Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine

Abstract

Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase (AChE). Compared with tacrine, donepezil, and rivastigmine, HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. HupA has been found to improve cognitive deficits in a broad range of animal models. HupA possesses the ability to protect cells against hydrogen peroxide, β-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53, and caspase-3, protect mitochondria, upregulate nerve growth factor and its receptors, and interfere with amyloid precursor protein metabolism. Antagonizing effects of HupA on N-methyl-D-aspartate receptors and potassium currents may also contribute to its neuroprotection as well. Pharmacokinetic studies in rodents, canines, and healthy human volunteers indicated that HupA was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate with the property of slow and prolonged release after oral administration. Animal and clinical safety tests showed that HupA had no unexpected toxicity, particularly the dose-limiting hepatotoxicity induced by tacrine. The phase IV clinical trials in China have demonstrated that HupA significantly improved memory deficits in elderly people with benign senescent forgetfulness, and patients with Alzheimer disease and vascular dementia, with minimal peripheral cholinergic side effects and no unexpected toxicity. HupA can also be used as a protective agent against organophosphate intoxication.

References

  1. 1

    Bartus RT, Dean RL III, Beer B, Lippa AS . The cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217: 408–14.

    CAS  PubMed  Google Scholar 

  2. 2

    Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH . Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. BMJ 1978; 2: 1457–9.

    CAS  PubMed  Google Scholar 

  3. 3

    Giacobini E . Cholinesterase inhibitors for Alzheimer's disease therapy: from tacrine to future applications. Neurochem Int 1998; 32: 413–9.

    CAS  PubMed  Google Scholar 

  4. 4

    Kumar V . Introduction to cholinesterase inhibitors used in Alzheimer's disease therapy. In: Giacobini E, Becker R editors Alzheimer's disease: therapeutic strategies. Boston: Birkhäuser; 1994. p 99–102.

    Google Scholar 

  5. 5

    Ellis JM . Cholinesterase inhibitors in the treatment of dementia. J Am Osteopath Assoc 2005; 105: 145–58.

    PubMed  Google Scholar 

  6. 6

    Francis PT, Nordberg A, Arnold S . A preclinical view of cholinesterase inhibitors in neuroprotection: do they provide more than symptomatic benefits in Alzheimer's disease? Trends Pharmacol Sci 2005; 26: 104–11.

    CAS  PubMed  Google Scholar 

  7. 7

    Farlow M, Gracon SI, Hershey LA, Lewis KW, Sadowsky CH, Dolan-Ureno J . A controlled trial of tacrine in Alzheimer's disease. JAMA 1992; 268: 2523–9.

    CAS  PubMed  Google Scholar 

  8. 8

    Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SL . A 30–week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. JAMA 1994; 271: 985–91.

    CAS  PubMed  Google Scholar 

  9. 9

    Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT . A 24–week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Neurology 1998; 50: 136–45.

    CAS  PubMed  Google Scholar 

  10. 10

    Wang T, Tang XC . Reversal of scopolamine-induced deficits in radial maze performance by (-)-huperzine A: comparison with E2020 and tacrine. Eur J Pharmacol 1998; 349: 137–42.

    CAS  PubMed  Google Scholar 

  11. 11

    Wang YE, Yue DX, Tang XC . Anticholinesterase activity of huperzine A. Acta Pharmacol Sin 1986; 7: 110–3. Chinese.

    CAS  Google Scholar 

  12. 12

    Zhao Q, Tang XC . Effects of huperzine A on acetylcholinest-erase isoforms in vitro: comparison with tacrine, donepezil, rivastigmine and physostigmine. Eur J Pharmacol 2002; 455: 101–7.

    CAS  PubMed  Google Scholar 

  13. 13

    Liang YQ, Tang XC . Comparative effects of huperzine A, donepezil and rivastigmine on cortical acetylcholine level and acetylcholinesterase activity in rats. Neurosci Lett 2004; 361: 56–9.

    CAS  PubMed  Google Scholar 

  14. 14

    Xu SS, Gao ZX, Weng Z, Du ZM, Xu WA, Yang JS, et al. Efficacy of tablet huperzine A on memory, cognition, and behavior in Alzheimer's disease. Acta Pharmacol Sin 1995; 16: 391–5.

    CAS  Google Scholar 

  15. 15

    Xu SS, Xie HB, Du ZW, Tong ZH, Shi QC, Lu KM, et al. Efficacy of tablet huperzine A on memory and cognition in patients with benign senescent forgetfulness. Chin J Clin Pharmacol Ther 1997; 2: 1–4. Chinese.

    Google Scholar 

  16. 16

    Xu SS, Cai ZY, Qu ZW, Yang RM, Cai YL, Wang GQ . Huperzine A in capsules and tablets for treating patients with Alzheimer's disease. Acta Pharmacol Sin 1999; 20: 486–90.

    CAS  Google Scholar 

  17. 17

    Zhang ZX, Wang XD, Chen QT, Shu L, Wang JZ, Shan GL . Clinical efficacy and safety of huperzine alpha in treatment of mild to moderate Alzheimer disease, a placebo-controlled, double-blind, randomized trial. Natl Med J China 2002; 82: 941–4. ( Chinese).

    CAS  Google Scholar 

  18. 18

    Ellman GL, Courtney KD, Andre V Jr, Featherstone RM . A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961; 7: 88–95.

    CAS  PubMed  Google Scholar 

  19. 19

    Wang H, Tang XC . Anticholinesterase effects of huperzine A, E2020, and tacrine in rats. Acta Pharmacol Sin 1998; 19: 27–30.

    CAS  Google Scholar 

  20. 20

    Wang RP, Zhao ZK, Hu LL . Effects of huperzine A on the cognition and daily life ability in vascular dementia: 36 cases for 6 months follow-up study. Chin J Clin Rehabil 2004; 8: 3892. Chinese.

    Google Scholar 

  21. 21

    Ogura H, Kosasa T, Kuriya Y, Yamanishi Y . Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro. Methods Find Clin Pharmacol 2000; 22: 609–13.

    CAS  Google Scholar 

  22. 22

    Cheng DH, Ren H, Tang XC . Huperzine A, a novel promising acetylcholinesterase inhibitor. Neuoreport 1996; 8: 97–101.

