Huperzine A (HupA), isolated from Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase. It has been found to reverse or attenuate cognitive deficits in a broad range of animal models. Clinical trials in China have demonstrated that HupA significantly relieves memory deficits in aged subjects, patients with benign senescent forgetfulness, Alzheimer’s disease (AD) and vascular dementia (VD), with minimal peripheral cholinergic side effects compared with other AChEIs in use. 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, and interfere with APP metabolism. Antagonizing effects on NMDA receptors and potassium currents may contribute to the neuroprotection as well. It is also possible that the non-catalytic function of AChE is involved in neuroprotective effects of HupA. The therapeutic effects of HupA on AD or VD are probably exerted via a multi-target mechanism.
© 2005 S. Karger AG, Basel
- Huperzine A
- Alzheimer’s disease
- Cholinesterase inhibitor
- Cognitive enhancer
- Oxidative stress
- Amyloid precursor protein
- Cerebral ischemia
- Apoptotic-related gene
- NMDA receptor
- Potassium current
- Bartus RT, Dean RL 3rd, Beer B, Lippa AS: The cholinergic hypothesis of geriatric memory dysfunction. Science 1982;217:408–414.
- Behl C, Moosmann B: Antioxidant neuroprotection in Alzheimer’s disease as preventive and therapeutic approach. Free Radic Biol Med 2002;33:182–191.
- Bliss TVP, Collingridge GL: A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993;361:31–39.
- Bon S, Vigny M, Massoulie J: Asymmetric and globular forms of AChE in mammals and birds. Proc Natl Acad Sci USA 1979;76:2540–2550.
- 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.
- Brimijoin S: Molecular forms of acetylcholinesterase in brain, nerve and muscle: nature, localization and dynamics. Prog Neurobiol 1983;21:291–322.
- Butterfield DA, Howard B, Yatin S, Koppal T, Drake J, Hensley K, Aksenov M, Subramaniam R, Varadarajan S, Harris-White ME, Pedigo NW Jr, Carney JM: Elevated oxidative stress in models of normal brain aging and Alzheimer’s disease. Life Sci 1999;65:1883–1892.
- 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.
- Cheng DH, Tang XC: Comparative studies of huperzine A, E2020, and tacrine on behavior and cholinesterase activities. Pharmacol Biochem Behav 1998;60:377–386.
- Choi DW: Calcium-mediated neurotoxicity: Relationship to specific channel types and role in ischemic damage. Trends Neurosci 1988;11:465–469.
- Choi DW: Calcium and excitotoxic neuronal injury. Ann NY Acad Sci 1994;747:162–171.
- Choi DW: Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci 1995;18:58–60.
- DiFiglia M: Excitotoxic injury of the neostriatum: A model for Huntington’s disease. Trends Neurosci 1990;13:286–289.
- Dirnagl U, Iadecola C, Moskowitz MA: Pathobiology of ischaemic stroke: An integrated view. Trends Neurosci 1999;22:391–397.
- Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward PJ: Cleavage of amyloid beta-peptide during constitutive processing of its precursor. Science 1990:248:1122–1124.
- Gao Y, Tang XC, Guan LC, Kuang PZ: Huperzine A reverses scopolamine- and muscimol-induced memory deficits in chick. Acta Pharmacol Sin 2000;21:1169–1173.
- Gasparini L, Racchi M, Binetti G, Trabucchi M, Solerte SB, Alkon D, Etcheberrigaray R, Gibson G, Blass J, Paoletti R, Govoni S: Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer’s disease. FASEB J 1998;12:17–34.
- 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;777:393–398.
- Gilgun-Sherki Y, Melamed E, Offen D: Antioxidant treatment in Alzheimer’s disease: Current state. J Mol Neurosci 2003;21:1–12.
- 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–S51.
- Graham SH, Chen J: Programmed cell death in cerebral ischemia. J Cereb Blood Flow Metab 2001;21:99–109.
- 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;387:457–469.
- Guan LC, Chen SS, Cui QG, Lu WH, Tang XC: The effects of huperzine A on behavior and ECoG in animals. Acta Psychol Sin 1991;23:404–411.
