Huperzine A Studies

1: Zhongguo Yao Li Xue Bao. 1999 Jul;20(7):601-3.
Huperzine-A capsules enhance memory and learning

performance in 34 pairs of matched adolescent students.
Sun QQ, Xu SS, Pan JL, Guo HM, Cao WQ.
Xiaoshan Mental Hospital, Zhejiang, China.
AIM: To study the efficacy of huperzine-A capsules (Hup) on memory and learning
performance of adolescent students. METHODS: Using double-blind and matched pair
method, 34 pairs of junior middle school students complaining of memory inadequacy
were divided into two groups by normal psychological health inventory (PHI), similar
memory quotient (MQ), same sex and class. The Hup group was administrated orally 2
capsules of Hup (each contains Hup 50 micrograms) b.i.d., and the placebo group was
given 2 capsules of placebo (starch and lactose inside) b.i.d. for 4 wk. RESULTS: At the
end of trial, the Hup group's MQ (115 +/- 6) was more than that of the placebo group (104
+/- 9, P < 0.01), and the scores of Chinese language lesson in the Hup group were
elevated markedly too. CONCLUSION: The Hup capsules enhance the memory and
learning performance of adolescent students.
http://www.ncbi.nlm.nih.gov/pubmed/10678121?
ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_Defa
ultReportPanel.Pubmed_RVDocSum
1: J Neural Transm. 2009 Apr;116(4):457-65. Epub 2009 Feb 17.
Efficacy and safety of natural acetylcholinesterase

inhibitor huperzine A in the treatment of Alzheimer's
disease: an updated meta-analysis.
Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ.
Department of Pharmacology and Biostatistics, Institute of Medical Sciences, Shanghai

Jiaotong University School of Medicine, 200025, Shanghai, China.
The objective of this study was to provide an updated meta-analysis of the efficacy and
safety of huperzine A (HupA) in Alzheimer's disease (AD). We searched for randomized
trials comparing HupA with placebo in the treatment of AD. The primary outcome
measures were mini-mental state examination (MMSE) and activities of daily living scale
(ADL). Data were extracted from four randomized clinical trials and analyzed using
standard meta-analysis and meta-regression methods. Oral administration of HupA for 8-
24 weeks (300-500 microg daily) led to significant improvements in MMSE and ADL.
The results of meta-regression showed that the estimated effect size of MMSE and ADL
was increased over the treatment time. Most adverse events were cholinergic in nature
and no serious adverse events occurred. Huperzine A is a well-tolerated drug that could
significantly improve cognitive performance and ADL in patients with AD.
ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_Disc
overyPanel.Pubmed_Discovery_RA&linkpos=3&log$=relatedarticles&logdbfrom=pubmed
1: Curr Med Chem. 2000 Mar;7(3):355-74.
Huperzine A, a potential therapeutic agent for treatment of Alzheimer's

disease.
Bai DL, Tang XC, He XC.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 294 Taiyuan Road,
Shanghai, 200031, China.
HupA is a potent, reversible and selective inhibitor of AChE with a rapid absorption and
penetration into the brain in animal tests. It exhibits memory-enhancing activities in
animal and clinical trials. Compared to tacrine and donepezil, HupA possesses a longer
duration of action and higher therapeutic index, and the peripheral cholinergic side effects
are minimal at therapeutic doses. This review article deals with a comprehensive survey
of the progress in chemical and pharmacological studies of HupA including the isolation
and structure elucidation, pharmacological actions, total synthesis, SAR studies and the
future development of HupA. Recently, it has been reported that HupA could reduce
neuronal cell death caused by glutamate. The dual bio-activities of HupA would further
enhance its value and potentiality as the therapeutic agent for Alzheimer s disease.
ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_Def
aultReportPanel.Pubmed_RVDocSum
1: Neurosignals. 2005;14(1-2):71-82.
Neuroprotective effects of huperzine A. A natural

cholinesterase inhibitor for the treatment of Alzheimer's
disease.
Wang R, Tang XC.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai
Institutes for Biological Sciences, Chinese Academy of Sciences, Zhangjiang Hi-Tech
Park, Shanghai, China.
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,
beta-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
ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_Dis
coveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedreviews&logdbfrom=pub
med
1: Acta Pharmacol Sin. 2006 Jan;27(1):1-26.
Progress in studies of huperzine A, a natural

cholinesterase inhibitor from Chinese herbal medicine.
Wang R, Yan H, Tang XC.
Institutes for Biological Sciences, Chinese Academy of Sciences, China.
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,
beta-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.
med
1: Chem Biol Interact. 2008 Sep 25;175(1-3):396-402. Epub 2008 May 13. Links
Potential therapeutic targets of huperzine A for