    CAS  Google Scholar 

  23. 23

    Gong ZH, Qin BY . The inhibitory characteristics of fordine on cholinesterases. Bull Acad Mil Med Sci 1986; 10: 451–6. Chinese.

    Google Scholar 

  24. 24

    Hao XY, Gong ZH, Qin BY . Effects of huperzine A on cholinesterase isoenzymes in plasma of mice and dogs. Acta Pharmacol Sin 1988; 9: 312–6. Chinese.

    CAS  Google Scholar 

  25. 25

    Darvesh S, Arora RC, Martin E, Magee D, Hopkins DA, Armour JA . Cholinesterase inhibitors modify the activity of intrinsic cardiac neurons. Exp Neurol 2004; 188: 461–70.

    CAS  PubMed  Google Scholar 

  26. 26

    Cheng DH, Tang XC . Comparative studies of huperzine A, E2020, and tacrine on behavior and cholinesterase activities. Pharmacol Biochem Behav 1998; 60: 377–86.

    CAS  PubMed  Google Scholar 

  27. 27

    Brimijoin S . Molecular forms of acetylcholinesterase in brain, nerve and muscle: nature, localization and dynamics. Prog Neurobiol 1983; 21: 291–322.

    CAS  PubMed  Google Scholar 

  28. 28

    Massoulie J, Bon S . The molecular forms of cholinesterase and acetylcholinesterase invertebrate. Annu Rev Neurosci 1982; 5: 57–106.

    CAS  PubMed  Google Scholar 

  29. 29

    Bon S, Vigny M, Massoulie J . Asymmetric and globular forms of AChE in mammals and birds. Proc Natl Acad Sci USA 1979; 76: 2540–50.

    Google Scholar 

  30. 30

    Grassi J, Vigny M, Massoulie J . Molecular forms of acetylcholinesterase in bovine caudate nucleus and superior cervical ganglion: solubility properties and hydrophobic character. J Neurochem 1982; 387: 457–69.

    Google Scholar 

  31. 31

    Tang XC, de Sarno P, Sugaya K, Giacobini E . Effect of huperzine A, a new cholinesterase inhibitor, on the central cholinergic system of the rat. J Neurosci Res 1989; 24: 276–85.

    CAS  PubMed  Google Scholar 

  32. 32

    Tang XC, Kindel GH, Kozikowski AP, Hanin I . Comparison of the effects of natural and synthetic huperzine A on rat brain cholinergic function in vitro and in vivo. J Ethnopharmacol 1994; 44: 147–55.

    CAS  PubMed  Google Scholar 

  33. 33

    Laganiere S, Corey J, Tang XC, Wülfert E, Hanin I . Acute and chronic studies with the anticholinesterase huperzine A: Effect on central nervous system cholinergic parameters. Neuropharmacology 1991; 30: 763–8.

    CAS  PubMed  Google Scholar 

  34. 34

    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: 143–6.

    CAS  PubMed  Google Scholar 

  35. 35

    Raves ML, Harel M, Pang YP, Silman I, Kozilowski AP, Sussman JL . Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A. Nat Strut Biol 1997; 4: 57–63.

    CAS  Google Scholar 

  36. 36

    Dvir H, Jiang HL, Wong DM, Harel M, Chetrit M, He XC, et al. X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-huperzine A and (-)-huperzine B: structural evidence for an active site rearrangement. Biochemistry 2002; 41: 10810–8.

    CAS  PubMed  Google Scholar 

  37. 37

    Ashani Y, Peggins JO III, Doctor BP . Mechanism of inhibition of cholinesterase by huperzine A. Biochem Biophys Res Commun 1992; 184: 7719–26.

    Google Scholar 

  38. 38

    Pang YP, Kozikowski AP . Prediction of the bonding site of huperzine A in acetylcholinesterase by docking studies. J Computer Aided Mol Des 1994; 8: 669–81.

    CAS  Google Scholar 

  39. 39

    Skolnick AA . Old Chinese herbal medicine used for fever yields possible new Alzheimer disease therapy. JAMA 1997; 277: 776.

    CAS  PubMed  Google Scholar 

  40. 40

    Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, et al. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci USA 1993; 90: 9031–5.

    CAS  PubMed  Google Scholar 

  41. 41

    Saxena A, Qian N, Kovach IM, Kozikowski AP, Pang YP, Vellom DC, et al. Identification of amino acid residues involved in the binding of huperzine A to cholinesterase. Protein Sci 1994; 3: 1770–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, et al. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science 1991; 253: 872–9.

    CAS  PubMed  Google Scholar 

  43. 43

    Lin JH, Hu GY, Tang XC . Facilitatory effect of huperzine A on mouse neuromuscular transmission in vitro. Acta Pharmacol Sin 1996; 17: 299–301.

    CAS  Google Scholar 

  44. 44

    Lin JH, Hu GY, Tang XC . Comparison between huperzine A, tacrine and E2020 on cholinergic transmission at mouse neuromuscular junction in vitro. Acta Pharmacol Sin 1997; 18: 6–10.

    CAS  Google Scholar 

  45. 45

    Zhang GB, Wang MY, Zheng JQ, Tang XC . Facilitation of cholinergic transmission by huperzine A in toad paravertebral ganglia in vitro. Acta Pharmacol Sin 1994; 15: 158–61.

    CAS  Google Scholar 

  46. 46

    Mo N, Dun NJ, Karczmar AG . Facilitation and inhibition of nicotine transmission by eserine in the sympathetic ganglia of the rabbit. Neuropharmacology 1985; 24: 1093–101.

    CAS  PubMed  Google Scholar 

  47. 47

    Wang MY . Enhancement and depression of cholinergic transmission by 9–amino-1,2,3,4–tetrahydroacridine in rat superior cervical ganglia. Chin Pharmacol Bull 1993; 9: 298–300. Chinese.

    CAS  Google Scholar 

  48. 48

    Fayuk D, Yakel JL . Regulation of nicotinic acetylcholine receptor channel function by acetylcholinesterase inhibitors in rat hippocampal CA1 interneurons. Mol Pharmacol 2004; 66: 658–66.

    CAS  PubMed  Google Scholar 

  49. 49

    Yan XF, Lu WH, Lou WJ, Tang XC . Effects of huperzine A and B on skeletal muscle and electroencephalogram. Acta Pharmacol Sin 1987; 8: 117–23. Chinese.