- Haass C, Selkoe DJ: Cellular processing of beta-amyloid precursor protein and the genesis of amyloid-beta peptide. Cell 1993;75:1039–1042.
- Halestrap AP, McStay GP, Clarke SJ: The permeability transition pore complex: Another view. Biochimie 2000;84:153–166.
- Hossmann KA: Glutamate-mediated injury in focal cerebral ischemia: The excitotoxin hypothesis revised. Brain Pathol 1994;4:23–36.
- Hynd MR, Scott HL, Dodd PR: Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochem Int 2004;45:583–595.
- Kim JS, He L, Lemasters JJ: Mitochondrial permeability transition: A common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 2003;304:463–470.
- Ko LJ, Prives C: p53: Puzzle and paradigm. Genes Dev 1996;10:1054–1072.
- Eckert A, Marques CA, Keil U, Schussel K, Muller WE: Increased apoptotic cell death in sporadic and genetic Alzheimer’s disease. Ann NY Acad Sci 2003;1010:604–609.
- Lee JM, Zipfel GJ, Choi DW: The changing landscape of ischaemic brain injury mechanisms. Nature 1999;399(suppl):A7–A14.
- Li HN, Min QY: Huperzine A improved the cognition of vascular dementia: A report of 30 patients in therapeutics. Xian Dai Kang Fu 2001;5:59
- Li Y, Hu GY: Huperzine A inhibits the sustained potassium current in rat dissociated hippocampal neurons. Neurosci Lett 2002;329:153–156.
- Liang YQ, Tang XC: Comparative effects of huperzine A, donepezil and rivastigmine on cortical acetylcholine level and acetylcholinesterase activity in rats. Neurosci Lett 2004;361:56–59.
- Lipton SA, Rosenberg PA: Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994;330:613–622.
- 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;19:413–416.
- 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;9:11–15.
- Ma YX, Zhu Y, Gu YD, Yu ZY, Yu SM, Ye YZ: Double-blind trial of huperzine-A (HUP) on cognitive deterioration in 314 cases of benign senescent forgetfulness, vascular dementia, and Alzheimer’s disease. Ann NY Acad Sci 1998;854:506–507.
- Pi X, Liu Y, Jiang ZY, Hu XQ, Zhu GZ: Clinical observations on treatment of light and moderate vascular dementia with meclofenoxate plus huperzine A. Shanghai Med Pharmaceut J 2004;255:409–411.
- Markesbery WR: Oxidative stress hypothesis in Alzheimer’s disease. Free Rad Biol Med 1997;23:134–147.
- Massoulie J, Bon S: The molecular forms of cholinesterase and acetylcholinesterase in vertebrate. Annu Rev Neurosci 1982;5:57–106.
- Mori F, Lai CC, Fusi F, Giacobini E: Cholinesterase inhibitors increase secretion of APPs in rat brain cortex. NeuroReport 1995;6:633–636.
- Nitsch RM, Slack BE, Wurtman RJ, Growdon J: Release of Alzheimer amyloid precursor derivative stimulated by activation of muscarinic acetylcholine receptors. Science 1992;258:304–307.
- Ou LY, Tang XC, Cai JX: Effect of huperzine A on working memory in reserpine- or yohimbine-treated monkeys. Eur J Pharmacol 2001;433:151–156.
- Perry EK, Tomlinson VE, Blessed G, Bergman K, Gibson PH, Perry RH: Correlation of cholinergic abnormalities with senile plaques and mental scores. Br Med J 1978;ii:1457–1459.
- Racchi M, Govoni S: Rationalizing a pharmacological intervention on the amyloid precursor protein metabolism. Trends Pharmacol Sci 1999;20:418–423.
- Rossner S, Ueberham U, Schliebs R, Perez-Polo JR, Bigl V: The regulation of amyloid precursor protein metabolism by cholinergic mechanisms and neurotrophin receptor signaling. Prog Neurobiol 1998;56:541–569.
- 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;46:1820–1834.
- 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;20:824–828.
