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The effects of huperzine A on gastrointestinal acetylcholinesterase activity and motility after single and multiple dosing in mice
Abstract
The acetylcholinesterase inhibitor (AChEI), huperzine A has been used in the treatment of the cognitive deterioration associated with Alzheimer’s disease (AD). However, the side-effects of huperzine A associated with increased cholinergic activity, particularly in the gastrointestinal system, are evident. It is not yet known how quickly these side-effects become tolerated; this information would provide guidance to doctors on how to use huperzine A so as to attenuate the adverse events. The present study aimed to observe the effects of huperzine A on gastrointestinal motility and acetylcholinesterase (AChE) activity in mice. After oral administration of huperzine A with single and multiple dosing, the gastrointestinal motility and AChE activity of the mice were examined. The results revealed that, following a single dose of huperzine A, the AChE activity in the stomach and duodenum were significantly inhibited and the gastrointestinal motility was significantly increased. However, following multiple doses (7 or 28 doses, one dose per day), no significant changes in the AChE activity and gastrointestinal motility were identified. These findings indicate that the gastrointestinal adverse effects of huperzine A may be well-tolerated relatively quickly and do not recur. Additionally, it suggests that patients with AD are likely to have minimal gastrointestinal side-effects after taking multiple doses of huperzine A.
Introduction
Alzheimer’s disease (AD) is the most common form of dementia. Currently, there is no cure for the disease, which worsens as it progresses and eventually leads to mortality. The cause of the majority of Alzheimer’s cases remains unknown. The most significant hypothesis attempting to explain the cause of the disease is the cholinergic hypothesis ( 1 ), which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine.
Acetylcholinesterase inhibitors (AChEIs), including tacrine, rivastigmine, galantamine and donepezil, are currently used to treat the cognitive manifestations of AD ( 2 ). However, AChEIs may cause a broad spectrum of adverse events in the gastrointestinal system, including nausea, vomiting and diarrhea ( 3 , 4 ). These side-effects arise in ∼10–20% of users and are mild to moderate in severity. These adverse events, which force a number of patients to stop taking AChEI agents, are generally recognized to be a result of parasympathetic nervous system activity. AChEIs ameliorate dementia by inhibiting acetylcholinesterase (AChE) in the central nervous system ( 5 , 6 ).
The AChEI huperzine A, an alkaloid isolated from Huperzia serrata, has been used in the treatment of the cognitive deterioration associated with AD in China ( 7 ). It also results in nausea, vomiting and diarrhea, similar to other AChEIs. To date, it is not known how quickly these side-effects become tolerated. The present study aimed to observe the effects of huperzine A on gastrointestinal motility and AChE activity in mice, following varying periods of administration, to provide guidance to doctors on how to use huperzine A so as to attenuate adverse events.
Materials and methods
Chemicals and instruments
Huperzine A tablets were obtained from Henan Tailong Pharmaceutical Co., Ltd. (Henan, China). Loperamide hydrochloride capsules were obtained from Xian Janssen Pharmaceutical Ltd. (Xian, China). All other chemicals and reagents used in this study were of analytical grade.
Animals
Male Swiss mice weighing 20±2 g were obtained from the Experimental Animal Center of Luye Pharmaceutical Company (Shandong, China). All experimental procedures carried out in this study were performed in accordance with the guidelines for the care and use of laboratory animals of Yantai University and were approved by the Ethics Committee of the university. All mice were housed in diurnal lighting conditions (12 h/12 h) and allowed free access to food and water.
Gastrointestinal motility
Fifty mice were randomly divided into five groups (10 animals per group): a vehicle group, a loperamide group (Lop), a loperamide + 0.05 mg/kg huperzine A group (Lop+Hup A 0.05), a loperamide + 0.1 mg/kg huperzine A group (Lop+Hup A 0.1) and a loperamide + 0.2 mg/kg huperzine A group (Lop+Hup A 0.2). The animals in the vehicle and Lop groups received intragastric administration of solvent, while huperzine A was administered to the animals in the Lop+Hup A groups. Each mouse was fasted for 12 h prior to the gastrointestinal motility test. After single and multiple dosing (7 or 28 doses, one dose per day), the mice received an oral administration of 4 mg/kg loperamide, 1 h after the last administration of huperzine A. Thirty minutes later, each mouse received an oral administration of 0.2 ml charcoal meal. After 15 min, each animal was sacrificed and the intestinal distance of movement of the charcoal meal from the pylorus was measured and expressed as a percentage of the distance from the pylorus to the cecum.
AChE activity assays
Following the gastrointestinal motility test, the brain, stomach and duodenum of mice in each group were separated on ice and homogenized with ice-cold saline to form a 10% (w/v) homogenate. AChE activity was determined based on the methods of Ellman et al( 8 ). Briefly, a reaction mixture containing 955 μl sodium phosphate (0.1 M, pH 7.4), 25 μl 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB; final concentration, 0.5 mM) and 10 μl homogenate was incubated for 5 min at 37°C, then 10 μl 0.1 M acetylcholine iodide (final concentration, 1 mM) was added. After incubation for 15 min at 37°C, the absorbance was measured at 412 nm at room temperature. AChE activity was expressed as U/g protein.
