Huperzia serrata (PROSEA)
Huperzia serrata (Thunb. ex Murray) Trevis.
- Protologue: Atti Soc. Ital. Sci. Nat. Mus. Civ. St. Nat. (Milano) 17: 248 (1874).
- Family: Lycopodiaceae
- Chromosome number: 2n= 528 (India)
Lycopodium serratum Thunb. ex Murray (1784), L. javanicum Swartz (1801), L. sargassifolium Liebm. (1848).
- Philippines: kodlala (Igorot), sinang padayao (Bontoc)
- Vietnam: nbó ri (Moi).
Origin and geographic distribution
H. serrata is found from India, the eastern Himalayas to Korea, and through Japan, Taiwan and Indo-China to Indonesia, the Philippines, Polynesia, the Sandwich Islands and Haiti. A secondary disjunct population exists in wet mountain forests in Mexico, Cuba and Hispaniola.
For many centuries H. serrata has been used in China as a herbal medicine ("qian ceng ta", "jin bu huang") to treat fever and inflammations and as a diuretic, haemostyptic, antispasmodic and analgesic. Drugs based on huperzine A extracted from H. serrata are currently awaiting official approval for human use in western medicine and are being applied in clinical trials for the treatment of Alzheimer's disease and myasthenia gravis (disorder of neuromuscular function). Huperzine A is also used in the United States as a supplementary drug for the correction of memory impairment, under the trade name "Cerebra". Nowadays it is marketed as "smart drug" to boost brain power.
Production and international trade
Although H. serrata is quite important in traditional Chinese medicine in and outside China and is traded internationally, production and trade statistics are not available. In July 2002 the price per kg extract powder with 1-5% huperzine content was US$ 1098-2440, and per g of purified (99%) huperzine A US$ 400-700.
H. serrata contains a wide spectrum of alkaloids, namely the huperzines A, B, G, I, J, K, L, and P, huperzinine, huperserratinine, fawcettimine, lucidioline, phlegmariunine, serratinine, serratezomine A, B, and C, N-methylhuperzine B, and 6-α-hydroxylycopodino. It also contains the triterpenoids 16-oxodiepiserratenediol, 21-episerratenediol, 21-episerratenediol-3-acetate, serratanediol-21-acetate, serratenediol, serratenediol-3-acetate and a phenolic glycoside-arbutin. Huperzine A is identical to selagine and is a slow, reversible inhibitor of the enzyme acetylcholinesterase which is involved in the breakdown of the neurotransmitter acetylcholine. Huperzine A is a more potent inhibitor than tacrine by several orders of magnitude and has a slower dissociation rate. The natural (-)-huperzine A isomer is up to 50 times more effective than the synthetic (+)-huperzine A. In current pharmacological research huperzine A is the focus of much attention as a possible drug for Alzheimer's disease. One of the pathological marks of this disease is the formation of senile plaques from the deposition of β amyloid causing the death of neuronal cells. Both stereomers protect neuronal cells against β-amyloid toxicity. It activates anti-oxidant enzymes that neutralize the free radicals involved in the neurodegeneration. It has also been shown to alleviate the cognitive dysfunction associated with β amyloid.
Nicotinic compounds can act synergetically with huperzine A and B to protect cells of the central nerve system against cell death by excitory amino acids or β amyloid. The combination is expected to prevent or reverse neuronal dysfunction caused by Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke and injuries of the spinal chord or peripheral nervous system.
Systemic huperzine A increases norepinephrine and dopamine levels. In aged rats huperzine A lowered the concentrations of malondialdehyde and the activities of Mn-superoxide dismutase. The effects of huperzine A on learning and memory are superior to those of physostigmine. Huperzine capsules are claimed to enhance the memory and learning performance of adolescent students.
Huperzine A has been successfully tested as prophylactic agent in the pretreatment of organophosphate nerve agents, such as the chemical warfare compound soman. These compounds act as irreversible acetylcholinesterase inhibitors. Huperzine A protects the enzyme by binding to it and thus preventing a bond with the organophosphate agent. Unlike the frequently used prophylaxis pyridostigmine bromide, huperzine A passes the blood-brain barrier and can protect the cerebral nerve system. Furthermore, it does not inhibit the plasma butyrylcholinesterase, which is helpful in detoxifying the organophosphate agent.
Huperzine B and huperzine C have similar properties as huperzine A, but have been less investigated. Huperzine B exhibited higher selectivity and efficacy than tacrine in the inhibition of acetylcholinesterase and lower toxicity in mice. Huperzine B, huperzine C and, less pronouncedly, huperzine P show marked inhibitory activity against acetylcholinesterase.
There are very few reports of cases of acute hepatitis and incidentally fibrosis ascribed to the use of the Chinese herb "jin bu huan". It has been questioned whether this name applies to H. serrata , as allegedly several other herbs are known by the same name. Cases of acute intoxication were recorded in Europe, where Lycopodium clavatum L. can be easily confused with Huperzia selago (L.) Bernh. Herbal products from Lycopodium are generally reputed to be non-toxic and are occasionally used for preparing a health-giving tea, but patients who drank a tea, erroneously prepared from dried herbs of H. selago , were hospitalized with symptoms such as sweating, vomiting, diarrhoea, dizziness, cramps and slurred speech, which were attributed to poisoning by huperzine A.
