Huperzine A
Scientific Name(s):Isolated from Huperzia serrata (Thunb.) Trev. Family: Lycopodiaceae (club moss)
Common Name(s): Qian Ceng Ta = Chien Tseng Ta . Other products that contain huperzine A are Memorzine , Brainmax , Neuroflow
Clinical Overview
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Uses of Huperzine A
Historically, huperzine A has been used for the treatment of bruises, strains, swelling, schizophrenia, and fevers. It is being studied for potential use in treating Alzheimer disease and preventing nerve gas poisoning.
Huperzine A Dosing
Huperzine A in pure form has been studied at oral doses of 0.2 to 0.4 mg/day for Alzheimer disease. It also has been administered IM at 0.06 to 0.1 mg/day for the same indication. 1 , 2 , 3 , 4
Contraindications
Contraindications have not yet been identified.
Pregnancy/Lactation
Information regarding safety and efficacy in pregnancy and lactation is lacking. Avoid use.
Huperzine A Interactions
None well documented.
Huperzine A Adverse Reactions
No data.
Toxicology
There is little published evidence concerning its safety.
Botany
Huperzine A is isolated from the club moss Huperzia serrata , also known as Lycopodium serratum Thunb. Club mosses are primitive, vascular plants that were dominant in the Carboniferous period when they grew to the size of trees and contributed to the coal deposits then being formed. They differ from true mosses by having specialized fluid-conducting tissues, but like mosses, they reproduce by means of spores, which are either clustered into small cones or borne in the axils of the small scale-like leaves. Some species of Lycopodium are called ground pine or creeping cedar, especially those that resemble miniature hemlocks with flattened fan-shaped branches often used for Christmas decorations.
History
The club moss H. serrata has been used in Chinese folk medicine under the name Qian Ceng Ta, for the treatment of bruises, strains, swelling, and schizophrenia. 5 It also has been used for fever.
Chemistry
The novel alpha-pyridone alkaloids of huperzines A and B were isolated in 1986 from H. serrata . 6 The identity of huperzine A with selagine, an alkaloid isolated earlier from a Lycopodium species, was established in 1989. The structure of selagine originally proposed was incorrect. 7 X-ray crystallography provided a final confirmation of the structure, 8 and nuclear magnetic resonance (NMR) assignments have been made. 9 The huperzine structure is distinctly different from many of the alkaloids isolated from club mosses, 10 though systematic investigations of Chinese club mosses have found huperzine A in numerous species. 11 The yield of huperzine A from H. serrata is reported to be about 0.1% on a dry weight basis. 12 A number of syntheses of huperzine A have been published, 5 , 13 , 14 , 15 and the structure-activity relationships of analogs with regard to cholinesterase activity have been investigated in detail. 16
Huperzine A Uses and Pharmacology
Huperzine A is a specific, reversible inhibitor of acetylcholinesterase and is active at low nanomolar concentrations. A crystallographic analysis of a huperzine A complex with the enzyme from an electric eel has been published. 17 More detailed analyses of huperzine B and the enantiomer of natural huperzine A also have been made. 18 These structural biological investigations have assisted in an understanding of the pharmacophore and in rational design of analogs. 19 , 20 , 21 , 22
Treatment of Alzheimer disease (AD)Animal data
Huperzine A's profile vs 2 cholinesterase isoforms from different brain regions has been compared with the other cholinesterase inhibitors tacrine, donepezil, rivastigmine, and physostigmine. Huperzine A preferentially inhibited the tetrameric (G4) form of cholinesterase in all brain regions, while the other drugs were most active against the monomeric (G1) form. 23 Racemic huperzine A was less active vs rat cholinesterase in vivo than the natural compound, 24 which is consistent with the findings of the crystallographic studies. 18
In neuronal cell cultures, huperzine A reduces cell death caused by glutamate, 25 nitric oxide, 26 or hydrogen peroxide. 27 The latter effect involves the apoptosis-related genes p53 and bcl-2. 28 Similarly, oxygen and glucose deprivation of pheochromocytoma cells leads to apoptosis through regulation of the same genes; these effects were blocked by huperzine A and donepezil. 29 , 30 Further studies of apoptosis and the role played by caspase-3 in cultured rat cortical neurons found that huperzine improved neuronal survival by inhibiting the mitochondrial apoptotic pathway. 31
Patch-clamp studies of rat hippocampal neurons have demonstrated that huperzine A is capable of inhibiting N -methyl-D-aspartate (NMDA)-induced currents while having no effect on kainate- or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced currents. 32 Other studies by the same laboratory found a very weak inhibition of potassium currents by huperzine A. 33 , 34
Huperzine A was capable of displacing the NMDA receptor ligand MK-801 from rat brain membranes with an IC-50 of 37 micromolar. Tacrine was also weakly active at the same concentration; however, binding inhibition and cholinesterase potencies did not correlate. 35 Furthermore, both enantiomers of huperzine A had similar potency in this assay. 36 Spermine shifted the dose response curve to the right, suggesting that huperzine A is a weak, noncompetitive NMDA receptor antagonist acting at polyamine binding sites. 37
