|
Huperzine-A
by Jim English
Alzheimer’s Disease (AD) is a progressive
degenerative disease that most commonly appears after the age of
50. Currently, Alzheimer’s afflicts approximately 40% of all
individuals over the age of 85, for a total of 4 million people
in the U.S. alone. When symptoms occur before the age of 65 the
disease is designated Presenile Dementia of the Alzheimer’s
Type (PDAT). When symptoms occur after age 65 the syndrome
is referred to as Senile Dementia of the Alzheimer’s Type
(SDAT). Symptoms include a gradual yet inexorable loss of memory,
mental performance, communication skills, abstract thinking and
personality. Ultimately, Alzheimer’s ends in the death of
the patient, with a mean life expectancy of 8 years.
As well as being a profound personal tragedy for
afflicted individuals and their loved ones, the financial costs
of caring for victims of the disease exceed $80 billion per year.
The current trend towards longer life expectancy, combined with
the increased incidence of senile dementia with age, means that
cases of Alzheimer’s increase alarmingly as the median age
of the population grows, underscoring the urgency for finding an
effective treatment for this disorder.
Huperzine-A is a new supplement derived from an
ancient traditional Chinese herbal medicine that offers hope to
those suffering from Alzheimer’s disease and other age-related
mental conditions. In addition to benefiting patients suffering
from Alzheimer’s, Huperzine’s memory-enhancing properties
suggest that it may be an effective agent for improving memory and
learning in healthy humans as well.
Alzheimer’s is characterized by the destruction of nerve cells
in several key areas of the brain devoted to mental functions. This
results in tangles of nerve fibers and plaque formation of an abnormal,
insoluble protein called amyloid. While there is a general reduction
in the concentration of all neurotransmitting substances, a marked
clinical feature of the disease is a dramatic decrease in the neurotransmitter
acetylcholine.
Acetylcholine is a vital neurotransmitter with
a fundamental role in memory. It is also necessary for proper intracellular
communication between nerve cells. Research has shown that levels
of acetylcholine are deficient in the brains of patients with Alzheimer's
disease.
Biopsy and postmortem studies have shown that
there is a substantial loss of presynaptic cholinergic neurons in
brains of patients with Alzheimer’s.1 What little acetylcholine
that is still produced in the patient’s brain is quickly broken
down by the brain enzyme, acetylcholinesterase (AchE), leading to
a shortage of the neurotransmitter and contributing to the patient’s
loss of memory and other cognitive functions.
Two drugs are currently approved for use in the U.S. to treat Alzheimer's—Tacrine™
and Donepezil hydrochloride (Aricept™). Both drugs are moderately
effective cholinesterase inhibitors, that work by interfering with
the actions of AChE. Since acetylcholine is normally degraded and
recycled by acetylcholinesterase, this approach counteracts any
further reduction of already low levels of acetylcholine.
By inhibiting the actions of AChE it is hoped
that the small amounts of acetylcholine still being produced will
persist longer within the synaptic cleft and lead to improvements
in memory and cognitive abilities. While both drugs are effective
cholinesterase inhibitors, they suffer from a number of drawbacks.
First, they are available only by prescription; second, they are
expensive, costing between $100 - $240 per month; and third, both
drugs can cause debilitating side effects including liver toxicity
(Tacrine), and nausea and diarrhea (Donepezil).1
Huperzine A is a natural compound derived from an ancient Chinese
remedy, Qian Ceng Ta. This traditional herbal medicine was prepared
from Huperzia serrata, a clubmoss that grows on the ground in damp
forests and rock crevices. Brewed as an herbal tea, Qian Ceng Ta
has been used in China to treat fever, inflammation, and irregular
menstruation, and has been used as a diuretic.
In the late 1980’s, researchers in China
discovered that a purified alkaloid extracted from Huperzia, Huperzine
A, was a potent, reversible inhibitor of acetylcholin-esterase (AChE).
Huperzine A readily crosses the blood-brain barrier to prevent acetylcholinesterase
(AchE) from destroying acetylcholine.
A study at the Weizmann Institute in Israel uncovered how Huperzine
A (Hup-A) works to block acetylcholinesterase.2 Scientists had previously
learned that AchE inhibitors such as tacrine and donepezil worked
by sliding into the AChE molecule to "jam up" its molecular
machinery and impair its ability to degrade acetylcholine.
By imaging a 3-dimensional structure of the AChE
molecule, the researchers were able to peer into the complex folded
protein structure to discover a deep chasm, called the active-site
gorge. The scientists determined that the active-site gorge acts
as a guide to funnel acetylcholine into the interior of the enzyme
where it is cut apart prior to recycling.
This study revealed that Huperzine A has a strong
specificity for AChE, and is exceptionally well suited to its new
role, fitting into the active sites of acetylcholinesterase much
like a key slipping into a lock. "Hup-A appears to bind more
tightly and specifically to acetylcholinesterase than the other
AChE inhibitors," crystallographer Prof. Joel Sussman, one
of the authors of the study said. "It is as if this natural
substance were ingeniously designed to fit into the exact spot in
AChE where it will do the most good."
Hup-A has undergone double blind, placebo-controlled clinical trials
in China in patients suffering from various memory disorders, including
AD. In fact, it is estimated that in the past few years 100,000
people have been treated in China with Hup-A. Researchers in China
claim that it helps normal elderly with memory problems as well
as people with AD.