Statistical analysis
Data were analyzed using one-way analysis of variance (ANOVA) with Bonferroni post hoc test for multiple t-tests. A value of P<0.05 was considered to indicate a statistically significant difference. All data in this study were expressed as mean ± standard deviation.
Results
Effects of huperzine A on gastrointestinal motility
Following a single dose of huperzine A, the intestinal propulsion rates were significantly increased; however, following the administration of multiple doses (7 or 28 doses, one dose per day), no significant differences in intestinal propulsion rates were observed compared with those in the Lop group ( Fig. 1 ).

Effects of huperzine A on gastrointestinal motility. (A) Following a single dose of huperzine A, the intestinal propulsion rates were significantly increased; however, following the administration of (B) 7 doses or (C) 28 doses (one dose per day), no significant differences of intestinal propulsion rates were observed. Data are expressed as mean ± standard deviation (SD); n=10; **P<0.01 vs. the Lop group; ΔΔP<0.01 vs. the vehicle group. Lop, loperamide; Hup A, huperzine A.
Effects of huperzine A on AChE activity of gastrointestinal tissues in mice
Following a single dose of huperzine A, AChE activity in the stomach and duodenum was significantly inhibited; however, following the administration of multiple doses (7 or 28 doses, one dose per day), no significant differences in AChE activity were observed compared with those in the Lop group ( Fig. 2 ).
Effects of huperzine A on AChE activity in gastrointestinal tissues in mice. Following a single dose of huperzine A, AChE activity in (A) the stomach and (B) the duodenum was significantly inhibited; however following the administration of (C and D) 7 doses or (E and F) 28 doses (one dose per day), no significant differences in AChE activity were observed. Data are expressed as mean ± standard deviation (SD), n=10; *P<0.05, **P<0.01 vs. the Lop group. AChE, acetylcholinesterase; Lop, loperamide; Hup A, huperzine A.
Effects of huperzine A on AChE activity in the brain
Following single- or multiple-dose administration of huperzine A, the AChE activities in the brains of the mice were significantly inhibited compared with that in the Lop group ( Fig. 3 ).

Effects of huperzine A on AChE activity in the brains of mice. Following the oral administration of single and multiple doses of huperzine A, the AChE activity was significantly inhibited. (A) Single dose; (B) 7 doses; and (C) 28 doses. Data are expressed as mean ± standard deviation (SD), n=10; *P<0.05,**P<0.01 vs. the Lop group. AChE, acetylcholinesterase; Lop, loperamide; Hup A, huperzine A.
Discussion
AChEIs have been approved for the symptomatic treatment of AD for approximately twenty years. However, the side-effects associated with increased cholinergic activity, particularly in the gastrointestinal system, prevent patients from receiving effective doses of the drug. In addition, the advanced age and frail nature of many patients with AD mean that poor tolerability is a serious concern.
Gastrointestinal motor activity is mainly regulated by the neural and hormonal systems ( 9 ). Cholinergic neurons are considered to be the major excitatory neurons involved in gastrointestinal motor activity since the majority of gastrointestinal contractions are markedly inhibited by atropine, a muscarinic receptor antagonist ( 10 , 11 ). Acetylcholine (ACh) is an important regulator of gastrointestinal motility and the inhibition of AChE activity has been reported to enhance gastrointestinal motility ( 12 , 13 ).
In the present study we investigated gastrointestinal motility and AChE activity in the stomach and duodenum following single- and multiple-dose oral administration of huperzine A at therapeutic doses in mice ( 14 , 15 ).
In order to enhance the detection sensitivity of huperzine A on gastrointestinal motility, mice were administered loperamide, an opioid-receptor agonist often used against diarrhea, to slow down the gastrointestinal motility. The results revealed that the AChE activities in the brains of mice receiving single- and multiple-dose huperzine A treatment were significantly reducted, which indicates that the dosage of huperzine A administered would be effective for AD. After a single dose of huperzine A, the gastrointestinal AChE activity was reduced and intestinal propulsion rate was significantly increased, which demonstrates that gastrointestinal side-effects are likely to occur during the initial period of treatment with huperzine A. However, after multiple-dose (7 or 28 doses, one dose per day) administration, no significant differences in gastrointestinal AChE activity and intestinal propulsion rates were observed. These results indicate that huperzine A affects gastrointestinal motility by inhibiting AChE activity, but after multiple-dose administration it is well-tolerated in the gastrointestinal system of mice. The molecular mechanisms explaining how gastrointestinal motility and AChE activity are unaffected by multiple-dose administration require further study.
These findings indicate that the gastrointestinal adverse effects of huperzine A may be well-tolerated relatively quickly and that patients with AD are likely to have minimal gastrointestinal side-effects after taking multiple doses of huperzine A.
Acknowledgments
This study was supported by the Taishan Scholar Project, a project of Shandong Province Higher Educational Science and Technology Program (grant no. J10LF76) and the Foundation for Outstanding Middle-aged and Young Scientists (grant no. BS2011YY061).