Studies with beta-amyloid peptide fragments have shown huperzine A to oppose its suppression of long-term potentiation in rat hippocampal slices, 38 protect against induction of oxidative injury in pheochromocytoma cells, 39 , 40 and block apoptosis in rat cortical neurons. 41 This protection was not stereospecific, indicating that cholinesterase was probably not involved in these neuroprotective effects. 42 In a whole animal model, huperzine A reversed the negative effects of beta-amyloid protein on maze learning. 43
Other whole animal models of learning and memory have shown huperzine A to have activity. Huperzine A protected gerbils from neuronal damage and cognitive deficits produced by transient ischemia. 44 Similar results were found in rats with hypoxic/ischemic brain injuries 45 and by chronic cerebral hypoperfusion. 46 Scopolamine-induced impaired maze performance was improved by huperzine A, while tacrine and E2020 were less effective. 47 , 48 In macaques treated with reserpine, yohimbine, or scopolamine, huperzine A improved working memory. 49 , 50 It also was effective in improving memory in otherwise untreated, aged macaques. 50
Clinical dataA variety of cholinergic agents, including cholinesterase inhibitors, have been studied for symptomatic treatment of AD. 51 Human clinical studies of huperzine A for AD have been conducted only in China. 52 , 53 The pharmacokinetics of huperzine A in humans was evaluated by high pressure liquid chromatography; the drug was rapidly absorbed, widely distributed to tissue, and eliminated at a moderate rate. 54 An early efficacy study in 56 multi-infarct and senile dementia patients and 104 patients with senile or presenile memory disorders found efficacy, as evaluated by the Wechsler memory scale, at doses of 0.05 and 0.03 mg twice daily, respectively. Side effects were minimal, but treatment was limited to 2 to 4 weeks. 55 A double-blind, placebo-controlled trial in 50 Alzheimer patients over 8 weeks found improvement in memory, cognitive, and behavioral scores with 0.2 mg of huperzine A twice daily. 56 A similar study of 60 AD patients over 60 days compared tablet and capsule formulations, finding both dosage forms comparably effective in reducing oxygen-free radicals and improving psychological ratings. 57 A larger randomized study (N = 202) of mild to moderate AD patients found that huperzine A improved cognitive function, activity of daily life, and noncognitive disorders over a 12-week period compared with placebo. 58
Soman nerve gas antidoteHuperzine A's potent inhibition of cholinesterase also has made it a candidate for prevention of poisoning by the nerve agent soman and other organophosphates. In contrast to pyridostigmine, huperzine A crosses the blood-brain barrier and, therefore, may be effective in preventing seizures and other neuropathology caused by soman. 59
Animal dataIn mice, huperzine A provided longer lasting protection against soman poisoning than pyridostigmine (6 hours vs 90 minutes). 60 In rats, it protected against soman-induced seizures and lethality. 61
Clinical dataResearch reveals no clinical data regarding the use of huperzine A as a soman gas antidote.
Other usesHuperzine A is selective for brain acetyl cholinesterase over plasma butyryl cholinesterase. 62 It possesses analgesic properties in common with other cholinergic drugs. 63 The antinociceptive actions of huperzine were reduced by antisense inhibition of the M1 muscarinic receptor in mice and by scopolamine but not naloxone. 63 Finally, huperzine A was isolated as the insecticidal and antifeedant principle from a New Zealand club moss. 64
Dosage
Huperzine A in pure form has been studied at oral doses of 0.2 to 0.4 mg/day for Alzheimer disease. It also has been administered IM at 0.06 to 0.1 mg/day for the same indication. 1 , 2 , 3 , 4
Pregnancy/Lactation
Information regarding safety and efficacy in pregnancy and lactation is lacking. Avoid use.
Interactions
None well documented.
Adverse Reactions
Research reveals little or no information regarding adverse reactions with the use of this product.
Toxicology
Huperzine A is approved for use as a drug for the treatment of AD in China; however, it is regulated as an herbal supplement in the United States. 65 Several firms (Solgar, Pharmavite, GNC, Kingchem, and NOW Foods) filed the required premarket notifications with the FDA between 1997 and 2000 for huperzine A products manufactured in China from natural sources. 66 The marketing of a pure pharmaceutical compound as a supplement raises questions about the scope and intent of the Dietary Supplement Health and Education Act of 1994 legislation that makes this possible. The acute oral LD-50 of huperzine A in rats has been reported as 4.6 mg/kg in an FDA filing. Other FDA filings report oral LD-50 values of 5.2 mg/kg in mice and 26 mg/kg in rats.
Bibliography
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37. Zhang YH, Zhao XY, Chen XQ, Wang Y, Yang HH, Hu GY. Spermidine antagonizes the inhibitory effect of huperzine A on [3H]dizocilpine (MK-801) binding in synaptic membrane of rat cerebral cortex. Neurosci Lett . 2002;319:107-110.
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42. Zhang HY, Liang YQ, Tang XC, He XC, Bai DL. Stereoselectivities of enantiomers of huperzine A in protection against beta-amyloid(25-35)-induced injury in PC12 and NG108-15 cells and cholinesterase inhibition in mice. Neurosci Lett . 2002;317:143-146.
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