Huperzine A Explained

Huperzine A is a naturally-occurring sesquiterpene alkaloid compound found in the firmoss Huperzia serrata and in varying quantities in other food Huperzia species, including H. elmeri, H. carinat, and H. aqualupian.[1] 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.[2] 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.

Pharmacological effects

Huperzine A is extracted from Huperzia serrata.[3] It is a reversible acetylcholinesterase inhibitor[4] [5] [6] [7] and NMDA receptor antagonist[8] that crosses the blood–brain barrier.[9] 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).[10]

Huperzine A has been investigated as a possible treatment for diseases characterized by neurodegeneration such as Alzheimer's disease,[11] 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,[12] 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,[13] 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.[14] 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.[15]

Drug interactions

Huperzine A may have additive effects if taken with drugs causing bradycardia, such as beta-blockers,[16] 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.[17]

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. However, according to sds sheet, the LD50 in rat is 15mg/kg, which fail to be consistent with previous claim and suggests to take huperazine with caution. The extract is active for 6 hours at a dose of 2 μg/kg with no remarkable side effects.[18]

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.[19] [20]

Synthesis

Two scalable and efficient total syntheses of huperzine A have been reported.[21] [22]

External links

Notes and References

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

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