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]
3.3
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
- ^Howes MJ, Perry NS, Houghton PJPlants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disordersPhytother Res.(2003 Jan)
- ^Ha GT, Wong RK, Zhang YHuperzine a as potential treatment of Alzheimer's disease: an assessment on chemistry, pharmacology, and clinical studiesChem Biodivers.(2011 Jul)
- ^Ma X, Gang DRIn vitro production of huperzine A, a promising drug candidate for Alzheimer's diseasePhytochemistry.(2008 Jul)
- ^Total Synthesis of (−)-Huperzine A
- ^Wang XD, Chen XQ, Yang HH, Hu GYComparison of the effects of cholinesterase inhibitors on {3H}MK-801 binding in rat cerebral cortexNeurosci Lett.(1999 Sep 3)
- ^Rajendran V, Saxena A, Doctor BP, Kozikowski APSynthesis of more potent analogues of the acetylcholinesterase inhibitor, huperzine BBioorg Med Chem Lett.(2002 Jun 3)
- ^Zhang HY, Tang XCHuperzine B, a novel acetylcholinesterase inhibitor, attenuates hydrogen peroxide induced injury in PC12 cellsNeurosci Lett.(2000 Sep 29)
- ^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)
- ^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)
- ^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)
- ^Li YX, Zhang RQ, Li CR, Jiang XHPharmacokinetics of huperzine A following oral administration to human volunteersEur J Drug Metab Pharmacokinet.(2007 Oct-Dec)
- ^Effects of huperzine A on acetylcholinesterase isoforms in vitro: comparison with tacrine, donepezil, rivastigmine and physostigmine
- ^Chemistry, Pharmacology, and Clinical Efficacy of the Chinese Nootropic Agent Huperzine A
- ^Development of huperzine A and B for treatment of Alzheimer’s disease
- ^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)
- ^Lane RM, Potkin SG, Enz ATargeting acetylcholinesterase and butyrylcholinesterase in dementiaInt J Neuropsychopharmacol.(2006 Feb)
- ^Ved HS, Koenig ML, Dave JR, Doctor BPHuperzine A, a potential therapeutic agent for dementia, reduces neuronal cell death caused by glutamateNeuroreport.(1997 Mar 3)
- ^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
- ^Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine
- ^The NMDA receptor ion channel: a site for binding of Huperzine A
- ^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)