References
Articles from Experimental and Therapeutic Medicine are provided here courtesy of Spandidos Publications
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13 Huperzine-A Health Benefits + Dosage Side Effects

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Huperzine A is an alkaloid extracted from a club moss called Huperzia serrata. Huperzine A has neuroprotective and nootropic properties and is suggested as a treatment for Alzheimer’s disease. Read this post to learn more about huperzine A and its health benefits.
Contents
- What is Huperzine?
- How Huperzine A Works
- Huperzine A Inhibits an Enzyme that Breaks Down Acetylcholine
- Huperzine A Changes Neurotransmitter Levels
- Pharmacokinetics of Huperzine A
- Huperzine Crosses the Blood-Brain Barrier
- Huperzine is Readily Absorbed and Turned Over
- Huperzine A Crosses the Placenta
- Most Huperzine A in the Body is Eliminated in the Urine
- Dosage Studies in Humans
- Health Benefits of Huperzine A
- 1-5) Huperzine A is Neuroprotective
- 6) Huperzine A Helps with Brain Damage from Severe Bacterial Infections (Sepsis)
- 7) Huperzine A Helps with Cognitive Symptoms from Depression
- 8) Huperzine A Helps with Epileptic Seizures
- 9) Huperzine Could be a Safe way to Treat Addiction
- 10) Huperzine A Promotes Liver Health
- 11) Huperzine A as a Nootropic
- 12) Huperzine A Promotes Growth of Neural Cells
- 13) Huperzine A Helps with Myasthenia Gravis
- Drug Interaction
- Dosage
- Side Effects
- Technical/Mechanisms
- Buy Huperzine A Tablets
What is Huperzine?
Huperzine A (HupA) is an alkaloid extracted from the club moss (Huperzia serrata).
Club moss (Qian Ceng Ta) was traditionally used in Chinese medicine for fever, inflammation , and schizophrenia [ R , R ].
It has demonstrated both memory enhancement and neuroprotective effects in animal and clinical trials [ R ].
There are two forms of huperzine A, (+) and (-). The (-) form is found naturally in the Huperzia moss and is more potent than the (+) form.
How Huperzine A Works
The impact of huperzine A can vary among people due to their genetic differences. Visit SelfDecode to learn how you can investigate your own genetic makeup to see how it affects the use of huperzine A.
Huperzine A Inhibits an Enzyme that Breaks Down Acetylcholine
Huperzine A is a potent, reversible, and specific inhibitor of the enzyme acetylcholine esterase (ACHE), which breaks down acetylcholine, although huperzine A also has other brain-supporting effects that do not involve ACHE [ R ].
Huperzine A binds to ACHE but its structure is not similar to that of acetylcholine.
Huperzine A works in similar ways to Alzheimer’s drugs, including donepezil, rivastigmine, tacrine, and galantamine, although with fewer side effects and somewhat more favorable pharmacokinetics [ R ].
Huperzine A helps with inflammation by reducing activities of NF-kB signaling, which may happen both through inhibition of acetylcholine esterase or in other ways [R].
Huperzine A Changes Neurotransmitter Levels
Huperzine A Increases Acetylcholine
Huperzine A increases acetylcholine levels in rat brain for up to 6 hours post administration [ R ].
An increase of acetylcholine seems to differ between different parts of the rat brain. Following administration, maximum levels are observed in the hippocampus after 30 min and in the frontal and prefrontal cortex after 60 min. This shows that it can influence the function of diseases that specifically affect these parts of the brain [ R , R ].
Huperzine A results in a more prolonged increase in acetylcholine in the whole brain than tacrine , physostigmine, and metrifonate [ R , R , R ].
Huperzine A Increases Norepinephrine and Dopamine, but not Serotonin
Huperzine A increases levels of norepinephrine and dopamine, but not that of serotonin [ R ].
Pharmacokinetics of Huperzine A
Huperzine Crosses the Blood-Brain Barrier
After injecting mice with 183 micrograms/kg Huperzine A, it was found throughout all regions of the brain, particularly in the cortex, hippocampus, and nucleus accumbens [ R ]. Thus, huperzine A crossed the blood-brain barrier and readily distributes throughout the brain.
Huperzine is Readily Absorbed and Turned Over
In humans, oral huperzine A is absorbed quickly, distributed widely and eliminated at a moderate rate [ R ].
In mice, huperzine A is highest in kidney and liver 15 minutes after injection. After 12 hours no trace of huperzine A is found anywhere in the body [ R ].
Huperzine A Crosses the Placenta
In pregnant mice a small amount of huperzine A is found in the fetus, suggesting huperzine A crosses the placenta [ R ].
Most Huperzine A in the Body is Eliminated in the Urine
In mice, 73% of huperzine A is excreted in urine 24 hours post-injection, and only 2.4% is found in feces [ R ].
Dosage Studies in Humans
At a very high dose of 0.99 mg, a peak serum concentration is reached at 79 minutes. Half of huperzine A is found (half-life) at 288 minutes, suggesting that it may be necessary to dose huperzine A multiple times a day to achieve continuous effects. No notable side effects were observed at doses between 0.18 – 0.54 mg in humans [ R ].
No tolerance for continued use has been reported from repeated use [ R ].