- Simon RP, Swan JH, Griffiths T, Meldrum BS: Blockade of N-methyl-aspartate receptors may protect against ischemic damage in the brain. Science 1984;226:850–852.
- Smale G, Nichols NR, Brady DR, Finch CE, Horton WE Jr: Evidence for apoptotic cell death in Alzheimer’s disease. Exp Neurol 1995;133:225–230.
- Sucher NJ, Awobuluyi M, Choi YB, Lipton SA: NMDA receptors: From genes to channels. Trends Pharmacol Sci 1996;17:348–355.
- Szalai G, Krishnamurthy R, Hajnoczky G: Apoptosis driven by IP(3)-linked mitochondrial calcium signals. EMBO J 1999;18:6349–6361.
- 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;7:507–511.
- 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;24:276–285.
- Tang XC, He XC, Bai DL: Huperzine A: A novel acetylcholinesterase inhibitor. Drug Future 1999;24:647–663.
- Turski L, Huth A, Sheardown M, McDonald F, Neuhaus R, Schneider HH, Dirnagl U, Wiegand F, Jacobsen P, Ottow E: ZK200775: A phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma. Proc Natl Acad Sci USA 1998;95:10960–10965.
- 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;8:963–968.
- 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 Abstr 1987;13:844.
- Wang H, Tang XC: Anticholinesterase effects of huperzine A, E2020, and tacrine in rats. Acta Pharmacol Sin 1998;19:27–30.
- 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.
- Wang LS, Zhou J, Shao XM, Tang XC: Huperzine A attenuates cognitive deficits and brain injury in neonatal rats after hypoxia-ischemia. Brain Res 2002;949:162–170.
- Wang R, Xiao XQ, Tang XC: Huperzine A attenuates hydrogen peroxide-induced apoptosis by regulation expression of apoptosis-related genes in rat PC12 cells. NeuroReport 2001;12:2629–2634.
- 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;421:149–156.
- 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;349:137–142.
- Wang XD, Zhang JM, Yang HH, Hu GY: Modulation of NMDA receptor by huperzine A in rat cerebral cortex. Acta Pharmacol Sin 1999;20:31–35.
- Wang YE, Yue DX, Tang XC: Anticholinesterase activity of huperzine A. Acta Pharmacol Sin 1986;7:110–113.
- Xiao XQ, Yang JW, Tang XC: Huperzine A protects rat pheochromocytoma cells against hydrogen peroxide-induced injury. Neurosci Lett 1999;275:73–76.
- Xiao XQ, Wang R, Han YF and Tang XC: Protective effects of huperzine A on β-amyloid25–25 induced oxidative injury in rat pheochromocytoma cells. Neurosci Lett 2000;286:155–158.
- Xiao XQ, Wang R, Tang XC: Huperzine A and tacrine attenuate β-amyloid peptide induced oxidative injury. J Neurosci Res 2000;61:564–569.
- 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;67:30–36.
- Xiong ZQ, Tang XC: Effect of huperzine A, a novel acetylcholinesterase inhibitor, on radial maze performance in rats. Pharmacol Biochem Behav 1995;51:415–419.
- Xiong ZQ, Han YF, Tang XC: Huperzine A ameliorates the spatial working memory impairments induced by AF64A. NeuroReport 1995;6:2221–2224.
- Xiong ZQ, Cheng DH, Tang XC: Effects of huperzine A on nucleus basalis magnocellularis lesion-induced spatial working memory deficit. Acta Pharmacol Sin 1998;19:128–132.
- Xu SS, Gao ZX, Weng Z, Du ZM, Xu WA, Yang JS, Zhang ML, Tong ZH, Fang YS, Chai XS, Li SL: Efficacy of tablet huperzine A on memory, cognition, and behavior in Alzheimer’s disease. Acta Pharmacol Sin 1995;16:391–395.
- Xu SS, Xie HB, Du ZW, Tong ZH, Shi QC, Lu KM, Li SL, Lin B: Efficacy of tablet huperzine A on memory and cognition in patients with benign senescent forgetfulness. Chin J Clin Pharmacol Ther 1997;2:1–4.
- 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;20:486–490.
- 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;288:814–819.