A terrestrial, moss-like, repeatedly forked herb with serrate leaves and a ragged appearance. Stem erect, decumbent at the base, 3-15(-21) cm × 1-2 mm (not including the leaves), 1-3 times dichotomously branched, green but the older parts yellower. Leaves reflexed near the base, spreading in the younger parts, spirally in many ranks, petiolate; lamina elliptical to lanceolate, 7-17(-30) mm × (1-)2-4(-5) mm, base narrowed, margins deeply irregularly serrate or double serrate, apex abruptly acuminate, deep-green, thin chartaceous, costa distinctly raised above; between the leaves trilobed gemmae may be present. True strobili are absent; sporangia scattered, neither in distinct zones, nor only terminally, on stem parts that are only little different from the vegetative parts of the stem; sporophylls lanceolate, 3-5 mm long; sporangia lunate, wider than the sporophyll bases. Spores trilete, distinctly triangular, concave, truncate.
Growth and development
Gametophytes of H. serrata have rarely been observed. The spore walls of Huperzia Bernh. are strong and the spore may germinate only after a long time, developing into a slowly maturing, mycotrophic, subterranean (or in the substrate when epiphytic) gametophyte. After developing antheridia and archegonia, fertilization takes place and sporophyte development can begin.
Other botanical information
The Lycopodiaceae do not have close affinities to other groups. In older views there was only one genus, Lycopodium L. At present, although there is no general agreement, 3 genera have been separated from Lycopodium , bringing the total to 4. Huperzia Bernh. is now the largest genus and comprises about (200-)300(-400) species which are, however, difficult to distinguish due to the wide plasticity of the characteristics. Its diversity is highest in tropical evergreen montane forests. The tropical representatives of H. serrata have longer leaves than the typical ones from Japan, and have been distinguished as var. longipetiolatum Spring. However, the size and shape of the leaves are so variable that this distinction is hardly justified.
H. serrata grows terrestrially in evergreen montane forest above 1000 m altitude. Seasonal growth cycles may leave marked constrictions on the stem with shorter leaves, alternated by zones with much longer leaves, giving the plant a rather ragged appearance.
Propagation and planting
Results of trials with spore culture of H. serrata are not known. The easiest way to propagate H. serrata is by planting the propagules on moist, humus-rich soil in a cool climate.
Genetic resources and breeding
No germplasm collections or breeding programmes of H. serrata are known to exist. Although rather widely distributed, in tropical Asia at least H. serrata is not very common and in its natural habitat it is vulnerable to over-collection.
At present the alkaloids extracted from H. serrata are the focus of much attention and new pharmacological properties are published frequently. Huperzine A has the potential to become a useful agent to reduce neuronal cell damage from strokes, epilepsy and other brain disorders. A successful medicine against Alzheimer's disease would give access to a very large market. Huperzine A is a high-ranking candidate for a prophylactic agent to prevent brain injury from organophosphate nerve gas poisons. The technology for industrial synthesis of its biologically active components is being improved and will alleviate the strain on natural populations of H. serrata .
- Ashani, Y., Peggins, J.O. & Doctor, B.P., 1992. Mechanism of inhibition of cholinesterases by huperzine A. Biochemical and Biophysical Research Communications 184(2): 719-726.
- Felgenhauer, N., Zilker, T., Worek, F. & Eyer, P., 2000. Intoxication with huperzine A, a potent anticholinesterase found in the fir club moss. Journal of Toxicology and Clinical Toxicology 38(7): 803-808.
- Kozikowski, A.P. & Tuckmantel, W., 1999. Chemistry, pharmacology and clinical efficacy of the Chinese nootropic agent huperzine A. Accounts of Chemical Research 32: 641-650.
- Lallement, G., Baille, V., Baubichon, D., Carpentier, P., Colombet, J. et al., 2002. Review of the value of huperzine as pretreatment of organophosphate poisoning. NeuroToxicology 23: 1-5.
- Øllgaard, B., 1987. A revised classification of the Lycopodiaceae sensu lato. Opera Botanica 92: 153-178.
- Sun, Q.Q., Xu, S.S., Pan, J.L., Guo, H. M. & Cao, W.Q., 1999. Huperzine-A capsules enhance memory and learning performance in 34 pairs of matched adolescent students. Acta Pharmacologica Sinica 20(7): 601-603.
- Tsai, J.L. & Shieh, W.C., 1994. Lycopodiaceae. In: Huang, T.C. et al. (Editors): Flora of Taiwan. 2nd Edition. Vol. 1. Editorial Committee of the Flora of Taiwan, Department of Botany, National Taiwan University, Taipei, Taiwan. pp. 29-44.
- Wang, L.M., Han, Y.F. & Tang, X.C., 2000. Huperzine A improves cognitive deficits caused by chronic cerebral hypoperfusion in rats. European Journal of Pharmacology 398: 65-72.
- Zhang, H.Y., Liang, Y.Q., Tang, X.C., He, X.C. & Bay, D.L., 2002. Stereoselectivities of enantiomers of huperzine A in protection against β-amyloid-(25-35)-induced injury in PC12 and NG108-15 cells and cholinesterase inhibition in mice. Neuroscience Letters 317: 143-146.
W.P. de Winter