Huperzine-A

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Huperzine-A is a compound extracted from the herbs of the Huperziceae family. It is known as an acetylcholinesterase inhibitor, which means that it stops an enzyme from breaking down acetylcholine which results in increases in acetylcholine.

Acetylcholine is known as the learning neurotransmitter, and is involved in muscle contraction as well. Increasing levels of acetylcholine is routinely used as a technique amongst weight-lifters and scholars.

Huperzine-A appears to be a relatively safe compound from animal studies of toxicity and studies in humans showing no side-effects at dosages routinely supplemented with. Huperzine-A is in preliminary trials for usage in fighting Alzheimer's Disease as well.

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Typical dosages of Huperzine-A for neuroprotection are 50mcg taken up to twice daily.

More salient effects of Huperzine-A for performance or cognition are typically 200mcg, taken up to twice daily.

Edit1. Structure and sources

Huperzine-A is a compound found in the plant families of Huperziaceae, Lycopodiaceae, and Selaginella.^[1][2] It is normally extracted from the plants of the Huperziaceae family, but can be propogated in other cell lines for cheap mass production.^[3] This synthetic Huperzine-A has bioequivlance to the natural version.

Its chemical structure is a pyridone moiety fused to a benzo3,3,1ring system with a ethylidene group attached to it. The (-)Huperzine stereoisomer is more bioactive than the (+)Huperzine Isomer.^[2][4]

Edit2. Pharmacodynamics and Pharmacokinetics

Orally administered tablets tend to appear in the blood in 15 minutes or less and peak at a variable time around 70 minutes post-ingestion.^[5][6] It shows a biphasic response of a rapid serum increase followed by a slower excretion rate^[5] and has an alpha and beta half-life of 21.13+/-7.28 and 716.25+/-130.18 min, respectively.^[6] These half-lifes were noted to be different in another study though, in which Huperzine-A fitted a one-compartment model at 0.99mg.^[5]

It appears in the cerebrospinal fluid and is easily able to cross the blood-brain barrier.^[2]

Edit3. Effects on Neurology

Huperzine-A's most renowned action is that of an acetylcholinesterase inhibitor. Specifically, it can inhibit the G4 isoform of acetylcholine which is highly prevalent in mammalian brains.^[7] It is of greater or equal potency to other Acetylcholinesterase inhibitors such as Tacrine or Rivastigmine.^[7]

It has a high affinity for acetylcholinesterase as an inhibitor, and a slow dissociation constant which enables a long active half-life.^[8]

In addition to acetylcholinesterase inhibition, it can also be seen as neuroprotective against glutamate,^[9] beta-amyloid pigmentation,^[10] and H2O2-induced toxicity.^[11] Huperzine-A can also block the NDMA receptor ion channel without psychomimetic side-effects.^[12]

It may be preferable for usage as a cholinergic since it has been reported to have less cholinergic-related side-effects,^[13] possibly through its high affinity for brain G4 acetylcholine resulting in less availability for systemic butrylcholine inhibition, which leads to various systemic effects which may be seen as side effects.^[14][15]

Edit4. Huperzine-B

Huperzine-B is a congener (like compound) to that of Huperzine-A with a similar pharmacodynamic profile. Huperzine-B is less potent acutely^[16]MK-801 binding in rat cerebral cortex|published=1999 Sep 3|authors=Wang XD, Chen XQ, Yang HH, Hu GY|journal=Neurosci Lett]MK-801 binding in rat cerebral cortex|published=1999 Sep 3|authors=Wang XD, Chen XQ, Yang HH, Hu GY|journal=Neurosci Lett]MK-801 binding in rat cerebral cortex] but has a longer dissiciation and subsequently a greater potential safety index and therapeutic index.^[17] It is also an NMDA antagonist^[16]MK-801 binding in rat cerebral cortex|published=1999 Sep 3|authors=Wang XD, Chen XQ, Yang HH, Hu GY|journal=Neurosci Lett]MK-801 binding in rat cerebral cortex|published=1999 Sep 3|authors=Wang XD, Chen XQ, Yang HH, Hu GY|journal=Neurosci Lett]MK-801 binding in rat cerebral cortex] and neural anti-oxidant.^[18]

It is currently being chemically modified to increase potency without risking the longer dissociation.^[19][20]

Edit5. Safety and Toxicity

A study in rats concluded that the LD50 (dose needed to acutely kill half a population of rats) was 2-4mg/kg bodyweight in females and >4mg/kg in males whereas others pinpoint the level at around 3mg/kg bodyweight over a longer period (180 days).^[8] The NOAEL (No Observable Adverse Effects Limit) is postulated to be 1mg/kg for females rats, 3mg/kg for males rats, and 0.1mg/kg for canines. No toxicity data for humans currently exists.

References

1. Howes MJ, Perry NS, Houghton PJ. Plants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disorders. Phytother Res. (2003)
2. Ha GT, Wong RK, Zhang Y. Huperzine a as potential treatment of Alzheimer's disease: an assessment on chemistry, pharmacology, and clinical studies. Chem Biodivers. (2011)
3. Ma X, Gang DR. In vitro production of huperzine A, a promising drug candidate for Alzheimer's disease. Phytochemistry. (2008)
4. Total Synthesis of (−)-Huperzine A
5. Qian BC, et al. Pharmacokinetics of tablet huperzine A in six volunteers. Zhongguo Yao Li Xue Bao. (1995)
6. Li YX, et al. Pharmacokinetics of huperzine A following oral administration to human volunteers. Eur J Drug Metab Pharmacokinet. (2007)
7. Effects of huperzine A on acetylcholinesterase isoforms in vitro: comparison with tacrine, donepezil, rivastigmine and physostigmine
8. Chemistry, Pharmacology, and Clinical Efficacy of the Chinese Nootropic Agent Huperzine A
9. Ved HS, et al. Huperzine A, a potential therapeutic agent for dementia, reduces neuronal cell death caused by glutamate. Neuroreport. (1997)
10. Huperzine A regulates amyloid precursor protein processing via protein kinase C and mitogen-activated protein kinase pathways in neuroblastoma SK-N-SH cells over-expressing wild type human amyloid precursor protein 695
11. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine
12. The NMDA receptor ion channel: a site for binding of Huperzine A
13. Development of huperzine A and B for treatment of Alzheimer’s disease
14. Boudinot E, et al. Effects of acetylcholinesterase and butyrylcholinesterase inhibition on breathing in mice adapted or not to reduced acetylcholinesterase. Pharmacol Biochem Behav. (2005)
15. Lane RM, Potkin SG, Enz A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int J Neuropsychopharmacol. (2006)
16. Comparison of the effects of cholinesterase inhibitors on [3H
17. Rajendran V, et al. Synthesis of more potent analogues of the acetylcholinesterase inhibitor, huperzine B. Bioorg Med Chem Lett. (2002)
18. Zhang HY, Tang XC. Huperzine B, a novel acetylcholinesterase inhibitor, attenuates hydrogen peroxide induced injury in PC12 cells. Neurosci Lett. (2000)
19. Feng S, et al. Bis-huperzine B: highly potent and selective acetylcholinesterase inhibitors. J Med Chem. (2005)
20. He XC, et al. Study on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunctional huperzine B. Bioorg Med Chem. (2007)

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