Huperzine A

Huperzine A is a naturally-occurring sesquiterpene alkaloid compound found in the firmoss Huperzia serrata^[2] and in varying quantities in other food Huperzia species, including H. elmeri, H. carinat, and H. aqualupian.^[3] Huperzine A has been investigated as a treatment for neurological conditions such as Alzheimer's disease, but a 2013 meta-analysis of those studies concluded that they were of poor methodological quality and the findings should be interpreted with caution.^[4][5] Huperzine A inhibits the breakdown of the neurotransmitter acetylcholine (ACh) by the enzyme acetylcholinesterase. It is also an antagonist of the NMDA-receptor. It is commonly available over the counter as a nutritional supplement and marketed as a memory and concentration enhancer.

Huperzine A

Clinical data
Other names	HupA
Routes of administration	Oral
ATC code	N06
Pharmacokinetic data
Elimination half-life	10-14h[1]
Identifiers
IUPAC name (1R,9R,13E)-1-Amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.02,7]trideca-2(7),3,10-trien-5-one
CAS Number	102518-79-6 N
PubChem CID	854026
DrugBank	DB01928 Y
ChemSpider	16736021 Y
UNII	0111871I23
ChEBI	CHEBI:78330 N
ChEMBL	ChEMBL395280 Y
CompTox Dashboard (EPA)	DTXSID8046038
ECHA InfoCard	100.132.430
Chemical and physical data
Formula	C15H18N2O
Molar mass	242.322 g·mol−1
3D model (JSmol)	Interactive image
Melting point	217 to 219 °C (423 to 426 °F)
SMILES C/C=C/1\[C@@H]2CC3=C([C@]1(CC(=C2)C)N)C=CC(=O)N3
InChI InChI=1S/C15H18N2O/c1-3-11-10-6-9(2)8-15(11,16)12-4-5-14(18)17-13(12)7-10/h3-6,10H,7-8,16H2,1-2H3,(H,17,18)/b11-3+/t10-,15+/m0/s1 Y Key:ZRJBHWIHUMBLCN-YQEJDHNASA-N Y
NY (what is this?)  (verify)

Huperzine A has also been noted to help induce lucid dreaming.^[6]

Pharmacological effects

Huperzine A is extracted from Huperzia serrata.^[2] It is a reversible acetylcholinesterase inhibitor^{[7][8][9][10]} and NMDA receptor antagonist^[11] that crosses the blood–brain barrier.^[12] Acetylcholinesterase is an enzyme that catalyzes the breakdown of the neurotransmitter ACh and other choline esters that function as neurotransmitters. The structure of the complex of huperzine A with acetylcholinesterase has been determined by X-ray crystallography (PDB code: 1VOT; see the 3D structure).^[13]

Huperzine A has been investigated as a possible treatment for diseases characterized by neurodegeneration such as Alzheimer's disease,^[2][14] and there is some evidence from small-scale studies that it can benefit cognitive functioning, global clinical status, and ability to engage in activities of daily living (ADLs) among individuals with the disease. In a 2016 systematic review of systematic reviews,^[15] huperzine A was associated with a standardized mean difference of 1.48 (95% CI, 0.95-2.02) compared to placebo on measures of ADL among people with dementia, but the evidence was very low-quality and uncertain. In a 2022 umbrella review,^[16] huperzine A was associated with broad benefits to dementia patients' cognitive functioning, but the degree of heterogeneity in measurements and outcomes of the reviewed studies indicated publication bias toward huperzine A benefit.

Adverse effects

Huperzine A may present with mild cholinergic side effects such as nausea, vomiting, and diarrhea.^[5] Slight muscle twitching and slurred speech might also occur, as well as excessive saliva excretion and sweating. The use of huperzine A during pregnancy and lactation is not recommended due to the lack of sufficient safety data.^[17]

Drug interactions

Huperzine A may have additive effects if taken with drugs causing bradycardia, such as beta-blockers,^[18] which may decrease heart rate. Theoretically, there may be possible additive cholinergic effects if huperzine A is taken with other acetylcholinesterase inhibitors or cholinergic agents.^[19]

Safety

Huperzine A, in spite of the possible cholinergic side effects, seems to have a wide margin of safety. Toxicology studies show huperzine A to be non-toxic even when administered at 50-100 times the human therapeutic dose. The extract is active for 6 hours at a dose of 2 μg/kg with no remarkable side effects.^[20]

Other possible uses

Huperzine A might be useful in the treatment of organophosphate nerve agent poisoning by preventing damage to the central nervous system caused by such agents. ^{[21] [22]}

Synthesis

Two scalable and efficient total syntheses of huperzine A have been reported.^[23][24]

