Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter November 28, 2019

The use of Huperzia species for the treatment of Alzheimer’s disease

  • Dang Kim Thu , Dao Thi Vui , Nguyen Thi Ngoc Huyen , Duong Ky Duyen and Bui Thanh Tung EMAIL logo


Alzheimer’s disease (AD), which relates to nervous degeneration, is the most popular form of memory loss. The pathogenesis of AD is not fully understood, and there are no therapies for this disorder. Some drugs have been used in clinical applications for preventing and treating AD, but they have significant adverse reactions. Therefore, there is a need to develop treatment for AD. Traditional medicine has used many medicinal plants to alleviate the symptoms of AD. Medicinal plants may reduce neurodegenerative disorders with fewer side effects than chemical drugs, and they are promising drug candidates for AD therapy. This review is the summary of the pathogenesis and treatments of AD and includes information about the chemistry and bioactivities of some medicinal plants from the Huperzia species, such as Huperzia saururus, Huperzia selago, Huperzia phlegmaria, Huperzia fargesii, Huperzia serrata, Huperzia reflexa and Huperzia quadrifariata, that are used for the treatment of AD. We searched literature, including Medline, Embase, Google Scholar and PubMed database, and did a bibliographic review of relevant articles. Key words included Huperzia species, huperzine, huperin, Huperzia and Alzheimer’s disease. We found that the main bioactive compounds of the Huperzia species are alkaloids, which have shown significant effects on preventing the development of AD. They are new promising compounds against AD due to their antioxidant, anti-inflammatory and acetylcholinesterase inhibitory activities in the neural system. Our conclusion from this review is that the Huperzia species are potential source containing various pharmaceutical compounds for the treatment of AD.


The authors would like to thank the financial support from the Vietnam National University, Ha Noi, Vietnam (grant number QG.19.57).

  1. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  2. Competing interests: The authors state no conflict of interest.


[1] Pilcher H. Alzheimer’s disease could be “type 3 diabetes”. Lancet Neurol 2006;5:388–9.10.1016/S1474-4422(06)70434-3Search in Google Scholar

[2] Reus VI, Fochtmann LJ, Eyler AE, Hilty DM, Horvitz-Lennon M, Jibson MD, et al. The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Am J Psychiatry 2016;173:543–6.10.1176/appi.ajp.2015.173501Search in Google Scholar PubMed

[3] Tobore TO. On the central role of mitochondria dysfunction and oxidative stress in Alzheimer’s disease. Neurol Sci 2019;40:1527–40.10.1007/s10072-019-03863-xSearch in Google Scholar PubMed

[4] Wimo A, Winblad B, Aguero-Torres H, von Strauss E. The magnitude of dementia occurrence in the world. Alzheimer Dis Assoc Disord 2003;17:63–7.10.1097/00002093-200304000-00002Search in Google Scholar PubMed

[5] Howes M-JR, Fang R, Houghton PJ. Effect of Chinese herbal medicine on Alzheimer’s disease. Int Rev Neurobiol 2017;135:29–56.10.1016/bs.irn.2017.02.003Search in Google Scholar PubMed

[6] Perry E, Perry R. A review of neuropathological and neurochemical correlates of Alzheimer’s disease. Danish Med Bull 1985;32:27–34.Search in Google Scholar

[7] Jahn H. Memory loss in Alzheimer’s disease. Dialogues Clin Neurosci 2013;15:445–4.10.31887/DCNS.2013.15.4/hjahnSearch in Google Scholar

[8] Colović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol 2013;11:315–35.10.2174/1570159X11311030006Search in Google Scholar PubMed PubMed Central

[9] Ortega MG, Vallejo MG, Cabrera JL, Pérez MF, Almirón RS, Ramírez OA, et al. Huperzia saururus, activity on synaptic transmission in the hippocampus. J Ethnopharmacol 2006;104:374–8.10.1016/j.jep.2005.11.002Search in Google Scholar PubMed

[10] Ortega MG, Agnese AM, Cabrera JL. Anticholinesterase activity in an alkaloid extract of Huperzia saururus. Phytomedicine 2004;11:539–43.10.1016/j.phymed.2003.07.006Search in Google Scholar PubMed