Another study found that huperzine A appears in the blood at 5 – 10 minutes after subjects ingest 0.4 mg of huperzine A.
Huperzine A in the blood reaches the maximum concentration at around 58 minutes. After 10 hours 50% of it still present (half-life = 10 hours) and its mostly eliminated after 24 hours [ R ].
Health Benefits of Huperzine A
1-5) Huperzine A is Neuroprotective
Huperzine A Protects Against Toxic Organophosphates
Nerve gasses and organophosphates are irreversible inhibitors of acetylcholine esterase. Huperzine A use can prevent seizures and nervous system dysfunctions caused by soman, an organophosphate [ R ].
Huperzine A Protects Neurons Against Glutamate Toxicity
Glutamate is an amino acid neurotransmitter that can kill neuronal cells by overstimulating the NMDA receptors, especially in more mature neurons [ R ].
Huperzine A is an NMDA receptor antagonist, which means it can help prevent neurons from cell death due to glutamate toxicity [ R ].
Huperzine A Protects the Brain From Oxidative Damage
In addition to binding to NMDA receptors, huperzine A also alleviates oxidative damage from glutamate toxicity by activating BDNF -dependent and mTOR signaling pathways [ R ].
Huperzine A also protects against oxidative damage from iron overload [ R ].
Huperzine A Helps With Recovering from Traumatic Brain Injury and Spinal Cord Injury
Huperzine A, together with other brain-supporting substances (vinpocetine, acetyl-L-carnitine, n-acetylcysteine, and alpha lipoic acid), multivitamin and fish oil , seems to help increase brain blood flow and improve cognitive functions in retired NFL football players with a history of concussions [ R ].
Huperzine A aids in recovery from brain bleeding by preventing damage to the mitochondria and postponing cell death [ R ].
Huperzine A decreases apoptosis and improved neurological symptoms in rats with spinal cord trauma [ R ].
Huperzine A Prevents and Treats Alzheimer’s Disease
In a systematic review of different interventions for Alzheimer’s , aggregate data from multiple studies show that huperzine A has a stronger (most statistically significant) effect in mitigating Alzheimer‘s and cognitive decline than other interventions. However, the quality of these studies is lower than the quality of studies of other interventions [ R ].
Many of such studies are poorly controlled or were not designed to rule out biases from the authors. In addition, most of the studies and clinical trials were from China.
In some patients with Alzheimer’s Disease, a clinical trial has shown that huperzine A improves mental ability and overall well-being [ R ].
Huperzine A significantly reduces the NF-kB pathway in immune cells in the brain, suggesting it reduces inflammation, which can help with Alzheimer’s [ R ].
Figure (1): How Huperzine A Helps with Alzheimer’s [ R ].
6) Huperzine A Helps with Brain Damage from Severe Bacterial Infections (Sepsis)
In rats model of severe bacterial infection (sepsis), huperzine A protects the brain from damage by reducing inflammation and increasing functions of cholinergic neurons [ R ].
7) Huperzine A Helps with Cognitive Symptoms from Depression
As an add-on treatment for depression, huperzine A helped resolved some cognitive symptoms associated with depression but did not resolve depression itself [ R ].
8) Huperzine A Helps with Epileptic Seizures
In studies done on animals, Huperzine A was shown to protect brain cells from overexcitement and death associated with convulsions [ R ].
Huperzine A is an effective treatment for epilepsy in rats [ R ].
Huperzine A can make the tissue more resistant to seizures associated with various forms of epilepsy [ R ].
9) Huperzine Could be a Safe way to Treat Addiction
A study based on self-administration showed that huperzine A decreased the individual’s perception of the effects of cocaine and could be a safe way to treat addiction [ R ].
10) Huperzine A Promotes Liver Health
Huperzine A protects liver cells that receive oxygen after a prolonged period of deoxygenation.
Through its role as a controller of signaling pathways that govern oxidation and cell death, it can decrease the amount of damage caused to cells because of liver reoxygenation such as that which occurs during an organ transplant [ R ].
11) Huperzine A as a Nootropic
Huperzine A helps with memory in high school students when compared to a placebo [ R ].
Huperzine A helps with chemical-induced cognitive impairment in mice [ R ].
12) Huperzine A Promotes Growth of Neural Cells
Huperzine A can stimulate the growth of neuronal cells in the hippocampus of mice [ R ].
13) Huperzine A Helps with Myasthenia Gravis
Myasthenia gravis is an autoimmune disease where the immune system attacks acetylcholine receptors, and the treatments involve immunosuppressants and acetylcholine esterase inhibitors [ R ].
In one clinical study, involving 128 patients, huperzine A helped with muscle weakness in Myasthenia gravis patients [ R ].
Drug Interaction
Huperzine A is unlikely to interact with cytochrome P450 .
Experiments using human liver cells have shown that it is not modified and excreted whole making it unable to react with other drugs that are metabolized by the cytochrome P450 system [ R ].
Dosage
For Alzheimer’s patients, a dosage of 0.4 mg twice daily was required to produce clinically significant results, as 0.2 mg twice daily did not [ R ].