Alzheimer's disease and vascular dementia.
Zhang HY, Zheng CY, Yan H, Wang ZF, Tang LL, Gao X, Tang XC.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, China.
Huperzine A (HupA), a novel Lycopodium alkaloid isolated from Chinese folk medicine
Huperzia serrata (Qian Ceng Ta), is a potent, selective and well-tolerated inhibitor of
acetylcholinesterase (AChE). It has been proven to significantly improve the learning and
memory impairment in Alzheimer's disease (AD) and vascular dementia (VaD) patients in
China. Interestingly, our recent data indicate that HupA also possesses other protective
functions. This paper will give an overview on the protective effects of HupA, which
includes regulating beta-amyloid precursor protein (APP) metabolism, protecting against
Abeta-mediated oxidative stress, apoptosis and mitochondrial dysfunction, as well as anti-
inflammation. The multiple neuroprotective effects of HupA might yield additional
beneficial effects in AD and VaD therapy.
med
1: Trends Pharmacol Sci. 2006 Dec;27(12):619-25. Epub 2006 Oct 23.
Neuroprotective effects of huperzine A: new therapeutic

targets for neurodegenerative disease.
Zhang HY, Tang XC.
Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
In recent years, the most common pharmacological treatment for Alzheimer's disease
(AD) has been acetylcholinesterase (AChE) inhibition. However, this single-target
approach has limited effectiveness and there is evidence that a multitarget approach might
be more effective. Huperzine A (HupA), a novel alkaloid isolated from a Chinese herb,
has neuroprotective effects that go beyond the inhibition of AChE. Recent data have
demonstrated that HupA can ameliorate the learning and memory deficiency in animal
models and AD patients. Its potentially beneficial actions include modification of beta-
amyloid peptide processing, reduction of oxidative stress, neuronal protection against
apoptosis, and regulation of the expression and secretion of nerve growth factor (NGF)
and NGF signaling.
coveryPanel.Pubmed_Discovery_RA&linkpos=3&log$=relatedarticles&logdbfrom=pub
med
1: Cell Mol Neurobiol. 2008 Feb;28(2):173-83. Epub 2007 Jul 27.
Non-cholinergic effects of huperzine A: beyond

inhibition of acetylcholinesterase.
Zhang HY, Yan H, Tang XC.
Academy of Sciences, 555 Zu Chong Zhi Rd, Shanghai, 201203, China.
The use of acetylcholinesterase inhibitors to decrease the breakdown of the

neurotransmitter acetylcholine has been the main symptomatic therapy for mild to
moderate Alzheimer's patients, though the etiology of Alzheimer's disease remains
unclear and seems to involve multiple factors. Further evidence has indicated that some of
these acetylcholinesterase inhibitors also have non-cholinergic functions on the
pathogenesis of Alzheimer's disease including the formation and deposition of beta-
amyloid. Huperzine A, a potent and reversible inhibitor of acetylcholinesterase that was
initially isolated from a Chinese herb, has been found to improve cognitive deficits in a
broad range of animal models and has been used for Alzheimer's disease treatment in
China. The novel neuroprotective effects of huperzine A might yield beneficial effects in
Alzheimer's disease therapy and provide a potential template for the design of new
selective and powerful anti-Alzheimer's drugs. The present paper gives an overview on
the neuroprotective effects of huperzine A beyond its acetylcholinesterase inhibition.
These effects include regulating beta-amyloid precursor protein metabolism, protecting
against beta-amyloid-mediated oxidative stress and apoptosis. The structure-function
relationship of huperzine A is also discussed.
med
1: Eur J Pharmacol. 2005 Sep 5;519(1-2):9-15. Links
Huperzine A protects SHSY5Y neuroblastoma cells against