    CAS  Google Scholar 

  50. 50

    Guan LC, Chen SS, Cui QG, Lu WH, Tang XC . The effect of huperzine A on behavior and ECoG in animals. Acta Psychol Sin 1991; 23: 404–11.

    Google Scholar 

  51. 51

    Guan LC, Chen SS, Lu WH, Tang XC . The effect of huperzine Aon behavior and ECoG in animals. Acta Pharmacol Sin 1991; 12: 496–500. Chinese.

    Google Scholar 

  52. 52

    Patil KD, Buerki RA, Patil PN . Potentiation of acetylcholine action by huperzine-A and physostigmine on some vertebrate effectors, including human iris sphincter muscle. J Ocul Pharmacol Ther 2003; 19: 135–43.

    CAS  PubMed  Google Scholar 

  53. 53

    de Sarno P, Pomponi M, Giacobini E, Tang XC, Williams E . The effect of heptylphysostigmine, a new cholinesterase inhibitor, on the central cholinergic system of the rat. Neurochem Res 1989; 14: 971–7.

    CAS  PubMed  Google Scholar 

  54. 54

    Nordberg A, Nilsson L, Adem A, Hardy J, Winblad B . Effect of THA on acetylcholine release and cholinergic receptor in Alzheimer brains. In: Giacobini E, Becker R editors Current research in Alzheimer therapy. New York: Taylor and Francis; 1988. p 247–58.

    Google Scholar 

  55. 55

    Hallak M, Giacobini E . Physostigmine, tacrine and metrifonate. The effect of multiple doses on acetylcholine metabolism in rat brain. Neuropharmacology 1989; 28: 199–206.

    CAS  PubMed  Google Scholar 

  56. 56

    Zhu XD, Giacobini E . Second generation cholinesterase inhibitors: effect of (L)-huperzine A on cortical biogenic amines. J Neurosci Res 1995; 41: 828–35.

    CAS  PubMed  Google Scholar 

  57. 57

    Bowen DM, Allen SJ, Benton JS, Goodhardt MJ, Haan EA, Palmer AM, et al. Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy in Alzheimer's disease. J Neurochem 1983; 41: 266–72.

    CAS  PubMed  Google Scholar 

  58. 58

    Lu WH, Shou J, Tang XC . Improving effect of huperzine A on discrimination performance in aged rats and adult rats with experimental cognitive impairment. Acta Pharmacol Sin 1988; 9: 11–5. Chinese.

    CAS  Google Scholar 

  59. 59

    Tang XC, Han YF, Chen XP, Zhu XD . Effects of huperzine A on learning and retrieval process of discrimination performance in rats. Acta Pharmacol Sin 1986; 7: 507–11. Chinese.

    CAS  Google Scholar 

  60. 60

    Zhu XD, Tang XC . Facilitatory effects of huperzine A and B on learning and memory of spatial discrimination in mice. Acta Pharmacol Sin 1987; 22: 812–7. Chinese.

    CAS  Google Scholar 

  61. 61

    Zhu XD, Tang XC . Improvement of impaired memory in mice by huperzine A and huperzine B. Acta Pharmacol Sin 1988; 9: 492–7. Chinese.

    CAS  Google Scholar 

  62. 62

    Gao Y, Tang XC, Guan LC, Kuang PZ . Huperzine A reverses scopolamine- and muscimol-induced memory deficits in chick. Acta Pharmocol Sin 2000; 21: 1169–73.

    CAS  Google Scholar 

  63. 63

    Liu J, Zhang HY, Tang XC, Wang B, He XC, Bai DL . Effects of synthetic (-)-huperzine A on cholinesterase activities and mouse water maze performance. Acta Pharmacol Sin 1998; 19: 413–6.

    CAS  Google Scholar 

  64. 64

    Ye JW, Shang YZ, Wang ZM, Tang XC . Huperzine A ameliorates the impaired memory of aged rat in the Morris water maze performance. Acta Pharmacol Sin 2000; 21: 65–9.

    CAS  PubMed  Google Scholar 

  65. 65

    Xiong ZQ, Tang XC . Effect of huperzine A, a novel acetylcholinesterase inhibitor, on radial maze performance in rats. Pharmacol Biochem Behav 1995; 51: 415–9.

    CAS  PubMed  Google Scholar 

  66. 66

    Ye JW, Cai JX, Wang LM, Tang XC . Improving effects of huperzine A on spatial working memory in aged monkeys and young adult monkeys with experimental cognitive impairment. J Pharmacol Exp Ther 1999; 288: 814–9.

    CAS  PubMed  Google Scholar 

  67. 67

    Ou LY, Tang XC, Cai JX . Effect of huperzine A on working memory in reserpine- or yohimbine-treated monkeys. Eur J Pharmacol 2001; 433: 151–6.

    CAS  Google Scholar 

  68. 68

    Vincent GP, Rumennik L, Cumin R, Martin J, Sepinwall J . The effects of huperzine A, an acetylcholinesterase inhibitor, on the enhancement of memory in mice, rats and monkeys. Neurosci Abs 1987; 13: 844.

    Google Scholar 

  69. 69

    Xiong ZQ, Han YF, Tang XC . Huperzine A ameliorates the spatial working memory impairments induced by AF64A. Neuroreport 1995; 6: 2221–4.

    Google Scholar 

  70. 70

    Zhang C, Wang SZ, Zuo PP, Cui X, Cai J . Protective effect of tetramethylpyrazine on learning and memory function in D-galactose-lesioned mice. Chin Med Sci J 2004; 19: 180–4.

    CAS  PubMed  Google Scholar 

  71. 71

    Tang XC, Xiong ZQ, Qian BC, Zhou ZF, Zhang CC . Cognitive improvement by oral huperzine A: a novel acetylcholinesterase inhibitor. In: Giacobini E, Becker R editors Alzheimer therapy: therapeutic strategies. Boston: Birkhäuser; 1994. p 113–9.

    Google Scholar 

  72. 72

    Xiong ZQ, Cheng DH, Tang XC . Effects of huperzine A on nucleus basalis magnocellularis lesion-induced spatial working memory deficit. Acta Pharmacol Sin 1998; 19: 128–32.

    CAS  Google Scholar 

  73. 73

    Coyle JT, Price DL, Delong MR . Alzheimer's disease: A disorder of cortical cholinergic innervation. Science 1983; 219: 1184–90.

