Huperzine A

Huperzine A may present with mild cholinergic side effects such as nausea, vomiting, and diarrhea. Slight muscle twitching and slurred speech might also occur, as well as hypersalivation and sweating. The use of huperzine A during pregnancy and lactation is not recommended due to the lack of sufficient safety data.{{cite web |title=Huperzine A |url=https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=764#safety |access-date=29 October 2014 |website=Natural Standard: The Authority on Integrative Medicine |publisher=Natural Standard}}

Huperzine A is a reversible acetylcholinesterase inhibitor{{cite journal | vauthors = Wang R, Yan H, Tang XC | title = Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine | journal = Acta Pharmacologica Sinica | volume = 27 | issue = 1 | pages = 1–26 | date = January 2006 | pmid = 16364207 | doi = 10.1111/j.1745-7254.2006.00255.x | quote = Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase (AChE). | doi-access = free }}{{cite book | url=https://books.google.com/books?id=a5AMBY9ekzcC&q=Huperzine&pg=PA191 | title=Herbs and Nutrients for the Mind: A Guide to Natural Brain Enhancers | publisher=Greenwood Publishing Group | vauthors = Meletis CD, Barke JE | date=2004 | pages=191 | isbn=978-0-275-98394-9}}{{cite journal | vauthors = Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ | title = Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis | journal = Journal of Neural Transmission | volume = 116 | issue = 4 | pages = 457–465 | date = April 2009 | pmid = 19221692 | doi = 10.1007/s00702-009-0189-x | s2cid = 8655284 }}{{cite journal | vauthors = Tang XC, He XC, Bai DL | title=Huperzine A: A novel acetylcholinesterase inhibitor | journal=Drugs of the Future | date=1999 | volume=24 | issue=6 | pages=647 | doi=10.1358/dof.1999.024.06.545143 }} and NMDA receptor antagonist{{cite journal | vauthors = Coleman BR, Ratcliffe RH, Oguntayo SA, Shi X, Doctor BP, Gordon RK, Nambiar MP | title = [+]-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats | journal = Chemico-Biological Interactions | volume = 175 | issue = 1–3 | pages = 387–395 | date = September 2008 | pmid = 18588864 | doi = 10.1016/j.cbi.2008.05.023 | bibcode = 2008CBI...175..387C }} that crosses the blood–brain barrier.{{cite journal | vauthors = Patocka J | title = Huperzine A--an interesting anticholinesterase compound from the Chinese herbal medicine | journal = Acta Medica | volume = 41 | issue = 4 | pages = 155–157 | date = 1998 | pmid = 9951045 | doi = 10.14712/18059694.2019.181 | doi-access = free }} 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: [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1vot 1VOT]; [http://www.proteopedia.org/wiki/index.php/1vot see the 3D structure]).{{cite journal | vauthors = Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL | title = Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A | journal = Nature Structural Biology | volume = 4 | issue = 1 | pages = 57–63 | date = January 1997 | pmid = 8989325 | doi = 10.1038/nsb0197-57 | s2cid = 236518 }}

Huperzine A may have additive effects if taken with drugs causing bradycardia, such as beta-blockers,{{cite journal | vauthors = Pepping J | title = Huperzine A | journal = American Journal of Health-System Pharmacy | volume = 57 | issue = 6 | pages = 530, 533-530, 534 | date = March 2000 | pmid = 10754762 | doi = 10.1093/ajhp/57.6.530 | doi-access = free }} 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.{{cite journal | vauthors = Skolnick AA | title = Old Chinese herbal medicine used for fever yields possible new Alzheimer disease therapy | journal = JAMA | volume = 277 | issue = 10 | pages = 776 | date = March 1997 | pmid = 9052690 | doi = 10.1001/jama.1997.03540340010004 }}{{Failed verification|date=April 2025}}

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.{{cite journal | vauthors = Lallement G, Baille V, Baubichon D, Carpentier P, Collombet JM, Filliat P, Foquin A, Four E, Masqueliez C, Testylier G, Tonduli L, Dorandeu F | title = Review of the value of huperzine as pretreatment of organophosphate poisoning | journal = Neurotoxicology | volume = 23 | issue = 1 | pages = 1–5 | date = May 2002 | pmid = 12164543 | doi = 10.1016/S0161-813X(02)00015-3 | bibcode = 2002NeuTx..23....1L }}