[11] Vallejo MG, Dimmer JA, Ortega MG, Cabrera JL, Agnese AM. Amino acid content and acetylcholinesterase inhibition of Huperzia saururus infusion and decoction. Pharm Biol 2013;51:1341–5.10.3109/13880209.2013.784921Search in Google Scholar PubMed

[12] Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid Med Cell Longev 2013;2013:316523.10.1155/2013/316523Search in Google Scholar

[13] Ma X, Tan C, Zhu D, Gang DR, Xiao P. Huperzine A from Huperzia species – an ethnopharmacolgical review. J Ethnopharmacol 2007;113:15–34.10.1016/j.jep.2007.05.030Search in Google Scholar

[14] Zhang L, Yu H, Zhao X, Lin X, Tan C, Cao G, et al. Neuroprotective effects of salidroside against beta-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Neurochem Int 2010;57:547–55.10.1016/j.neuint.2010.06.021Search in Google Scholar

[15] Harris JR. Protein aggregation and fibrillogenesis in cerebral and systemic amyloid disease. Vol. 65. Berlin, Germany: Springer Science & Business Media, 2012.10.1007/978-94-007-5416-4Search in Google Scholar

[16] Ma X-Q, Jiang S-H, Zhu D-Y. Alkaloid patterns in Huperzia and some related genera of Lycopodiaceae sensu lato occurring in China and their contribution to classification. Biochem Syst Ecol 1998;26:723–8.10.1016/S0305-1978(98)00022-2Search in Google Scholar

[17] Szypula WJ, Mistrzak P, Olszowska O. A new and fast method to obtain in vitro cultures of Huperzia selago (Huperziaceae) sporophytes, a club moss which is a source of huperzine A. Acta Soc Bot Pol 2013;82:313–320.10.5586/asbp.2013.034Search in Google Scholar

[18] Ma X, Tan C, Zhu D, Gang DR. A survey of potential huperzine A natural resources in China: the Huperziaceae. J Ethnopharmacol 2006;104:54–67.10.1016/j.jep.2005.08.042Search in Google Scholar PubMed

[19] Zhang H-y. New insights into huperzine A for the treatment of Alzheimer’s disease. Acta Pharmacol Sin 2012;33:1170.10.1038/aps.2012.128Search in Google Scholar PubMed PubMed Central

[20] Vallejo MG, Ortega MG, Cabrera JL, Carlini VP, de Barioglio RS, Almiron RS, et al. Sauroine, an alkaloid from Huperzia saururus with activity in Wistar rats in electrophysiological and behavioral assays related to memory retention. J Nat Prod 2009;72:156–8.10.1021/np800151vSearch in Google Scholar PubMed

[21] Czapski GA, Szypuła W, Kudlik M, Wileńska B, Kania M, Danikiewicz W, et al. Assessment of antioxidative activity of alkaloids from Huperzia selago and Diphasiastrum complanatum using in vitro systems. Folia Neuropathol 2014;52:394–406.10.5114/fn.2014.47840Search in Google Scholar PubMed

[22] Staerk D, Larsen J, Larsen LA, Olafsdottir ES, Witt M, Jaroszewski JW. Selagoline, a new alkaloid from Huperzia selago. Nat Prod Res 2004;18:197–203.10.1080/14786410310001620600Search in Google Scholar PubMed

[23] Szypuła WJ, Kiss AK, Pietrosiuk A, Swist M, Danikiewicz W, Olszowska O. Determination of huperzine A in Huperzia selago plants from wild population and obtained in in vitro culture by high-performance liquid chromatography using a chaotropic mobile phase. Acta Chromatogr 2011;23:339–52.10.1556/AChrom.23.2011.2.11Search in Google Scholar

[24] Szypuła W, Pietrosiuk A, Suchocki P, Olszowska O, Furmanow M, Kazimierska O. Somatic embryogenesis and in vitro culture of Huperzia selago shoots as a potential source of huperzine A. Plant Sci 2005;168:1443–52.10.1016/j.plantsci.2004.12.021Search in Google Scholar

[25] Lenkiewicz AM, Czapski GA, Jęsko H, Wilkaniec A, Szypuła W, Pietrosiuk A, et al. Potent effects of alkaloid-rich extract from Huperzia selago against sodium nitroprusside-evoked PC12 cells damage via attenuation of oxidative stress and apoptosis. Folia Neuropathol 2016;54:156–66.10.5114/fn.2016.60361Search in Google Scholar PubMed

