Huperzine A

Last Updated: September 28 2022

Huperzine-A is a cognitive enhancer that inhibits an enzyme that degrades the learning neurotransmitter, acetylcholine; due to this, a relative increase occurs. It belongs to the cholinergics class of molecules, and may be useful in fighting cognitive decline in the elderly. May need to be cycled.

Huperzine A is most often used for




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    1.

    Structure and Sources

    1.1

    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 benzo{3,3,1}ring system with a ethylidene group attached to it. The (-)Huperzine stereoisomer is more bioactive than the (+)Huperzine Isomer.[2][4]

    1.2

    Isomers

    Huperzine-B is a congener (like compound) to that of Huperzine-A with a similar pharmacodynamic profile. Huperzine-B is less potent acutely[5] but has a longer dissiciation and subsequently a greater potential safety index and therapeutic index.[6] It is also an NMDA antagonist[5] and neural anti-oxidant.[7] It is currently being chemically modified to increase potency without risking the longer dissociation.[8][9]

    2.

    Pharmacology

    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.[10][11] It shows a biphasic response of a rapid serum increase followed by a slower excretion rate[10] and has an alpha and beta half-life of 21.13+/-7.28 and 716.25+/-130.18 min, respectively.[11] These half-lifes were noted to be different in another study though, in which Huperzine-A fitted a one-compartment model at 0.99mg.[10]

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

    3.

    Neurology

    3.1

    Cholinergic Neurotransmission

    Huperzine-A's most renowned action is that of an acetylcholinesterase inhibitor. Specifically, it can inhibit the G4 isoform of acetylcholinesterase which is highly prevalent in mammalian brains.[12] It is of greater or equal potency to other acetylcholinesterase inhibitors such as Tacrine or Rivastigmine.[12] It has a high affinity for acetylcholinesterase as an inhibitor, and a slow dissociation constant which enables a long active half-life.[13]

    It may be preferable for usage as a cholinergic since it has been reported to have less cholinergic-related side-effects,[14] 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.[15][16]

    3.2

    Neuroprotection

    In addition to acetylcholinesterase inhibition, it can also be seen as neuroprotective against glutamate,[17] beta-amyloid pigmentation,[18] and H2O2-induced toxicity.[19]

    Huperzine-A can also block the NMDA receptor ion channel without psychomimetic side-effects.[20]

    3.3

    Neurogenesis

    Huperzine-A is able to promote proliferation of hippocampal neural stem cells (NSCs) at a concentration of 1μM for 48 hours (which is more potent than 10-100μM) to 125% of control secondary to activating the ERK pathway,[21] and this neurogenesis was confimed in vivo with injections of 0.2mg/kg of huperzine-A for 4 weeks (about a 25% increase in BrdU stained cells, affecting both newborn and adult mice).[21]

    Appears to promote neurogenesis in biologically relevant dosages

    4.

    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).[13] 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
    6.^Rajendran V, Saxena A, Doctor BP, Kozikowski APSynthesis of more potent analogues of the acetylcholinesterase inhibitor, huperzine BBioorg Med Chem Lett.(2002 Jun 3)
    8.^Feng S, Wang Z, He X, Zheng S, Xia Y, Jiang H, Tang X, Bai DBis-huperzine B: highly potent and selective acetylcholinesterase inhibitorsJ Med Chem.(2005 Feb 10)
    9.^He XC, Feng S, Wang ZF, Shi Y, Zheng S, Xia Y, Jiang H, Tang XC, Bai DStudy on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunctional huperzine BBioorg Med Chem.(2007 Feb 1)
    10.^Qian BC, Wang M, Zhou ZF, Chen K, Zhou RR, Chen GSPharmacokinetics of tablet huperzine A in six volunteersZhongguo Yao Li Xue Bao.(1995 Sep)
    11.^Li YX, Zhang RQ, Li CR, Jiang XHPharmacokinetics of huperzine A following oral administration to human volunteersEur J Drug Metab Pharmacokinet.(2007 Oct-Dec)
    15.^Boudinot E, Taysse L, Daulon S, Chatonnet A, Champagnat J, Foutz ASEffects of acetylcholinesterase and butyrylcholinesterase inhibition on breathing in mice adapted or not to reduced acetylcholinesterasePharmacol Biochem Behav.(2005 Jan)
    16.^Lane RM, Potkin SG, Enz ATargeting acetylcholinesterase and butyrylcholinesterase in dementiaInt J Neuropsychopharmacol.(2006 Feb)
    21.^Ma T, Gong K, Yan Y, Zhang L, Tang P, Zhang X, Gong YHuperzine A promotes hippocampal neurogenesis in vitro and in vivoBrain Res.(2013 Apr 19)