Double-blind, placebo-controlled clinical trials
in China have demonstrated that patients suffering from Alzheimer’s
and various other memory disorders gain significant benefit, both
in terms of memory and life quality. Xu et al. conducted a placebo-controlled,
double-blind study in which subjects with AD were given 200 mcg/day
Hup-A or placebo for 8 weeks. Statistically significant improvement
was achieved in 58% of the treated group with respect to cognitive
function and their ability to retrieve past memories.3
In one study, Chinese researchers of the Department
of Pharmacology, Zhejiang Academy of Medical Sciences, Hangzhou,
China, examined the effects of Hup-A on six volunteers. They concluded
that Hup-A had a high rate of absorption and distribution in the
body, and was without adverse side effects.4
A second study conducted by researchers at Zhejiang
Medical University, focused on the efficacy of Hup-A on memory,
cognition, and behavior in Alzheimer's disease. This multicenter,
double-blind, placebo controlled study found that about 58% (29/50)
of patients treated with Hup A showed improvements in their memory,
cognition, and behavioral functions. No severe side effects were
found. All patients were evaluated with Wechsler memory scale, Hasegawa
dementia scale, mini-mental state examination scale, activity of
daily living scale, treatment emergency symptom scale, and measured
with BP, HR, ECG, EEG, ALT, AKP, BUN, Cr, Hb, WBC, and urine routine.
Their conclusion was that "Hup-A is a promising drug for symptomatic
treatment of Alzheimer's disease."4
In the U.S., a recent paper by noted neurologist,
Alan A. Mazurek, M.D., reported on the results of an office-based
trial studying the safety and efficacy of Hup-A as a treatment for
Alzheimer's disease. Mazurek evaluated the safety and efficacy of
Hup-A in an open-label trial involving 29 patients with mild to
moderate AD.5
Twenty-two patients (75.9%) completed the three
month study. Only two patients reported adverse effects, one being
an apparently unrelated hemorrhagic infarct that resolved without
treatment. No gastrointestinal side effects, nausea, diarrhea, cardiac
effects or headache were reported. Status Examinations’ (SMMSE)
improvement of one point or greater was seen at one, two and three
months. Mazurek reported that improvements appeared to be dose related,
with those on the higher dosages exhibiting the greatest improvement.
Wrote Mazurek, "Huperzine A appears to be safe, well tolerated,
and effective in the symptomatic treatment of AD."
In addition to its activity as an AChE inhibitor, ongoing research
suggests that Hup-A has a wider role to play in supporting neuroprotective
functions. Researchers recently discovered that Hup-A inhibits glutamate-induced
cytotoxicity, protecting neonatal hippocampal and cerebellar neuronal
cells in culture from death caused by the amino acid glutamate.
In addition to protecting from glutamate-induced cytotoxicity, researchers
were also surprised to learn that Huperzine A promotes new dendrite
outgrowth of neuronal cultures.
Researchers at the Walter Reed Army Institute of Research in Washington
D.C. are conducting studies into Huperzine’s potential role
as a pretreatment drug to protect against chemical warfare nerve
agent poisoning. In one study, Huperzine A was found to be twice
as effective in protecting mice against the lethal effects of the
nerve agent soman when compared to physostigmine.6 Huperzine A’s
effects lasted for six hours compared to only 90 minutes for physostigmine,
providing further evidence for the slow clearance of Huperzine from
the body.
Huperzine A has a wide margin of safety. Toxicology studies show
Huperzine A to be non-toxic even when administered at 50-100 times
the human therapeutic dose! The extract is active for 6 hours at
a dose of 2 µg/kg with no remarkable side effects.
Huperzine A appears to be a safe memory supplement. Clinical research
has shown that Huperzine A is superior to other cholinesterase inhibitors
such as tacrine and donepezil. Huperzine A is rapidly absorbed when
taken orally, and possesses a very slow rate of dissociation from
the enzyme and a longer duration of action. Studies in rodents show
that AChE remains inhibited by 33% after 6 hours.
Huperzine A has been shown to be effective in
inhibiting the actions of AChE to increase acetylcholine concentrations
and alleviate some of the symptoms associated with acetylcholine
deficiencies. Significant effects have been noted in patients both
in terms of their life quality and their ability to retrieve past
memories. In view of the fact that Huperzia serrata was used for
many years in Chinese folklore medicine, and in accord with the
Dietary Supplement Health & Education Act of 1994 (DSHEA) in
this country, it has been possible to introduce Hup-A into the US
market as a dietary supplement.
These findings suggest that Hup-A not only protect
from the actions of Alzheimer’s and senile memory deficits,
but also provides a unique and exciting supplement for supporting
memory in the healthy aging human as well. Accordingly, Huperzine
A is currently available as an over the counter "nutriceutical"
for those individuals looking for support for memory.
References
1. Watkins PB, Zimmerman HJ, Knapp MJ.
Hepatotoxic effects of tacrine
administration in patients with Alzheimer's disease. JAMA 1994 Apr
6; 271:992-8
2. 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.
3. Xu SS; Gao ZX; Weng Z; Du ZM; Xu WA; Yang JS; Zhang ML; Tong
ZH; Fang YS;Chai XS; et al, Efficacy of tablet huperzine-A on memory'
cognition' and behavior in Alzheimer`s disease. Chung Kuo Yao Li,
Hsueh Pao16:391-5, 1995.
4. (Qian BC, Wang M, Zhou ZF, Chen K, Zhou RR, Chen GS. Pharmacokinetics
of tablet huperzine A in six volunteers. Chung Kuo Yao Li Hsueh
Pao 1995 Sep;16(5):396-8)
5. Mazurek, A. An open label trial of Huperzine A in the treatment
of Alzheimer’s disease. Alternative Therapies, March 1999.
Vol. 5, No. 2:97.
6. Saxena A, Qian N, Kovach IM, Kozikowski AP, Pang YP, Vellom DC,
Radic Z, Quinn D, Taylor P, Doctor BP. Identification of amino acid
residues involved in the binding of Huperzine A to cholinesterases.
Protein Sci 1994 Oct;3(10):1770-8. |