Two scalable and efficient total syntheses of huperzine A have been reported.{{cite journal | vauthors = un MK, Wüstmann DJ, Herzon SB | title=A robust and scalable synthesis of the potent neuroprotective agent (−)-huperzine A | journal=Chemical Science | date=2011 | volume=2 | issue=11 | pages=2251–2253 | doi=10.1039/C1SC00455G | s2cid=98224866 }}{{cite journal | vauthors = Tudhope SR, Bellamy JA, Ball A, Rajasekar D, Azadi-Ardakani M, Meera HS, Gnanadeepam JM, Saiganesh R, Gibson F, He L, Behrens CH | title=Development of a Large-Scale Synthetic Route to Manufacture (−)-Huperzine A | journal=Organic Process Research & Development | date=2012 | volume=16 | issue=4 | pages=635–642 | doi=10.1021/op200360b }}

In 1989, a research study found{{cite journal |vauthors=Ayer WA, Browne LM, Orszanska H, Valenta Z |date=October 1989 |title=Alkaloids of Lycopodium selago. On the identity of selagine with huperzine A and the structure of a related alkaloid. |journal=Canadian Journal of Chemistry |volume=67 |issue=10 |pages=1538–1540 |bibcode=1989CaJCh..67.1538A |doi=10.1139/v89-234}} that the chemical structure of the alkaloid selagine reported in 1960 from a study of Lycopodium slago L.{{cite journal |vauthors=Valenta Z, Yoshimura H, Rogers EF, Ternbah M, Wiesner K |date=January 1960 |title=The structure of selagine. |journal=Tetrahedron Letters |volume=1 |issue=31 |pages=26–33 |doi=10.1016/S0040-4039(01)99300-1}} (analyzed using 60-MHz NMR) was identical to that of Huperzine A.

Huperzine A has been investigated as a possible treatment for diseases characterized by neurodegeneration such as Alzheimer's disease,{{cite journal |vauthors=Zangara A |date=June 2003 |title=The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer's disease |journal=Pharmacology, Biochemistry, and Behavior |volume=75 |issue=3 |pages=675–686 |doi=10.1016/S0091-3057(03)00111-4 |pmid=12895686 |s2cid=36435892}}{{cite journal |vauthors=Bai DL, Tang XC, He XC |date=March 2000 |title=Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease |journal=Current Medicinal Chemistry |volume=7 |issue=3 |pages=355–374 |doi=10.2174/0929867003375281 |pmid=10637369}} 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,{{cite journal |vauthors=Laver K, Dyer S, Whitehead C, Clemson L, Crotty M |date=April 2016 |title=Interventions to delay functional decline in people with dementia: a systematic review of systematic reviews |journal=BMJ Open |volume=6 |issue=4 |pages=e010767 |doi=10.1136/bmjopen-2015-010767 |pmc=4854009 |pmid=27121704}} 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,{{cite journal |vauthors=Fan F, Liu H, Shi X, Ai Y, Liu Q, Cheng Y |date=2022-02-01 |title=The Efficacy and Safety of Alzheimer's Disease Therapies: An Updated Umbrella Review |journal=Journal of Alzheimer's Disease |volume=85 |issue=3 |pages=1195–1204 |doi=10.3233/JAD-215423 |pmid=34924395 |s2cid=245311001}} 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.

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.{{cite journal |vauthors=Lallement G, Baille V, Baubichon D, Carpentier P, Collombet JM, Filliat P, Foquin A, Four E, Masqueliez C, Testylier G, Tonduli L, Dorandeu F |date=May 2002 |title=Review of the value of huperzine as pretreatment of organophosphate poisoning |journal=Neurotoxicology |volume=23 |issue=1 |pages=1–5 |doi=10.1016/s0161-813x(02)00015-3 |pmid=12164543|bibcode=2002NeuTx..23....1L }}{{cite journal |vauthors=Liu L, Sun JX |date=March 2005 |title=[Advances on study of organophosphate poisoning prevented by Huperzine A] |url=https://europepmc.org/article/med/15952670 |journal=Wei Sheng Yan Jiu = Journal of Hygiene Research |language=Chinese |volume=34 |issue=2 |pages=224–226 |pmid=15952670}}

{{Reflist}}

• [http://www.proteopedia.org/wiki/index.php/AChE_inhibitors_and_substrates AChE inhibitors and substrates] in Proteopedia

{{Antidementia}}

{{Acetylcholine metabolism and transport modulators}}

{{Ionotropic glutamate receptor modulators}}

Category:Acetylcholinesterase inhibitors

Category:Enones

Category:Conjugated dienes

Category:2-Pyrones

Category:NMDA receptor antagonists

Category:Nootropics

Category:Sesquiterpene alkaloids

Category:Treatment of Alzheimer's disease