- 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;21:65–69.
- 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;275:187–190.
- 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(2):81–88.
- Yuan J, Yankner BA: Apoptosis in the nervous system. Nature 2000;407:802–809.
- Zamzami N, Kroemer G: The mitochondrion in apoptosis: How Pandora’s box opens. Nature Reviews in Molecular and Cellular Biology 2001;21:67–71.
- Zhang CL, Wang GZ: Effects of huperzine A tablet on memory. New Drugs Clin Remed 1990;9:339–341.
- Zhang HY, Brimijoin S, Tang XC: Apoptosis induced by β-amyloid25–35 in acetylcholinesterase-overexpressing neuroblastoma cells. Acta Pharmacol Sin 2003;24:853–858.
- Zhang HY, Liang YQ, Tang XC, He XC, Bai DL: Stereoselectivities of enantiomers of huperzine A in protection against amyloid 25–35-induced injury in PC12 and NG108–15 cells and cholinesterase inhibition in mice. Neurosci Lett 2002;317:143–146.
- Zhang HY, Tang XC: Huperzine A attenuates the neurotoxic effect of staurosporine in primary rat cortical neurons. Neurosci Lett 2003;340:91–94.
- Zhang HY, Yan H, Tang XC: Huperzine A enhances the level of secretory amyloid precursor protein and protein kinase C-α in intracerebroventricular β-amyloid-(1–40) infused rats and human embryonic kidney 293 Swedish mutant cells. Neurosci Lett 2004;360:21–24.
- Zhang JM, Hu GY: Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartate-induced current in rat dissociated hippocampal neurons. Neuroscience 2001;105:663–669.
- Zhang RW, Tang XC, Han YY, Sang GW, Zhang YD, Ma YX, Zhang CL, Yang RM: Drug evaluation of huperzine A in the treatment of senile memory disorders. Acta Pharmacol Sin 1991;12:250–252.
- 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;295:116–118.
- 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.
- Zhao Q, Tang XC: Effects of huperzine A on acetylcolinesterase isoforms in vitro: Comparison with tacrine, donepezil, rivastigmine and physostigmine. Eur J Pharmacol 2002;455:101–107.
- Zhou J, Fu Y, Tang XC: Huperzine A protects rat pheochromocytoma cells against oxygen-glucose deprivation. NeuroReport 2001;12:2073–2077.
- Zhou J, Fu Y, Tang XC: Huperzine A and donepezil protect rat pheochromocytoma cells against oxygen-glucose deprivation. Neurosci Lett 2001;306:53–56.
- Zhou J, Zhang HY, Tang XC: Huperzine A attenuates cognitive deficits and hippocampal neuronal damage after transient global ischemia in gerbils. Neurosci Lett 2001;313:137–140.
- Zhou J, Tang XC: Huperzine A attenuates apoptosis and mitochondria-dependent caspase-3 in rat cortical neurons. FEBS Lett 2002;526:21–25.
- Zhu XD, Tang XC: Facilitatory effects of huperzine A and B on learning and memory of spatial discrimination in mice. Acta Pharmacol Sin 1987;22:812–817.
- Zhu XD, Tang XC: Improvement of impaired memory in mice by huperzine A and huperzine B. Acta Pharmacol Sin 1988;9:492–497.
- Zhu XD, Giacobini E: Second generation cholinesterase inhibitors: Effect of (L)-huperzine A on cortical biogenic amines. J Neurosci Res 1995;41:828–835.
Prof. Xi Can Tang, State Key Laboratory of Drug Research
Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences
Chinese Academy of Sciences, 555 Zu Chong Zhi Road
Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
Tel. +86 21 5080 6710, Fax +86 21 5080 7088, E-Mail firstname.lastname@example.org
Received: September 23, 2004
Accepted after revision: November 8, 2004
Number of Print Pages : 12
Number of Figures : 7, Number of Tables : 0, Number of References : 100
Vol. 14, No. 1-2, Year 2005 (Cover Date: Released June 2005)
Journal Editor: N.Y. Ip, Hong Kong
ISSN: 1424–862X (print), 1424–8638 (Online)
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