    CAS  PubMed  Google Scholar 

  74. 74

    Walsh TJ, Stackman RW . Modulation of memory by benzodiaz-epineacetylcholine interactions. In: Butcher LL, Decker MW, Levin ED editors Neurotransmitter interactions and cognitive function. Boston: Birkhäuser; 1992. p 312–28.

    Google Scholar 

  75. 75

    Wenk GL, Pierce DJ, Struble RG, Price DL, Cork LC . Aged-related changes in multiple neurotransmitter systems in the monkey brain. Neurobiol Aging 1989; 10: 11–9.

    CAS  PubMed  Google Scholar 

  76. 76

    Wang R, Zhang HY, Tang XC . Huperzine A attenuates cognitive dysfunction and neuronal degeneration caused by beta-amyloid protein-(1–40) in rat. Eur J Pharmacol 2001; 21: 149–56.

    Google Scholar 

  77. 77

    Bliss TVP, Collingridge GL . A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993; 361: 31–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Sucher NJ, Awobuluyi M, Choi YB, Lipton SA . NMD A receptors: from genes to channels. Trends Pharmacol Sci 1996; 17: 348–55.

    CAS  PubMed  Google Scholar 

  79. 79

    Chen QS, Kagan BL, Hirakura Y, Xie CW . Impairment of hippocampal long-term potentiation by Alzheimer amyloid beta-peptides. J Neurosci Res 2000; 60: 65–72.

    CAS  PubMed  Google Scholar 

  80. 80

    Ye L, Qiao JT . Suppressive action produced by beta-amyloid peptide fragment 31–35 on long-term potentiation in rat hippocampus is N-methyl-D-aspartate receptor-independent: it's offset by (-)-huperzine A. Neurosci Lett 1999; 275: 187–90.

    CAS  PubMed  Google Scholar 

  81. 81

    Wang LM, Han YF, Tang XC . Huperzine A improves cognitive deficits caused by chronic cerebral hypoperfusion in rats. Eur J Pharmocol 2000; 398: 65–72.

    CAS  Google Scholar 

  82. 82

    Zhou J, Zhang HY, Tang XC . Huperzine A attenuates cognitive deficits and hippocampal neuronal damage after transient global ischemia in gerbils. Neurosci Lett 2001; 313: 137–40.

    CAS  Google Scholar 

  83. 83

    Wang LS, Zhou J, Shao XM, Tang XC . Huperzine A attenuates cognitive deficits and brain injury in neonatal rats after hypoxiaischemia. Brain Res 2002; 949: 162–70.

    CAS  Google Scholar 

  84. 84

    Butterfield DA, Howard B, Yatin S, Koppal T, Drake J, Hensley K, et al. Elevated oxidative stress in models of normal brain aging and Alzheimer's disease. Life Sci 1999; 65: 1883–92.

    CAS  PubMed  Google Scholar 

  85. 85

    Markesbery WR . Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med 1997; 23: 134–47.

    CAS  PubMed  Google Scholar 

  86. 86

    Selkoe DJ, Abraham CR, Podlisny MB, Duffy LK . Isolation of low-molecular-weight proteins form amyloid plaque fibers in Alzheimer's disease. J Neurochem 1986; 46: 1820–34.

    CAS  PubMed  Google Scholar 

  87. 87

    Gilgun-Sherki Y, Melamed E, Offen D . Antioxidant treatment in Alzheimer's disease: current state. J Mol Neurosci 2003; 21: 1–12.

    CAS  PubMed  Google Scholar 

  88. 88

    Xiao XQ, Yang JW, Tang XC . Huperzine A protects rat pheochromocytoma cells against hydrogen peroxide-induced injury. Neurosci Lett 1999; 275: 73–6.

    CAS  PubMed  Google Scholar 

  89. 89

    Xiao XQ, Wang R, Han YF, Tang XC . Protective effects of huperzine Aon β-amyloid25–35 induced oxidative injury in rat pheochromocytoma cells. Neurosci Lett 2000; 286: 155–8.

    CAS  PubMed  Google Scholar 

  90. 90

    Xiao XQ, Wang R, Tang XC . Huperzine A and tacrine attenuate β-amyloid peptide induced oxidative injury. J Neurosci Res 2000; 61: 564–9.

    CAS  Google Scholar 

  91. 91

    Xiao XQ, Zhang HY, Tang XC . Huperzine A attenuates amyloid β-peptide fragment 25–35–induced apoptosis in rat cortical neurons via inhibiting reactive oxygen species formation and caspase-3 activation. J Neurosci Res 2002; 67: 30–6.

    CAS  PubMed  Google Scholar 

  92. 92

    Zhou J, Fu Y, Tang XC . Huperzine A and donepezil protect rat pheochromocytoma cells against oxygen-glucose deprivation. Neurosci Lett 2001; 306: 53–6.

    CAS  PubMed  Google Scholar 

  93. 93

    Shang YZ, Ye JW, Tang XC . Improving effects of huperzine A on abnormal lipid peroxidation and superoxide dismutase in aged rats. Acta Pharmacol Sin 1999; 20: 824–8.

    CAS  Google Scholar 

  94. 94

    Lü PY, Yin Y, Wang WB, Liang CP, Li WB . Effects of huperzine A on [Ca2+]i level and expression of CaM, CaMPK II mRNA in hippocampal neurons of mice with vascular dementia. Clin J New Drugs Clin Rem 2004; 23: 73–6.

    Google Scholar 

  95. 95

    Yuan J, Yankner BA . Apoptosis in the nervous system. Nature 2000; 407: 802–9.

    CAS  PubMed  Google Scholar 

  96. 96

    Wang R, Xiao XQ, Tang XC . Huperzine A attenuates hydrogen peroxide-induced apoptosis by regulation expression of apoptosis-related genes in rat PC 12 cells. Neuroreport 2001; 12: 2629–34.

    CAS  PubMed  Google Scholar 

  97. 97

    Zhou J, Fu Y, Tang XC . Huperzine A protects rat pheochromocytoma cells against oxygen-glucose deprivation. Neuroreport 2001; 12: 2073–7.

    CAS  PubMed  Google Scholar 

  98. 98

    Zhou J, Tang XC . Huperzine A attenuates apoptosis and mitochondria-dependent caspase-3 in rat cortical neurons. FEBS Lett 2002; 526: 21–5.