oxidative stress damage via nerve growth factor
production.
Tang LL, Wang R, Tang XC.
Institutes for Biological Sciences, Shanghai 201203, PR China.
Our previous study demonstrated that huperzine A, a selective acetylcholinesterase inhibitor,
stimulates the synthesis of nerve growth factor (NGF) in cultured rat cortical astrocytes. The
present studies are designed to examine if huperzine A exerts its neuroprotective activity against
oxidative stress damage through increasing the synthesis of NGF in SHSY5Y neuroblastoma
cells. Transient exposure of the cells to 200 microM H2O2 triggered a significant reduction of
cell viability and decreased the mRNA and protein levels of NGF, neurotrophin receptor P75
(P75NTR) receptor and tyrosine kinase A (TrkA) receptor. Incubation of cells with 10 microM
huperzine A prior to H2O2 exposure significantly elevated their survival and restored the mRNA
and protein levels of NGF, P75NTR receptor and TrkA receptor. These neuroprotective effects of
huperzine A on H2O2-induced cytotoxicity were blocked by the TrkA receptor phosphorylation
inhibitor K252alpha, and were antagonized by the mitogen-activated protein (MAP)/extracellular
signal-regulated kinase (ERK) inhibitor, PD98059. The present results indicate that the
cytoprotective effect of huperzine A is mediated at least partly by up-regulated NGF and NGF
receptors. The results also show that the MAP/ERK kinase signal pathway is crucial for
huperzine A to protect against H2O2-induced damage in SHSY5Y cells.
http://www.ncbi.nlm.nih.gov/pubmed/16111675
Abstract:
Aim:
To study the effects of huperzine A (HupA) on neuritogenic activity and the expression of nerve
growth factor (NGF). Methods:
After being treated with 10 mol/L HupA, neurite outgrowth of PC12 cells was observed and
counted under phase-contrast microscopy. Mitogenic activity was assayed by [3H]thymidine
incorporation. Cell cytotoxicity was evaluated by lactate dehydrogenase (LDH) release. AChE
activity, mRNA and protein expression were measured by the Ellman's method, RT-PCR, and
Western blot, respectively. NGF mRNA and protein levels were determined by RT-PCR and
ELISA assays. Results:
Treatment of PC12 cells with 10 mol/L HupA for 48 h markedly increased the number of
neurite-bearing cells, but caused no significant alteration in cell viability or other signs of
cytotoxicity. In addition to inhibiting AChE activity, 10 mol/ L HupA also increased the
mRNA and protein levels of this enzyme. In addition, following 2 h exposure of the astrocytes to
10 mol/L HupA, there was a significant up-regulation of mRNA for NGF and P75 low-
affinity NGF receptor. The protein level of NGF was also increased after 24 h treatment with
HupA. Conclusion:
Our findings demonstrate for the first time that HupA has a direct or indirect neurotrophic
activity, which might be beneficial in treatment of neurodegenerative disorders such as
Alzheimer disease.
Keywords: huperzine A; nerve growth factor; neurite outgrowth; acetylcholinesterase inhibitors
Document Type: Research article
DOI: 10.1111/j.1745-7254.2005.00130.x
Affiliations: 1: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203,
China
http://www.ingentaconnect.com/content/bsc/aphs/2005/00000026/00000006/art00005
Neurosci Lett. 2001 Mar 16;300(3):145-8.
Long-term potentiation in hippocampus of

rats is enhanced by endogenous
acetylcholine in a way that is independent
of N-methyl-D-aspartate receptors.
Ye L, Qi JS, Qiao JT.
Department of Neurobiology, Shanxi Medical University, Taiyuan, 030001, Shanxi, PR China.
By using extracellular recordings of field potential, the exact pathway by which the endogenous
ACh influencing the induction of long-term potentiation (LTP) in CA1 area was analysed in
slices of rat hippocampus. The results showed that: (1) the application of (-) huperzine A, an
AChE inhibitor extracted from Chinese herb Qian Ceng Ta (Huperzia Serrata), could enhance the
induction of LTP, while this drug showed little effect on the second components of multiple
population spikes that were recorded in Mg(2+)-free medium and had proven to be N-methyl-D-
aspartate (NMDA) receptor-mediated response; and (2) scopolamine, a muscarinic receptor
antagonist, could significantly suppressed the induction of LTP, while most of the suppressive
effect of scopolamine was blocked when slices were pretreated by bicuculline, a gamma-
aminobutyric acid (GABA(A)) receptor antagonist. These results suggest that endogenous ACh
potentiates the induction of LTP through the inhibition of GABAergic interneurons that modulate
pyramidal neurons, but not through the activation of NMDA receptors located on pyramidal
neurons.
Acta Pharmacol Sin. 2000 Dec;21(12):1169-73.
Huperzine A reverses scopolamine- and