References

1. Li YX, Zhang RQ, Li CR, Jiang XH (2007). "Pharmacokinetics of huperzine A following oral administration to human volunteers". European Journal of Drug Metabolism and Pharmacokinetics. 32 (4): 183–187. doi:10.1007/BF03191002. PMID 18348466. S2CID 2702029.
2. Zangara A (June 2003). "The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer's disease". Pharmacology, Biochemistry, and Behavior. 75 (3): 675–686. doi:10.1016/S0091-3057(03)00111-4. PMID 12895686. S2CID 36435892.
3. Lim WH, Goodger JQ, Field AR, Holtum JA, Woodrow IE (September 2010). "Huperzine alkaloids from Australasian and southeast Asian Huperzia". Pharmaceutical Biology. 48 (9): 1073–1078. doi:10.3109/13880209.2010.485619. PMID 20731560.
4. Yang G, Wang Y, Tian J, Liu JP (2013). "Huperzine A for Alzheimer's disease: a systematic review and meta-analysis of randomized clinical trials". PLOS ONE. 8 (9): e74916. Bibcode:2013PLoSO...874916Y. doi:10.1371/journal.pone.0074916. PMC 3781107. PMID 24086396.
5. Li J, Wu HM, Zhou RL, Liu GJ, Dong BR (April 2008). Wu HM (ed.). "Huperzine A for Alzheimer's disease". The Cochrane Database of Systematic Reviews. CD005592 (2): CD005592. doi:10.1002/14651858.CD005592.pub2. PMID 18425924.
6. "Lucid Dreaming: A Beginner's Guide". The Four Hour Work Week. Retrieved 29 December 2016.
7. Wang R, Yan H, Tang XC (January 2006). "Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine". Acta Pharmacologica Sinica. 27 (1): 1–26. doi:10.1111/j.1745-7254.2006.00255.x. PMID 16364207. Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase (AChE).
8. Meletis CD, Barke JE (2004). Herbs and Nutrients for the Mind: A Guide to Natural Brain Enhancers. Greenwood Publishing Group. p. 191. ISBN 978-0-275-98394-9.
9. Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ (April 2009). "Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis". Journal of Neural Transmission. 116 (4): 457–465. doi:10.1007/s00702-009-0189-x. PMID 19221692. S2CID 8655284.
10. Tang XC, He XC, Bai DL (1999). "Huperzine A: A novel acetylcholinesterase inhibitor". Drugs of the Future. 24 (6): 647. doi:10.1358/dof.1999.024.06.545143.
11. Coleman BR, Ratcliffe RH, Oguntayo SA, Shi X, Doctor BP, Gordon RK, et al. (September 2008). "[+]-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats". Chemico-Biological Interactions. 175 (1–3): 387–395. doi:10.1016/j.cbi.2008.05.023. PMID 18588864.
12. Patocka J (1998). "Huperzine A--an interesting anticholinesterase compound from the Chinese herbal medicine". Acta Medica. 41 (4): 155–157. doi:10.14712/18059694.2019.181. PMID 9951045.
13. Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL (January 1997). "Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A". Nature Structural Biology. 4 (1): 57–63. doi:10.1038/nsb0197-57. PMID 8989325. S2CID 236518.
14. Bai DL, Tang XC, He XC (March 2000). "Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease". Current Medicinal Chemistry. 7 (3): 355–374. doi:10.2174/0929867003375281. PMID 10637369.
15. Laver K, Dyer S, Whitehead C, Clemson L, Crotty M (April 2016). "Interventions to delay functional decline in people with dementia: a systematic review of systematic reviews". BMJ Open. 6 (4): e010767. doi:10.1136/bmjopen-2015-010767. PMC 4854009. PMID 27121704.
16. Fan F, Liu H, Shi X, Ai Y, Liu Q, Cheng Y (2022-02-01). "The Efficacy and Safety of Alzheimer's Disease Therapies: An Updated Umbrella Review". Journal of Alzheimer's Disease. 85 (3): 1195–1204. doi:10.3233/JAD-215423. PMID 34924395. S2CID 245311001.
17. "Huperzine A". Natural Standard: The Authority on Integrative Medicine. Natural Standard. Retrieved 29 October 2014.
18. Pepping J (March 2000). "Huperzine A". American Journal of Health-System Pharmacy. 57 (6): 530, 533–530, 534. doi:10.1093/ajhp/57.6.530. PMID 10754762.
19. Skolnick AA (March 1997). "Old Chinese herbal medicine used for fever yields possible new Alzheimer disease therapy". JAMA. 277 (10): 776. doi:10.1001/jama.1997.03540340010004. PMID 9052690.
20. Lallement G, Baille V, Baubichon D, Carpentier P, Collombet JM, Filliat P, et al. (May 2002). "Review of the value of huperzine as pretreatment of organophosphate poisoning". Neurotoxicology. 23 (1): 1–5. doi:10.1016/S0161-813X(02)00015-3. PMID 12164543.
21. "Review of the Value of Huperzine as Pretreatment of Organophosphate Poisoning". Nutrition Review. 22 April 2013.
22. Liu L, Sun JX (March 2005). "[Advances on study of organophosphate poisoning prevented by Huperzine A]". Wei Sheng Yan Jiu = Journal of Hygiene Research. 34 (2): 224–226. PMID 15952670.
23. un MK, Wüstmann DJ, Herzon SB (2011). "A robust and scalable synthesis of the potent neuroprotective agent (−)-huperzine A". Chemical Science. 2 (11): 2251–2253. doi:10.1039/C1SC00455G. S2CID 98224866.
24. Tudhope SR, Bellamy JA, Ball A, Rajasekar D, Azadi-Ardakani M, Meera HS, et al. (2012). "Development of a Large-Scale Synthetic Route to Manufacture (−)-Huperzine A". Organic Process Research & Development. 16 (4): 635–642. doi:10.1021/op200360b.

External links

• AChE inhibitors and substrates in Proteopedia