Name:	Huperzine A
Other Names:	Cerebra capsule , Pharmassure Memorall capsule
Therapeutic Applications:	All stages of Alzheimer disease
Therapy Types:	Orally administered nutraceutical
Mechanisms:	Multiple mechanisms of action include potent and selective inhibition of AChE; alterations in APP processing; reduction of neurotoxicity by Aβ; antioxidant effects; increase of NGF production.
Development Status:	investigational in U.S.
FDA Phase:	Inactive
Primary Medical Role:	Huperzine A is a plant alkaloid derived from the club moss Huperzia serrata, previously used as a treatment for swelling and fever. Huperzine A is a potent, reversible, selective inhibitor of AChE with similar or higher potency than tacrine or donepezil. It is currently in phase 4 clinical testing in China for treatment of Alzheimer disease, and in the U.S., a multicenter (29 centers in 17 states), double-blind, placebo controlled phase 2 clinical trial is in enrollment stage (until late spring 2007), clinical trial NCT00083590.
Role in Alzheimer's Disease:	Animal and cell culture studies, along with molecular structure data, suggest that huperzine A is a potent acetylcholinesterase (AChE) inhibitor and protects neurons against glutamate-induced excitotoxicity, while decreasing glutamate-induced calcium mobilization (Gordon et al., 2001). Huperzine A increases sAPPa, by increasing levels of protein kinase C isoform a in ICV infused rats and cell culture (Zhang et al., 2004). Preincubation of cultured rat cortical neurons with huperzine A protects cells from Aβ(25-35)-induced apoptosis and inhibits reactive oxygen species generation and caspase 3 activation (Xiao et al., 2002). The molecule's strong specificity for AChE suggests it may have lower liver toxicity and other adverse effects.
Pharmacological Role:	Animal and cell culture studies, along with molecular structure data, suggest that Huperzine A is a potent acetylcholinesterase (AChE) inhibitor and may also protect neurons against glutamate-induced excitotoxicity. The molecule's strong specificity for AChE suggests it may have lower liver toxicity and other adverse effects. There is now considerable interest in exploiting the 3D structure of Huperzine A to synthesize even more potent and selective AChE inhibitors.
Contraindications:	Due to huperzine A effects on AChE inhibition, a history of active peptic ulcer disease is an exclusion criterion for the phase 2 clinical trial now enrolling (until late spring 2007). Huperzine A may counteract the effects of such drugs as dicyclomine or propantheline that are used to decrease acetylcholine’s effects in the treatment of diarrhea-prominent irritable bowel syndrome. Due to known adverse effects of huperzine A, a history of cardiac arrhythmia is also an exclusion criterion for the phase 2 trial.
Side Effects:	Huperzine A may cause seizures or heart rhythm changes. It may also be associated with blurred vision, dizziness, nausea, and increased saliva and sweat.
Companies:	Neuro-Hitech, Inc.
Notes:	Huperzine A is currently in phase 4 in China for treatment of Alzheimer disease, and in the U.S., a multicenter (29 centers in 17 states), double-blind, placebo controlled phase 2 clinical trial, ClinicalTrials.gov NCT00083590 was completed. The development of this drug is inactive. This record was last updated Dec 14, 2009.

References

Zhang HY, Tang XC. Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease. Trends Pharmacol Sci. 2006 Dec 1;27(12):619-25. Abstract

Wang R, Yan H, Tang XC. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin. 2006 Jan 1;27(1):1-26. Abstract

Zhang HY, Yan H, Tang XC. Huperzine A enhances the level of secretory amyloid precursor protein and protein kinase C-alpha in intracerebroventricular beta-amyloid-(1-40) infused rats and human embryonic kidney 293 Swedish mutant cells. Neurosci Lett. 2004 Apr 22;360(1-2):21-4. Abstract

Jiang H, Luo X, Bai D. Progress in clinical, pharmacological, chemical and structural biological studies of huperzine A: a drug of traditional chinese medicine origin for the treatment of Alzheimer's disease. Curr Med Chem. 2003 Nov ;10(21):2231-52. Abstract

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 Jan 14;317(3):143-6. Abstract

Xiao XQ, Zhang HY, Tang XC. Huperzine A attenuates amyloid beta-peptide fragment 25-35-induced apoptosis in rat cortical neurons via inhibiting reactive oxygen species formation and caspase-3 activation. J Neurosci Res. 2002 Jan 1;67(1):30-6. Abstract

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 Dec;21 Suppl 1:S47-51. Abstract

Zhou J, Fu Y, Tang XC. Huperzine A and donepezil protect rat pheochromocytoma cells against oxygen-glucose deprivation. Neurosci Lett. 2001 Jun 22;306(1-2):53-6. Abstract

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 Jun 15;421(3):149-56. Abstract

Zhang JM, Hu GY. Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartate-induced current in rat dissociated hippocampal neurons. Neuroscience. 2001;105 (3):663-9. Abstract

Camps P, El Achab R, Morral J, Munoz-Torrero D, Badia A, Banos JE, Vivas NM, Barril X, Orozco M, Luque FJ. New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease. J Med Chem. 2000 Nov 30;43(24):4657-66. Abstract

Xiao XQ, Wang R, Tang XC. Huperzine A and tacrine attenuate beta-amyloid peptide-induced oxidative injury. J Neurosci Res. 2000 Sep 1;61(5):564-9. Abstract

Xiao XQ, Wang R, Han YF, Tang XC. Protective effects of huperzine A on beta-amyloid(25-35) induced oxidative injury in rat pheochromocytoma cells. Neurosci Lett. 2000 Jun 9;286(3):155-8. Abstract

Bai DL, Tang XC, He XC. Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease. Curr Med Chem. 2000 Mar;7(3):355-74. Abstract

Xu SS, Cai ZY, Qu ZW, Yang RM, Cai YL, Wang GQ, Su XQ, Zhong XS, Cheng RY, Xu WA, Li JX, Feng B. Huperzine-A in capsules and tablets for treating patients with Alzheimer disease. Chung Kuo Yao Li Hsueh Pao. 1999 Jun;20(6):486-90. Abstract

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 Feb;288(2):814-9. Abstract

Cheng DH, Tang XC. Comparative studies of huperzine A, E2020, and tacrine on behavior and cholinesterase activities. Pharmacol Biochem Behav 1998 Jun;60(2):377-86. Abstract

Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL. Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A. Nat Struct Biol. 1997 Jan;4(1):57-63. Abstract

Tang XC. Huperzine A (shuangyiping): a promising drug for Alzheimer's disease. Zhongguo Yao Li Xue Bao. 1996 Nov;17 (6):481-4. Abstract

Zhi QX, Yi FH, XI CT. Huperzine A ameliorates the spatial working memory impairments induced by AF64A. Neuroreport. 1995 Nov 13;6(16):2221-4. Abstract

Ashani Y, Grunwald J, Kronman C, Velan B, Shafferman A. Role of tyrosine 337 in the binding of huperzine A to the active site of human acetylcholinesterase. Mol Pharmacol. 1994 Mar;45(3):555-60. Abstract

Geib SJ, Tuckmantel W, Kozikowski AP. Huperzine A--a potent acetylcholinesterase inhibitor of use in the treatment of Alzheimer's disease. Acta Crystallogr C. 1991 Apr 15;47(Pt 4):824-7. Abstract