Dosages of huperzine A in clinical trials for Alzheimer’s range from 0.2 mg to 0.8 mg [ R ].
In high school students who struggle with memory, 0.1 mg was sufficient to improve memory [ R ].
Side Effects
Reported adverse effects are very rare, but are cholinergic symptoms, such as dizziness, nausea , digestive upsets, headache , and decreased heart rate [ R ].
Technical/Mechanisms
- The neuroprotective effect of Huperzine A occurs concurrently with a decrease in ROS and an increase in ATP [ R ].
- It is substantially excreted by kidney unchanged rather than metabolized by the human liver and is unlikely to cause clinically relevant drug-drug interaction (DDI) when co-administrated with drugs that are metabolized by CYP isoenzyme system [ R ].
- Huperzine A can regulate NF-κB pathway to treat Alzheimer’s Disease [ R ].
- It provides protection from excitotoxicity and neuronal death as well as an increase in GABAergic transmission associated with an anticonvulsant activity [ R ].
- Huperzine A inhibits cell apoptosis through restraining microglia’s inflammatory response induced by Aβ1-42 [ R ].
- Muscarinic and GABA receptors play a role in Huperzine A-mediated seizure protection [ R ].
- Huperzine A inhibits NF-kB activation, which attenuates nitric oxide synthase, cyclooxygenase -2 and nitric oxide over-expression by indirectly activating a type of acetylcholine receptors called α7nAChRs [ R ].
- Huperzine A stimulates nerve growth factor secretion and signaling [ R ].
Buy Huperzine A Tablets
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Huperzine-A
Huperzine-A is a cognitive enhancer that inhibits an enzyme that degrades the learning neurotransmitter, acetylcholine; due to this, a relative increase occurs. It belongs to the cholinergics class of molecules, and may be useful in fighting cognitive decline in the elderly. May need to be cycled.
Our evidence-based analysis features 21 unique references to scientific papers.
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Each member of our research team is required to have no conflicts of interest, including with supplement
manufacturers, food companies, and industry funders. The team includes nutrition researchers, registered
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This page features 21 references. All factual claims are followed by specifically-applicable references.
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Summary of Huperzine-A
Primary Information, Benefits, Effects, and Important Facts
Huperzine-A is a compound extracted from the herbs of the Huperziceae family. It is known as an acetylcholinesterase inhibitor, which means that it stops an enzyme from breaking down acetylcholine which results in increases in acetylcholine.
Acetylcholine is known as the learning neurotransmitter, and is involved in muscle contraction as well. Increasing levels of acetylcholine is routinely used as a technique amongst weight-lifters and scholars.
Huperzine-A appears to be a relatively safe compound from animal studies of toxicity and studies in humans showing no side-effects at dosages routinely supplemented with. Huperzine-A is in preliminary trials for usage in fighting Alzheimer’s Disease as well.
Follow this Page for updates
Things to Know
Also Known As
(1R, 9S, 13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo- 7.3.1.0 2, 7 trideca-2(7), 3, 10-trien-5-on, Qian Ceng Ta (Huperzia Serrata)
Things to Note
Huperzine-A appears to be water-soluble, and taking with food is not needed
Although its initial spike is quick, it appears to have a long half-life; the pharmacokinetic profile might change when changing dosages though.
Is used for
- Cognitive Function and Brain Health
Is a form of
- Phytochemical
Goes Well With
Cholinergics
Racetams
Caution Notice
Consult your doctor before using if you are currently taking any anticholinergic drugs, acetylcholinesterase inhibitors, or cholinergic drugs.
Examine.com Medical Disclaimer
How to Take
Recommended dosage, active amounts, other details
Supplementation of huperzine-A tends to be in the range of 50-200mcg daily, and while this can be divided into multiple dosages throughout the day it tends to be taken at a single dose. Supplementation of huperzine-A does not require food to be coingested with it and can be taken in a fasted state.
Cycling of huperzine-A tends to be used since it can remain in the body for quite some time (half-life of 10-14 hours), and although a ‘cycle’ of huperzine-A tends to last 2-4 weeks followed by a break the optimal cycle length is not yet known.
Scientific Research
Table of Contents:
- 1
Structure and Sources- 1.1
Sources - 1.2
Isomers
- 1.1
- 2
Pharmacology - 3
Neurology- 3.1
Cholinergic Neurotransmission - 3.2
Neuroprotection - 3.3
Neurogenesis
- 3.1
- 4
Safety and Toxicity
1Structure and Sources
1.1. Sources
Huperzine-A is a compound found in the plant families of Huperziaceae, Lycopodiaceae, and Selaginella. [1] [2] It is normally extracted from the plants of the Huperziaceae family, but can be propogated in other cell lines for cheap mass production. [3] This synthetic Huperzine-A has bioequivlance to the natural version.