[26] Bolaños JP, Almeida A, Stewart V, Peuchen S, Land JM, Clark JB, et al. Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. J Neurochem 1997;68:2227–40.10.1046/j.1471-4159.1997.68062227.xSearch in Google Scholar PubMed

[27] Nguyen HT, Doan HT, Ho DV, Pham KT, Raal A, Morita H. Huperphlegmines A and B, two novel Lycopodium alkaloids with an unprecedented skeleton from Huperzia phlegmaria, and their acetylcholinesterase inhibitory activities. Fitoterapia 2018;129:267–71.10.1016/j.fitote.2018.07.016Search in Google Scholar PubMed

[28] Yang Y, Wang Z, Wu J, Chen Y. Chemical constituents of plants from the genus Phlegmariurus. Chem Biodivers 2016;13:269–74.10.1002/cbdv.201500043Search in Google Scholar PubMed

[29] Yumkham SD, Singh PK. Study on uses and trading of Huperzia squarrosa (G. Forst.) Trevis. (Lycopodiaceae) in Manipur, India. Ethnobotany Res Appl 2013;11:153–61.Search in Google Scholar

[30] Chuong NN, Huong NT, Hung TM, Luan TC. Anti-cholinesterase activity of lycopodium alkaloids from Vietnamese Huperzia squarrosa (Forst.) Trevis. Molecules 2014;19:19172–9.10.9734/bpi/cacb/v1/7263DSearch in Google Scholar

[31] Tung BT, Hai NT, Thu DK. Antioxidant and acetylcholinesterase inhibitory activities in vitro of different fraction of Huperzia squarrosa (Forst.) Trevis extract and attenuation of scopolamine-induced cognitive impairment in mice. J Ethnopharmacol 2017;198:24–32.10.1016/j.jep.2016.12.037Search in Google Scholar PubMed

[32] Xiong J, Meng W-J, Zhang H-Y, Zou Y, Wang W-X, Wang X-Y, et al. Lycofargesiines A-F, further Lycopodium alkaloids from the club moss Huperzia fargesii. Phytochemistry 2019;162:183–92.10.1016/j.phytochem.2019.03.015Search in Google Scholar PubMed

[33] Ferreira A, Rodrigues M, Fortuna A, Falcão A, Alves G. Huperzine A from Huperzia serrata: a review of its sources, chemistry, pharmacology and toxicology. Phytochem Rev 2016;15:51–85.10.1007/s11101-014-9384-ySearch in Google Scholar

[34] Ohba T, Yoshino Y, Ishisaka M, Abe N, Tsuruma K, Shimazawa M, et al. Japanese Huperzia serrata extract and the constituent, huperzine A, ameliorate the scopolamine-induced cognitive impairment in mice. Biosci Biotechnol Biochem 2015;79:1838–44.10.1080/09168451.2015.1052773Search in Google Scholar PubMed

[35] Tabira T, Kawamura N. A study of a supplement containing huperzine A and curcumin in dementia patients and individuals with mild cognitive impairment. J Alzheimers Dis 2018;63:75–8.10.3233/JAD-171154Search in Google Scholar PubMed

[36] Konrath EL, Ortega MG, de Loreto Bordignon S, Apel MA, Henriques AT, Cabrera JL. Alkaloid profiling and anticholinesterase activity of South American Lycopodiaceae species. J Enzyme Inhib Med Chem 2013;28:218–22.10.3109/14756366.2011.633908Search in Google Scholar PubMed

[37] Konrath EL, Neves BM, Passos CdS, Lunardi PS, Ortega MG, Cabrera JL, et al. Huperzia quadrifariata and Huperzia reflexa alkaloids inhibit acetylcholinesterase activity in vivo in mice brain. Phytomedicine 2012;19:1321–4.10.1016/j.phymed.2012.08.009Search in Google Scholar PubMed

[38] Van Duy N, Vinh TT, Nguyen HN, Vu TC, Trieu LN, Viet HAU H, et al. A new combination and a new species in Phlegmariurus (Herter) Holub (Lycopodiaceae) from Southern Vietnam. Adansonia 2016;38:151–8.10.5252/a2016n2a1Search in Google Scholar

Received: 2019-06-27
Accepted: 2019-10-10
Published Online: 2019-11-28

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 2.12.2023 from
Scroll to top button