displays less BChEI activity as well as less toxicity in mice than HupA. ZT-1 has similar properties to HupA regarding the ability to cross the blood–brain barrier, its oral bioavailability, and its longevity of action (Ma and Gang, 2004). ZT-1 is a promising new drug candidate and is expected to be the first Chinese new drug, with independent intellectual property rights owned by Chinese scientists, to move into the international major pharmaceutical markets.

A historical outline of HupA's discovery and development, beginning with its original discovery from traditional Chinese medicine Qiang Ceng Ta, is presented in Table 1. The discovery and development of HupA and ZT-1 as new drugs present a successful model for development of new drugs from traditional Chinese medicine.

Section snippets

Chemistry

Lycopodium alkaloids, triterpenes, flavones and phenolic acids are commonly found natural products in Huperziaceae plants (Towers and Maas, 1965, Voirin et al., 1976, Voirin and Jay, 1978, Li et al., 1988, Ma, 1997, Lu et al., 2002; Tong et al., 2003a, Tong et al., 2003b; Ma and Gang, 2004, Zhou et al., 2004b, Shi et al., 2005). The most extensively investigated of these compounds are the Lycopodium alkaloids and the most important and intensively studied by far is HupA.

Bioactivities of HupA

Several bioactivities have been described for HupA. The most important of these relate to its effects on memory and its neuronal protection capabilities. HupA improved memory retention processes in cognitively impaired aged and adult rats (Lu et al., 1988). In multicentre, placebo-controlled, doubleblind and randomized trials, HupA significantly improved memory and behavior in AD patients (Zhang et al., 1991, Zhang et al., 2002b, Xu et al., 1995). HupA was reported to be more selective for AChE

Toxicology

Toxicological studies conducted in different animal species indicated less severe undesirable side effects associated with cholinergic activation for HupA than for other ChEIs such as physostigmine and tacrine (Wang and Tang, 1998, Zangara, 2003). In mice, the LD50 doses were 4.6 mg (po), 3.0 mg (sc), 1.8 mg (ip), and 0.63 mg (iv). Histopathological examinations showed no changes in liver, kidney, heart, lung or brain after administration of HupA for 180 days, or in dogs (0.6 mg/kg, im) or rats (1.5 

Clinical trials with HupA

Clinical trials performed with HupA have demonstrated that HupA produces significant improvements in memory deficiencies in aged and AD patients. As mentioned in the Introduction, most of these studies have been performed in China, and an estimated 100,000 people have been treated with HupA (Chiu and Zhang, 2000). Several comprehensive reviews related to HupA clinical trials have been published recently and we recommend interested readers to refer to these sources for more detailed information (

HupA source plants

The original source plant of HupA is Huperzia serrata (Chinese herb name: Qian Ceng Ta, She Zu Cao, Jin Bu Huan, Shan Zhi, etc.) (Liu et al., 1986a, Liu et al., 1986b, Ma, 1997, Ma et al., 2006). As discussed above, it has been extensively used for over 1000 years in different areas of China as a popular traditional Chinese medicine (Ma et al., 2006). Huperzia serrata belongs to the Huperziaceae family, according to the system of Lycopodium (s.l.) plants currently in use in China. This system

Conclusion

Because of the significant pharmacological activities of HupA and its derivative ZT-1, Huperziaceae species have recently been a hot target of many investigations related to the chemical, biological, pharmacological, and medical properties of these plants. Results from these investigations clearly show that there is a strong relationship between the ethnopharmacological use of these plants and the medicinal properties of important compounds identified from them, such as HupA. HupA has only been

Acknowledgements

The authors would like to thank the financial support from the National Natural Science Foundation of China (NSFC, #39900013 to XM) for research related to this review and Professor M. Heinrich for critical review of the manuscript.

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