Its chemical structure is a pyridone moiety fused to a benzo3,3,1ring system with a ethylidene group attached to it. The (-)Huperzine stereoisomer is more bioactive than the (+)Huperzine Isomer. [2] [4]
1.2. Isomers
Huperzine-B is a congener (like compound) to that of Huperzine-A with a similar pharmacodynamic profile. Huperzine-B is less potent acutely [5] but has a longer dissiciation and subsequently a greater potential safety index and therapeutic index. [6] It is also an NMDA antagonist [5] and neural anti-oxidant. [7] It is currently being chemically modified to increase potency without risking the longer dissociation. [8] [9]
2Pharmacology
Orally administered tablets tend to appear in the blood in 15 minutes or less and peak at a variable time around 70 minutes post-ingestion. [10] [11] It shows a biphasic response of a rapid serum increase followed by a slower excretion rate [10] and has an alpha and beta half-life of 21.13+/-7.28 and 716.25+/-130.18 min, respectively. [11] These half-lifes were noted to be different in another study though, in which Huperzine-A fitted a one-compartment model at 0.99mg. [10]
It appears in the cerebrospinal fluid and is easily able to cross the blood-brain barrier. [2]
3Neurology
3.1. Cholinergic Neurotransmission
Huperzine-A’s most renowned action is that of an acetylcholinesterase inhibitor. Specifically, it can inhibit the G4 isoform of acetylcholinesterase which is highly prevalent in mammalian brains. [12] It is of greater or equal potency to other acetylcholinesterase inhibitors such as Tacrine or Rivastigmine. [12] It has a high affinity for acetylcholinesterase as an inhibitor, and a slow dissociation constant which enables a long active half-life. [13]
It may be preferable for usage as a cholinergic since it has been reported to have less cholinergic-related side-effects, [14] possibly through its high affinity for brain G4 acetylcholine resulting in less availability for systemic butrylcholine inhibition, which leads to various systemic effects which may be seen as side effects. [15] [16]
3.2. Neuroprotection
In addition to acetylcholinesterase inhibition, it can also be seen as neuroprotective against glutamate, [17] beta-amyloid pigmentation, [18] and H2O2-induced toxicity. [19]
Huperzine-A can also block the NMDA receptor ion channel without psychomimetic side-effects. [20]
3.3. Neurogenesis
Huperzine-A is able to promote proliferation of hippocampal neural stem cells (NSCs) at a concentration of 1μM for 48 hours (which is more potent than 10-100μM) to 125% of control secondary to activating the ERK pathway, [21] and this neurogenesis was confimed in vivo with injections of 0.2mg/kg of huperzine-A for 4 weeks (about a 25% increase in BrdU stained cells, affecting both newborn and adult mice). [21]
Appears to promote neurogenesis in biologically relevant dosages
4Safety and Toxicity
A study in rats concluded that the LD50 (dose needed to acutely kill half a population of rats) was 2-4mg/kg bodyweight in females and >4mg/kg in males whereas others pinpoint the level at around 3mg/kg bodyweight over a longer period (180 days). [13] The NOAEL (No Observable Adverse Effects Limit) is postulated to be 1mg/kg for females rats, 3mg/kg for males rats, and 0.1mg/kg for canines. No toxicity data for humans currently exists.
Scientific Support & Reference Citations
References
Howes MJ, Perry NS, Houghton PJ.
Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders .
Phytother Res. (2003)Ha GT, Wong RK, Zhang Y.
Huperzine a as potential treatment of Alzheimer’s disease: an assessment on chemistry, pharmacology, and clinical studies .
Chem Biodivers. (2011)Ma X, Gang DR.
In vitro production of huperzine A, a promising drug candidate for Alzheimer’s disease .
Phytochemistry. (2008)Total Synthesis of (−)-Huperzine A .
Wang XD, et al.
Comparison of the effects of cholinesterase inhibitors on 3HMK-801 binding in rat cerebral cortex .
Neurosci Lett. (1999)Rajendran V, et al.
Synthesis of more potent analogues of the acetylcholinesterase inhibitor, huperzine B .
Bioorg Med Chem Lett. (2002)Zhang HY, Tang XC.
Huperzine B, a novel acetylcholinesterase inhibitor, attenuates hydrogen peroxide induced injury in PC12 cells .
Neurosci Lett. (2000)Feng S, et al.
Bis-huperzine B: highly potent and selective acetylcholinesterase inhibitors .
J Med Chem. (2005)He XC, et al.
Study on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunctional huperzine B .
Bioorg Med Chem. (2007)Qian BC, et al.
Pharmacokinetics of tablet huperzine A in six volunteers .
Zhongguo Yao Li Xue Bao. (1995)Li YX, et al.
Pharmacokinetics of huperzine A following oral administration to human volunteers .
Eur J Drug Metab Pharmacokinet. (2007)Effects of huperzine A on acetylcholinesterase isoforms in vitro: comparison with tacrine, donepezil, rivastigmine and physostigmine .
Chemistry, Pharmacology, and Clinical Efficacy of the Chinese Nootropic Agent Huperzine A .
Development of huperzine A and B for
treatment of Alzheimer’s disease .Boudinot E, et al.
Effects of acetylcholinesterase and butyrylcholinesterase inhibition on breathing in mice adapted or not to reduced acetylcholinesterase .
Pharmacol Biochem Behav. (2005)Lane RM, Potkin SG, Enz A.
Targeting acetylcholinesterase and butyrylcholinesterase in dementia .