    CAS  PubMed  Google Scholar 

  99. 99

    Zhang HY, Tang XC . Huperzine A attenuates the neurotoxic effect of staurosporine in primary rat cortical neurons. Neurosci Lett 2003; 340: 91–4.

    CAS  PubMed  Google Scholar 

  100. 100

    Ko LJ, Prives C . p53: puzzle and paradigm. Genes Dev 1996; 10: 1054–72.

    CAS  PubMed  Google Scholar 

  101. 101

    Halestrap AP, McStay GP, Clarke SJ . The permeability transition pore complex: another view. Biochimie 2000; 84: 153–66.

    Google Scholar 

  102. 102

    Kim JS, He L, Lemasters JJ . Mitochondrial permeability transition: A common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 2003; 304: 463–70.

    CAS  PubMed  Google Scholar 

  103. 103

    Bossy-Wetzel E, Newmeyer DD, Green DR . Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 1998; 17: 37–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Zamzami N, Kroemer G . The mitochondrion in apoptosis: how Pandora's Box opens. Nat Rev Mol Cell Biol 2001; 2: 67–71.

    CAS  PubMed  Google Scholar 

  105. 105

    Yu SP, Yeh CH, Sensi SL, Gwag BJ, Canzoniero LM, Farhangrazi ZS, et al. Mediation of neuronal apoptosis by enhancement of outward potassium current. Science 1997; 278: 114–7.

    CAS  PubMed  Google Scholar 

  106. 106

    Yu SP, Farhangrazi ZS, Ying HS, Yeh CH, Choi DW . Enhancement of outward potassium current may participate in beta-amyloid peptide-induced cortical neuronal death. Neurobiol Dis 1998; 5: 81–8.

    CAS  PubMed  Google Scholar 

  107. 107

    Malin SA, Guo WX, Jafari G, Goate AM, Nerbonne JM . Presenilins upregulate functional K+ channel currents in mammalian cells. Neurobiol Dis 1998; 4: 398–409.

    CAS  PubMed  Google Scholar 

  108. 108

    Li Y, Hu GY . Huperzine A, a nootropic agent, inhibits fast transient potassium current in rat dissociated hippocampal neurons. Neurosci Lett 2002; 324: 25–8.

    CAS  PubMed  Google Scholar 

  109. 109

    Li Y, Hu GY . Huperzine A inhibits the sustained potassium current in rat dissociated hippocampal neurons. Neurosci Lett 2002; 329: 153–6.

    CAS  PubMed  Google Scholar 

  110. 110

    Choi DW . Calcium and excitotoxic neuronal injury. Ann NY Acad Sci 1994; 747: 162–71.

    CAS  PubMed  Google Scholar 

  111. 111

    DiFiglia M . Excitotoxic injury of the neostriatum: a model for Huntington's disease. Trends Neurosci 1990; 13: 286–9.

    CAS  PubMed  Google Scholar 

  112. 112

    Dirnagl U, Iadecola C, Moskowitz MA . Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999; 22: 391–7.

    CAS  Google Scholar 

  113. 113

    Hossmann KA . Glutamate-mediated injury in focal cerebral ischemia: the excitotoxin hypothesis revised. Brain Pathol 1994; 4: 23–36.

    CAS  PubMed  Google Scholar 

  114. 114

    Hynd MR, Scott HL, Dodd PR . Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. Neurochem Int 2004; 45: 583–95.

    CAS  PubMed  Google Scholar 

  115. 115

    Lipton SA, Rosenberg PA . Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994; 330: 613–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Choi DW . Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci 1988; 11: 465–9.

    CAS  PubMed  Google Scholar 

  117. 117

    Choi DW . Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci 1995; 18: 58–60.

    CAS  PubMed  Google Scholar 

  118. 118

    Lee JM, Zipfel GJ, Choi DW . The changing landscape of ischaemic brain injury mechanisms. Nature 1999; 399 Suppl 6738: A7–14.

    CAS  Google Scholar 

  119. 119

    Simon RP, Swan JH, Griffiths T, Meldrum BS . Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain. Science 1984; 226: 850–2.

    CAS  PubMed  Google Scholar 

  120. 120

    Turski L, Huth A, Sheardown M, McDonald F, Neuhaus R, Schneider HH, et al. ZK200775: a phosphonate quinoxaline-dione AMPA antagonist for neuroprotection in stroke and trauma. Proc Natl Acad Sci USA 1998; 95: 10960–5.

    CAS  PubMed  Google Scholar 

  121. 121

    Ved HS, Koening ML, Dave JR, Doctor BP . Huperzine A, a potential therapeutic agent for dementia, reduces neuronal cell death caused by glutamate. NeuroReport 1997; 8: 963–8.

    CAS  PubMed  Google Scholar 

  122. 122

    Gordon RK, Nigam SV, Weitz JA, Dave JR, Doctor BP, Ved HS . The NMDA receptor ion channel: a site for binding of huperzine A. J Appl Toxicol 2001; 21 ( Suppl 1): S47–51.

    CAS  PubMed  Google Scholar 

  123. 123

    Wang XD, Zhang JM, Yang HH, Hu GY . Modulation of NMDA receptor by huperzine A in rat cerebral cortex. Acta Pharmacol Sin 1999; 20: 31–5.

    Google Scholar 

  124. 124

    Zhang JM, Hu GY . Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartate-induced current in rat dissociated hippocampal neurons. Neuroscience 2001; 105: 663–9.

    CAS  PubMed  Google Scholar 

  125. 125

    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: 107–10.

    CAS  PubMed  Google Scholar 

  126. 126

    Zhang YH, Chen XQ, Yang HH, Jin GY, Bai DL, Hu GY . Similar potency of the enantiomers of huperzine A in inhibition of [(3) H]dizocilpine (MK-801) binding in rat cerebral cortex. Neurosci Lett 2000; 295: 116–8.

    CAS  PubMed  Google Scholar 

  127. 127

    Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, et al. Cleavage of amyloid beta-peptide during constitutive processing of its precursor. Science 1990: 248: 1122–4.

    CAS  PubMed  Google Scholar 

  128. 128

    Haass C, Selkoe DJ . Cellular processing of beta-amyloid precursor protein and the genesis of amyloid-beta peptide. Cell 1993; 75: 1039–42.

    CAS  PubMed  Google Scholar 

  129. 129

    Gasparini L, Racchi M, Binetti G, Trabucchi M, Solerte SB, Alkon D, et al. Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease. FASEB J 1998; 12: 17–34.