muscimol-induced memory deficits in
chick.
Gao Y, Tang XC, Guan LC, Kuang PZ.
Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China.
gaoy@s1000.psych.ac.cn
AIM: To study the effects of huperzine A on disruption of spatial memory induced by
scopolamine (a muscarinic antagonist) and muscimol (a GABAA agonist) in passive avoidance
task. METHODS: One-trial passive avoidance task was used to investigate the effects of
huperzine A. The avoidance rate was used to evaluate memory retention. RESULTS: Both
scopolamine (100 ng) and muscimol (50 ng), injected intracranially 5 min before training,
resulted in a decreased avoidance rate. Huperzine A (25 ng), injected intracranially 15 min before
training, reversed memory deficits induced by scopolamine and muscimol at 30 min after
training, and this reversal persisted at least 1 h. The improving effects of huperzine A exhibited a
bell-shaped dose-response curve. CONCLUSION: Huperzine A improved the process of memory
formation not only by acting as a highly potent and selective inhibitor of AChE, but also by
antagonizing effects mediated through the GABAA receptor.
PMID: 11603295 [PubMed - indexed for MEDLINE]
Zhongguo Yao Li Xue Bao. 1995 Sep;16(5):396-8.
Pharmacokinetics of tablet huperzine A in six

volunteers.
Qian BC, Wang M, Zhou ZF, Chen K, Zhou RR, Chen GS.
Department of Pharmacology, Zhejiang Academy of Medical Sciences, Hangzhou, China.
AIM: To study pharmacokinetics of tablet huperzine A (Hup-A) in Chinese volunteers to help
establishing its drug administration schedule. METHODS: For 6 volunteers after a single oral
dose of 0.99 mg, drug concentrations in plasma were assayed by reverse phase high pressure
liquid chromatography (HPLC) at 0.5, 0.75, 1.0, 1.25, 1.5, 2, 4, 6, 8, and 10 h. The
pharmacokinetic parameters were calculated with a 3P87 program by computer. RESULTS: The
time course of plasma concentrations conformed to a one-compartment open model with a first
order absorption. The pharmacokinetic parameters were as follows: T 1/2ka = 12.6 min, T 1/2ke
= 288.5 min, Tmax = 79.6 min, Cmax = 8.4 micrograms L-1, AUC = 4.1 mg L-1 min.
CONCLUSION: Hup-A was absorbed rapidly, distributed widely in the body, and eliminated at a
moderate rate.
Eur J Drug Metab Pharmacokinet. 2007 Oct-Dec;32(4):183-7.
Pharmacokinetics of huperzine A following

oral administration to human volunteers.
Li YX, Zhang RQ, Li CR, Jiang XH.
West China School of Pharmacy, Sichuan University, Sichuan, Peoples' Republic of China.
The objective of the present study was to investigate the in vivo pharmacokinetics of huperzine A
in healthy human volunteers. Twelve subjects (M 6, F 6; age ranged from 20-25 years)
participated in the study. Huperzine A was administered in tablet form at a single dose of 0.4 mg.
Following oral administration, the presence of huperzine A started to appear in the plasma at 5-10
min, and reached the peak concentrations with a Cmax of 2.59 +/- 0.37 ng/ml at 58.33 +/- 3.89
min (time to reach peak level, Tmax. The area under plasma vs time curve (AUC(0-t)) and the
area under plasma from zero to infinity (AUC(0-infinity) for huperzine A were found to be
1986.96 +/- 164.57 microg/l.min and 2450.34 +/- 233.32 microg/l.min, respectively. The results
of this study indicated that the pharmacokinetics of huperzine A conformed to a two-
compartmental open model. The mean values of alpha and the beta half-life were 21.13 +/- 7.28
min and 716.25 +/- 130.18 min respectively, and showed a biphasic profile with rapid
distribution followed by a slower elimination rate.

Huperzine A Studies

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1: Zhongguo Yao Li Xue Bao. 1999 Jul;20(7):601-3.

Huperzine-A capsules enhance memory and learning

Xiaoshan Mental Hospital, Zhejiang, China.

Efficacy and safety of natural acetylcholinesterase

Department of Pharmacology and Biostatistics, Institute of Medical Sciences, Shanghai

Huperzine A, a potential therapeutic agent for treatment of Alzheimer's

Bai DL, Tang XC, He XC.

Neuroprotective effects of huperzine A. A natural

Progress in studies of huperzine A, a natural

Potential therapeutic targets of huperzine A for

Neuroprotective effects of huperzine A: new therapeutic

Non-cholinergic effects of huperzine A: beyond

The use of acetylcholinesterase inhibitors to decrease the breakdown of the

Huperzine A protects SHSY5Y neuroblastoma cells against

Long-term potentiation in hippocampus of

Huperzine A reverses scopolamine- and

Pharmacokinetics of tablet huperzine A in six

Pharmacokinetics of huperzine A following

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