Int J Neuropsychopharmacol. (2006)Ved HS, et al.
Huperzine A, a potential therapeutic agent for dementia, reduces neuronal cell death caused by glutamate .
Neuroreport. (1997)Huperzine A regulates amyloid precursor protein processing via protein kinase C and mitogen-activated protein kinase pathways in neuroblastoma SK-N-SH cells over-expressing wild type human amyloid precursor protein 695 .
Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine .
The NMDA receptor ion channel: a site for binding of Huperzine A .
Ma T, et al.
Huperzine A promotes hippocampal neurogenesis in vitro and in vivo .
Brain Res. (2013)
(Common misspellings for Huperzine-A include Huperzine, huperizine, hooperzine, hooperzeen, huperzeen)
Cite this page
“Huperzine-A,” Examine.com, published on 12 July 2013, last updated on
22 July 2018,
https://examine.com/supplements/huperzine-a/
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Huperzine-A
Huperzine-A is a cognitive enhancer that inhibits an enzyme that degrades the learning neurotransmitter, acetylcholine; due to this, a relative increase occurs. It belongs to the cholinergics class of molecules, and may be useful in fighting cognitive decline in the elderly. May need to be cycled.
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This page features 21 references. All factual claims are followed by specifically-applicable references.
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Summary of Huperzine-A
Primary Information, Benefits, Effects, and Important Facts
Huperzine-A is a compound extracted from the herbs of the Huperziceae family. It is known as an acetylcholinesterase inhibitor, which means that it stops an enzyme from breaking down acetylcholine which results in increases in acetylcholine.
Acetylcholine is known as the learning neurotransmitter, and is involved in muscle contraction as well. Increasing levels of acetylcholine is routinely used as a technique amongst weight-lifters and scholars.
Huperzine-A appears to be a relatively safe compound from animal studies of toxicity and studies in humans showing no side-effects at dosages routinely supplemented with. Huperzine-A is in preliminary trials for usage in fighting Alzheimer’s Disease as well.
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Things to Know
Also Known As
(1R, 9S, 13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo- 7.3.1.0 2, 7 trideca-2(7), 3, 10-trien-5-on, Qian Ceng Ta (Huperzia Serrata)
Things to Note
Huperzine-A appears to be water-soluble, and taking with food is not needed
Although its initial spike is quick, it appears to have a long half-life; the pharmacokinetic profile might change when changing dosages though.
Is used for
- Cognitive Function and Brain Health
Is a form of
- Phytochemical
Goes Well With
Cholinergics
Racetams
Caution Notice
Consult your doctor before using if you are currently taking any anticholinergic drugs, acetylcholinesterase inhibitors, or cholinergic drugs.
Examine.com Medical Disclaimer
How to Take
Recommended dosage, active amounts, other details
Supplementation of huperzine-A tends to be in the range of 50-200mcg daily, and while this can be divided into multiple dosages throughout the day it tends to be taken at a single dose. Supplementation of huperzine-A does not require food to be coingested with it and can be taken in a fasted state.
Cycling of huperzine-A tends to be used since it can remain in the body for quite some time (half-life of 10-14 hours), and although a ‘cycle’ of huperzine-A tends to last 2-4 weeks followed by a break the optimal cycle length is not yet known.
Scientific Research
Table of Contents:
- 1
Structure and Sources- 1.1
Sources - 1.2
Isomers
- 1.1
- 2
Pharmacology - 3
Neurology- 3.1
Cholinergic Neurotransmission - 3.2
Neuroprotection - 3.3
Neurogenesis
- 3.1
- 4
Safety and Toxicity
1Structure and Sources
1.1. Sources
Huperzine-A is a compound found in the plant families of Huperziaceae, Lycopodiaceae, and Selaginella. [1] [2] It is normally extracted from the plants of the Huperziaceae family, but can be propogated in other cell lines for cheap mass production. [3] This synthetic Huperzine-A has bioequivlance to the natural version.