    CAS  PubMed  Google Scholar 

  130. 130

    Racchi M, Govoni S . Rationalizing a pharmacological intervention on the amyloid precursor protein metabolism. Trends Pharmacol Sci 1999; 20: 418–23.

    CAS  PubMed  Google Scholar 

  131. 131

    Nitsch RM, Slack BE, Wurtman RJ, Growdon J . Release of Alzheimer amyloid precursor derivative stimulated by activation of muscarinic acetylcholine receptors. Science 1992; 258: 304–7.

    CAS  PubMed  Google Scholar 

  132. 132

    Giacobini E, Mori F, Lai CC . The effect of cholinesterase inhibitors on the secretion of APPs from rat brain cortex. Ann NY Acad Sci 1996; 777: 393–8.

    CAS  PubMed  Google Scholar 

  133. 133

    Mori F, Lai CC, Fusi F, Giacobini E . Cholinesterase inhibitors increase secretion of APPs in rat brain cortex. NeuroReport 1995; 6: 633–6.

    CAS  PubMed  Google Scholar 

  134. 134

    Zhang HY, Yan H, Tang XC . Huperzine A enhances the level of secretory amyloid precursor protein and protein kinase C-β in intracerebroventricular β-amyloid-(1–40) infused rats and human embryonic kidney 293 Swedish mutant cells. Neurosci Lett 2004; 360: 21–4.

    CAS  Google Scholar 

  135. 135

    Hefti F, Hartikka J, Knusel B . Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative disease. Neurobiol Aging 1989; 10: 515–33.

    CAS  Google Scholar 

  136. 136

    Mufson EJ, Bothwell M, Kordower JH . Loss of nerve growth factor receptor-containing neurons in Alzheimer's disease: a quantitative analysis across subregions of the basal forebrain. Exp Neurol 1989; 105: 221–32.

    CAS  Google Scholar 

  137. 137

    Shigeta K, Ootaki K, Tatemoto H, Nakanishi T, Inada A, Muto N . Potentiation of nerve growth factor-induced neurite outgrowth in PC 12 cells by a Coptidis Rhizoma extract and protoberine alkaloids. Biosci Biotech Biochem 2002; 66: 2491–4.

    CAS  Google Scholar 

  138. 138

    Brimijoin S, Koenigsberger C . Cholinesterases in neural development: new findings and toxicologic implications. Environ Health Perspect 1999; 107 ( Suppl 1): 59–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Tang LL, Wang R, Tang XC . Effects of huperzine A on secretion of nerve growth factor in cultured rat cortical astrocytes and neurite outgrowth in rat PC 12 cells. Acta Pharmacol Sin 2005; 26: 673–8.

    CAS  PubMed  Google Scholar 

  140. 140

    Tang LL, Wang R, Tang XC . Huperzine A protects SHSY5Y neuroblastoma cells against oxidative stress damage via nerve growth factor production. Eur J Pharmacol 2005; 519: 9–15.

    CAS  PubMed  Google Scholar 

  141. 141

    Wang YE, Feng J, Lu WH, Tang XC . Pharmacokinetics of huperzine A in rats and mice. Acta Pharmacol Sin 1988; 9: 193–6. Chinese.

    CAS  Google Scholar 

  142. 142

    Wang Y, Chu D, Gu J, Fawcett JP, Wu Y, Liu W . Liquid chromatographic-tandem mass spectrometric method for the quantitation of huperzine A in dog plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2004; 803: 375–8.

    CAS  PubMed  Google Scholar 

  143. 143

    Ye J, Zeng S, Zhang W, Chen G . Ion-pair reverse-phase high performance liquid chromatography method for determination of huperzine-A in beagle dog serum. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 817: 187–91.

    CAS  PubMed  Google Scholar 

  144. 144

    Qian BC, Wang M, Zhou ZF, Chen K, Zhou RR, Chen GS . Pharmacokinetics of tablet huperzine A in six volunteers. Acta Pharmacol Sin 1995; 16: 396–8.

    CAS  Google Scholar 

  145. 145

    Hartvig P, Wiklund L, Aquilonius SM, Lindström B . Clinical pharmacokinetics of centrally acting cholinesterase inhibitors. In: Becker R, Giacobini E editors Cholinergic basis for Alzheimer therapy. Boston: Birkhäuser; 1991. p 68–73.

    Google Scholar 

  146. 146

    Ma XC, Wang HX, Xin J, Zhang T, Tu ZH . Indentification of cytochrome P450 1A2 as enzyme involved in the microsomal metabolism of huperzine A. Eur J Pharmacol 2003; 461: 89–92.

    CAS  PubMed  Google Scholar 

  147. 147

    Ma XC, Wang HX, Xin J, Zhang T, Tu ZH . Effects of huperzine A on liver cytochrome P-450 in rats. Acta Pharmacol Sin 2003; 24: 831–5.

    CAS  PubMed  Google Scholar 

  148. 148

    Ma XC, Xin J, Wang HX, Zhang T, Tu ZH . Acute effects of huperzine A and tacrine on rat liver. Acta Pharmacol Sin 2003; 24: 247–50.

    CAS  PubMed  Google Scholar 

  149. 149

    Boudinot E, Taysse L, Daulon S, Chatonnet A, Champagnat J, Foutz AS . Effects of acetylcholinesterase and butyrylcholinesterase inhibition on breathing in mice adapted or not to reduced acetylcholinesterase. Pharmacol Biochem Behav 2005; 80: 53–61.

    CAS  PubMed  Google Scholar 

  150. 150

    Grunwald J, Raveh L, Doctor P, Ashani Y . Huperzine A as a pretreatment candidate drug against nerve agent toxicity. Life Sci 1994; 54: 991–7.

    CAS  PubMed  Google Scholar 

  151. 151

    Ashani Y, Grundwald J, Alkalai D, Cohen G, Raveh L . Studies with huperzine A, a new candidate in the research of prophylaxis against nerve agent. In: King JM editor Proceedings of the Medical Defence Bioscience Review 1996. p 105–10.

  152. 152

    Tonduli L, Testylier G, Masqueliez C, Lallement G, Monmaur P . Effects of huperzine used as pretreatment against soman-in-duced seizures. Neurotoxicology 2001; 24: 276–85.

    Google Scholar 

  153. 153

    Lallement G, Baille V, Baubichon D, Carpentier P, Collombet JM, Filliat P, et al. Review of the value of huperzine as pretreatment of organophosphate poisoning. Neurotoxicology 2002; 23: 1–5.

    CAS  PubMed  Google Scholar 

  154. 154

    Lallement G, Demoncheaux JP, Foquin A, Baubichon D, Galonnier M, Clarencon D, et al. Subchronic compared efficacy against soman toxicity. Drug Chem Toxicol 2002; 25: 309–20.

    CAS  PubMed  Google Scholar 

  155. 155

    Lallement G, Veyret V, Masqueliez M, Aubriot S, Burckhart MF, Baubichon D . Efficacy of huperzine in preventing soman-in-duced seizures, neuropathological changes and lethality. Fund Clin Pharmacol 1997; 11: 387–94.

    CAS  Google Scholar 

  156. 156

    Zhang CL . Therapeutic effects of huperzine A on the aged with memory impairment. New Drugs Clin Remedies 1986; 5: 260–2. Chinese.

    Google Scholar 

  157. 157

    Liu FG, Fang YS, Gao ZX, Zhou JD, Su ML . Double-blind control treatment with huperzine A and placebo in 28 patients with Alzheimer disease. Clin J Pharmacoepidemiol 1995; 4: 196–8. Chinese.

    Google Scholar 

  158. 158

    Yang JS, Jiang ZH . Clinical report of huperzine A for the treatment of Alzheimer's disease. He Bei Jing Shen Wei Sheng 1996; 9: 84–5. Chinese.

    Google Scholar 

  159. 159

    Zhao CY, Li SF, Chen XL, Han MK . Efficacy of tablet huperzine A on treating 21 patients with Alzheimer's disease. Si Chuan Jing Shen Wei Sheng 1996; 9: 204. Chinese.

    Google Scholar 

  160. 160

    Wang LJ, Ji XX, Weng QS, Yang JS . Clinical observation of huperzine A on 36 patients with Alzheimer's disease. Nan Tong Yi Xue Yuan Xue Bao 1998; 18: 486–8. Chinese.

    Google Scholar 

  161. 161

    Liu JN, Huang ZY, Zhou YD, Ju YL . The clinical observation of Alzheimer's disease treated by huperzine A. Chin J Clin Phar 1998; 7: 270–2. Chinese.

    Google Scholar 

  162. 162

    Wang LJ, Ji XX, Weng QS, Yang JS . Clinical observation of huperzine A on 36 patients with Alzheimer's disease. Shanghai Yi Yao 1999; 20: 16–8. Chinese.

    CAS  Google Scholar 

  163. 163

    Chen YM, Ma YX, Chen MJ, Fang YS, Chai XS, Weng Z . Observation of aniracetam and huperzine on memory function of Alzheimer's disease. Modern Rehabil 2000; 4: 1622–3. Chinese.

    Google Scholar 

  164. 164

    Jiang YB, Huang SS, Huang LA . Improvement of huperzine A on the deficiency of cognitive and behavior in Alzheimer's disease. Clin Med China 2002; 18: 802–3. Chinese.

    CAS  Google Scholar 

  165. 165

    Song ZY, Lu H . Clinical efficacy of huperzine A on Alzheimer disease. Chin J Clin Rehabil 2003; 7: 112. Chinese.

    Google Scholar 

  166. 166

    Yang CY, Lv ZP, Zheng CG . Efficacy and reliability of huperzine A in mild and moderate Alzheimer's disease. Chin J Clin Rehabil 2003; 7: 4258–9. Chinese.

    Google Scholar 

  167. 167

    Kuang MZ, Xiao WM, Wang SF, Li RX . Clinical evaluation of huperzine A in improving intelligent disorder in patients with Alzheimer's disease. Chin J Clin Rehabil 2004; 8: 1216–7. Chinese.

    Google Scholar 

  168. 168

    Wu SF, Xie SZ, Lu WJ, Ma YX . Comparison of huperzine A in capsule and tablet on random, double-blind treating mild and moderate Alzheimer's disease. Shanghai Yi Yao 1999; 20: 36–7. Chinese.

    CAS  Google Scholar 

  169. 169

    Chen MJ, Gao ZX, Deng HY, Liu FG, Ma YX, Yu HZ, et al. Huperzine A capsules vs tablets in treatment of Alzheimer disease: multi-center studies. Chin J New Drugs Clin Remedies 2000; 19: 10–2. Chinese.

    Google Scholar 

  170. 170

    Sun QQ, Xu SS, Pan JL, Guo HM, Cao WQ . Huperzine-A capsules enhance memory and learning performance in 34 pairs of matched adolescent students. Acta Pharmacol Sin 1999; 20: 601–3.

    CAS  Google Scholar 

  171. 171

    Zhou BR, Xu ZQ, Kuang YF, Deng YH, Liu ZF . Effectiveness of polydrug therapy for senile dementia. Chin J Clin Rehabil 2004; 8: 1214–5. Chinese.

    Google Scholar 

  172. 172

    Wang RQ, Lei QY, Gu JQ, Wang XY, Liu YL, Fang SY, et al. Nilestriol combined with huperzine in improving cognition of female patients with Alzheimer's disease. Chin J Clin Rehabil 2003; 7: 1538–9. Chinese.

    Google Scholar 

  173. 173

    Miao XR . Huperzine A assisted with the training of daily life promotes rehabilitation of Alzheimer's disease. Chin J Clin Rehabil 2002; 6: 2551. Chinese.

    Google Scholar 

  174. 174

    Wang RQ, Meng HY, Liu W . Therapeutic effects of huperzine A complementing with 3R mental stimulation program in senile dementia patients. Chin J Clin Rehabil 2002; 6: 2560–1. Chinese.

    Google Scholar 

  175. 175

    Zhang RW, Tang XC, Han YY, Sang GW, Zhang YD, Ma YX, et al. Drug evaluation of huperzine A in the treatment of senile memory disorders. Acta Pharmacol Sin 1991; 12: 250–2. Chinese.

    CAS  Google Scholar 

  176. 176

    Sun CY, Chen XY . A self-control study of huperzine A on memory deficits in patients with multiple infarctions. Henan Yi Yao Xin Xi 1998; 6: 31–2. Chinese.