Its chemical structure is a pyridone moiety fused to a benzo3,3,1ring system with a ethylidene group attached to it. The (-)Huperzine stereoisomer is more bioactive than the (+)Huperzine Isomer. [2] [4]
1.2. Isomers
Huperzine-B is a congener (like compound) to that of Huperzine-A with a similar pharmacodynamic profile. Huperzine-B is less potent acutely [5] but has a longer dissiciation and subsequently a greater potential safety index and therapeutic index. [6] It is also an NMDA antagonist [5] and neural anti-oxidant. [7] It is currently being chemically modified to increase potency without risking the longer dissociation. [8] [9]
2Pharmacology
Orally administered tablets tend to appear in the blood in 15 minutes or less and peak at a variable time around 70 minutes post-ingestion. [10] [11] It shows a biphasic response of a rapid serum increase followed by a slower excretion rate [10] and has an alpha and beta half-life of 21.13+/-7.28 and 716.25+/-130.18 min, respectively. [11] These half-lifes were noted to be different in another study though, in which Huperzine-A fitted a one-compartment model at 0.99mg. [10]
It appears in the cerebrospinal fluid and is easily able to cross the blood-brain barrier. [2]
3Neurology
3.1. Cholinergic Neurotransmission
Huperzine-A’s most renowned action is that of an acetylcholinesterase inhibitor. Specifically, it can inhibit the G4 isoform of acetylcholinesterase which is highly prevalent in mammalian brains. [12] It is of greater or equal potency to other acetylcholinesterase inhibitors such as Tacrine or Rivastigmine. [12] It has a high affinity for acetylcholinesterase as an inhibitor, and a slow dissociation constant which enables a long active half-life. [13]
It may be preferable for usage as a cholinergic since it has been reported to have less cholinergic-related side-effects, [14] possibly through its high affinity for brain G4 acetylcholine resulting in less availability for systemic butrylcholine inhibition, which leads to various systemic effects which may be seen as side effects. [15] [16]
3.2. Neuroprotection
In addition to acetylcholinesterase inhibition, it can also be seen as neuroprotective against glutamate, [17] beta-amyloid pigmentation, [18] and H2O2-induced toxicity. [19]
Huperzine-A can also block the NMDA receptor ion channel without psychomimetic side-effects. [20]
3.3. Neurogenesis
Huperzine-A is able to promote proliferation of hippocampal neural stem cells (NSCs) at a concentration of 1μM for 48 hours (which is more potent than 10-100μM) to 125% of control secondary to activating the ERK pathway, [21] and this neurogenesis was confimed in vivo with injections of 0.2mg/kg of huperzine-A for 4 weeks (about a 25% increase in BrdU stained cells, affecting both newborn and adult mice). [21]
Appears to promote neurogenesis in biologically relevant dosages
4Safety and Toxicity
A study in rats concluded that the LD50 (dose needed to acutely kill half a population of rats) was 2-4mg/kg bodyweight in females and >4mg/kg in males whereas others pinpoint the level at around 3mg/kg bodyweight over a longer period (180 days). [13] The NOAEL (No Observable Adverse Effects Limit) is postulated to be 1mg/kg for females rats, 3mg/kg for males rats, and 0.1mg/kg for canines. No toxicity data for humans currently exists.
Scientific Support & Reference Citations
References
Howes MJ, Perry NS, Houghton PJ.
Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders .
Phytother Res. (2003)Ha GT, Wong RK, Zhang Y.
Huperzine a as potential treatment of Alzheimer’s disease: an assessment on chemistry, pharmacology, and clinical studies .
Chem Biodivers. (2011)Ma X, Gang DR.
In vitro production of huperzine A, a promising drug candidate for Alzheimer’s disease .
Phytochemistry. (2008)Total Synthesis of (−)-Huperzine A .
Wang XD, et al.
Comparison of the effects of cholinesterase inhibitors on 3HMK-801 binding in rat cerebral cortex .
Neurosci Lett. (1999)Rajendran V, et al.
Synthesis of more potent analogues of the acetylcholinesterase inhibitor, huperzine B .
Bioorg Med Chem Lett. (2002)Zhang HY, Tang XC.
Huperzine B, a novel acetylcholinesterase inhibitor, attenuates hydrogen peroxide induced injury in PC12 cells .
Neurosci Lett. (2000)Feng S, et al.
Bis-huperzine B: highly potent and selective acetylcholinesterase inhibitors .
J Med Chem. (2005)He XC, et al.
Study on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunctional huperzine B .
Bioorg Med Chem. (2007)Qian BC, et al.
Pharmacokinetics of tablet huperzine A in six volunteers .
Zhongguo Yao Li Xue Bao. (1995)Li YX, et al.
Pharmacokinetics of huperzine A following oral administration to human volunteers .
Eur J Drug Metab Pharmacokinet. (2007)Effects of huperzine A on acetylcholinesterase isoforms in vitro: comparison with tacrine, donepezil, rivastigmine and physostigmine .
Chemistry, Pharmacology, and Clinical Efficacy of the Chinese Nootropic Agent Huperzine A .
Development of huperzine A and B for
treatment of Alzheimer’s disease .Boudinot E, et al.
Effects of acetylcholinesterase and butyrylcholinesterase inhibition on breathing in mice adapted or not to reduced acetylcholinesterase .
Pharmacol Biochem Behav. (2005)Lane RM, Potkin SG, Enz A.
Targeting acetylcholinesterase and butyrylcholinesterase in dementia .
Int J Neuropsychopharmacol. (2006)Ved HS, et al.
Huperzine A, a potential therapeutic agent for dementia, reduces neuronal cell death caused by glutamate .
Neuroreport. (1997)Huperzine A regulates amyloid precursor protein processing via protein kinase C and mitogen-activated protein kinase pathways in neuroblastoma SK-N-SH cells over-expressing wild type human amyloid precursor protein 695 .
Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine .
The NMDA receptor ion channel: a site for binding of Huperzine A .
Ma T, et al.
Huperzine A promotes hippocampal neurogenesis in vitro and in vivo .
Brain Res. (2013)
(Common misspellings for Huperzine-A include Huperzine, huperizine, hooperzine, hooperzeen, huperzeen)
Cite this page
“Huperzine-A,” Examine.com, published on 12 July 2013, last updated on
22 July 2018,
https://examine.com/supplements/huperzine-a/