    Google Scholar 

  177. 177

    Sun CY, Cai ZH, Chen XY . A self-control study of huperzine A on memory deficits in patients with multiple infarctions. Zhong Yuan Jing Shen Yi Xue Xue Kan 1998; 4: 151–3. Chinese.

    Google Scholar 

  178. 178

    Ye Q, Wu RZ, Su BZ, Li HL . A study of the efficacy of huperzine A in the treatment of memory deficiency and recognition decline of cerebral organic disease. Sichuan Jing Shen Wei Sheng 2001; 14: 75–6. Chinese.

    Google Scholar 

  179. 179

    Yin FM, Du YY, Wang LE . The effects of huperzine A on vascular dementia. Modern Rehabil 2001; 5: 74–5. Chinese.

    Google Scholar 

  180. 180

    Chen YP, Mei YW, Cheng SQ . Treatment on 20 cases of multi-infarct dementia with huperzine A. Yi Yao Dao Bao 2002; 21: 275–6. Chinese.

    Google Scholar 

  181. 181

    Chang JJ . Huperzine A vs pyritinol in treating dementia from multiple infarctions. New Drugs Clin Remedies 1997; 16: 333–4. Chinese.

    Google Scholar 

  182. 182

    Qu CY, Wang HM, Yu W, Xue ZW . A pilot trial of huperzine A on treating the cognitive deficiency in endemic cretinism. Shanxi Yi Yao Za Zhi 1995; 24: 47–8. Chinese.

    Google Scholar 

  183. 183

    Yang XY, Zhang HY . Therapeutic effects of huperzine A on urinary incontinence after cerebral stroke. J Pract Nerv Dis 2004; 7: 77. Chinese.

    Google Scholar 

  184. 184

    Chang SY, Chen SM, Cao QL, Liu P, Wang FG, Wang ZX . A clinical study of the effect of huperzine A to improve the ability of verbal recall, retention and repetition in middle-aged and elderly patients with dysmnesia. Herald Med 2002; 21: 263–5. Chinese.

    Google Scholar 

  185. 185

    Liao JX, Chen L, Huang TS . Pilot trial of huperzine A to treat child language delay. J Pediatr Pharm 2002; 8: 26–7. Chinese.

    Google Scholar 

  186. 186

    Zhang JH, Fan JZ, Deng AW . A clinical study of huperzine Aon mild and moderate traumatic brain injury in memory and cognitive impairment. Chin J Rehabil Med 2002; 17: 162–4. Chinese.

    Google Scholar 

  187. 187

    Ma JD, Zheng H, Wang YJ . Effect of huperzine A on the memory disorders of schizophrenic patients during rehabilitation period. Health Psychol J 2003; 11: 340–1. Chinese.

    Google Scholar 

  188. 188

    Fang CX, Guo CR, Wu B, Jing YT . Effects of huperzine A on memory patients with schizophrenia. Shandong Jing Shen Yi Xue 2002; 15: 39–40. Chinese.

    Google Scholar 

  189. 189

    Yang JZ . The effects of huperzine A on the cognitive deficiency of rehabilitating schizophrenia. Chin J Clin Rehabil 2003; 7: 1440. Chinese.

    Google Scholar 

  190. 190

    Gao X, Yu QP, Cao QH . A clinical trial of day and night alternated administration of huperzine A and clonazepam to treat chronic insomnia. Chin J Nerv Ment Dis 2003; 29: 58–9. Chinese.

    Google Scholar 

  191. 191

    Zhang CL, Wang GZ . Effects of huperzine A tablet on memory. New Drugs Clin Remedies 1990; 9: 339–41. Chinese.

    Google Scholar 

  192. 192

    Zhang XQ, Ding MC, Meng C, Yang PJ . Oral administration of huperzine A improved memory disorder: a clinical study. Zhong Guo Xin Yao Za Zhi 1996; 5: 33–4. Chinese.

    Google Scholar 

  193. 193

    Du ZM, Li SL, Yang CF, Wang YY, Zhang HZ, Xu SS . Double-blind and placebo controlled study of huperzine A on treatment of benign senescent forgetfulness. Chin J Geriatr 1996; 15: 180. Chinese.

    Google Scholar 

  194. 194

    Zhu XY, Gu YD, Wang HH . Comparison of the efficacy between tablet and capsule of huperzine to treat age associated memory impairment by double blind trial method. Zhong Guo Lin Chuang Yao Xue Za Zhi 1999; 8: 227–9. Chinese.

    Google Scholar 

  195. 195

    Li SL, Xu SS . Huperzine A capsules vs tablets in treating senile amnesia: a double-blind study. Chin J New Drugs Clin Remedies 2000; 19: 33–5. Chinese.

    Google Scholar 

  196. 196

    Chai XS, Sheng JH . Huperzine A capsule vs huperzine A in treatment of age-associated memory impairment with a double-blind study. Shandong Arch Psychiatr 2001; 14: 88–90. Chinese.

    Google Scholar 

  197. 197

    Sheng JH, Gao ZX, Chai XS, Zhou F, Cui SS . Huperzine A capsule in treatment of age-associated memory impairment with a double-blind study. Sichuan Jing Shen Wei Sheng 2003; 16: 1–3. Chinese.

    Google Scholar 

  198. 198

    Cheng YS, Lu CZ, Ying ZL, Ni WY, Zhang CL, Sang GW . One hundred and twenty-eight cases of myasthenia gravis treated with huperzine A. New Drugs Clin Remedies 1986; 5: 197–9.

    Google Scholar 

  199. 199

    Xia Q, Liu QC . Clinical study of huperzine A on the treatment of myasthenia gravis. Proc J Med Pharm 2002; 19: 31. Chinese.

    Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Xi-can Tang.

Additional information

Project supported in part by the grants from Ministry of Science and Technology of China (G1998051110, G1998051115, 2004CB518907) and the National Natural Science Foundation of China (No 39170860, 39770846, 3001161954, 30123005, 30271496, and 30572169).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, R., Yan, H. & Tang, X. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin 27, 1–26 (2006). https://doi.org/10.1111/j.1745-7254.2006.00255.x

Download citation

Keywords

  • huperzine A
  • Alzheimer disease
  • acetylcholinesterase
  • cholinesterase inhibitors
  • cognitive enhancer
  • neuroprotect agents
  • oxidative stress
  • apoptosis

Further reading