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Curcumin and Alzheimer
Alzheimer's disease
Alzheimer’s disease (AD) is a progressive neurodegenerative disease.
It is characterized by progressive cognitive deterioration together
with declining activities of daily living and behavioral changes. It is
the most common type of pre-senile and senile dementia. According
to the World Health Organization (WHO), 5% of men and 6% of
woman of above the age of 60 years are affected with Alzheimer’s
type dementia worldwide.
In India, the total prevalence of dementia per 1000 people is 33.6%,
of which AD constitutes approximately 54% and vascular dementia
constitutes approximately 39%.
AD affects approximately 4.5 million people in the United States or
approximately 10% of the population over the age of 65, and this
number is projected to reach four times by 2050. The frequency
increases to 50% by the age of 80 years.
Neuropathology of AD
The neuropathological process consists of neuronal loss and atrophy,
principally in the temporoparietal and frontal cortex, with an
inflammatory response to the deposition of amyloid plaques and an
abnormal cluster of protein fragments and tangled bundles of fibers
(neurofibillary tangles). Neurotic plaques are relatively insoluble
dense cores of 5-10 nm thick amyloid fibrils with a pallor staining
‘halo’ surrounded by dystrophic neuritis, reactive astrocytes and
activated microglia. There is an increased presence of
monocytes/macrophages in the cerebral vessel wall and reactive or
activated microglial cells in the adjacent parenchyma. The main
protein component of amyloid in AD is the 39-42 amino acid (beta)
amyloid peptide (A-beta).
Curcumin
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Curcumin (Curcuma longa - Haldi) is the source of the spice
Turmeric and is used in curries and other spicy dishes from India,
Asia and the Middle East. Similar to many other herbal remedies,
people first used curcumin as a food and later discovered that it also
had impressive medicinal qualities.
It has been used extensively in Ayurveda (Indian system of Medicine)
for centuries as a pain relieving, anti-inflammatory agent to relieve
pain and inflammation in the skin and muscles. It has also proven to
have anti-cancer properties. Curcumin holds a high place in
Ayurvedic medicine as a ‘cleanser of the body,’ and today, science is
finding a growing list of diseased conditions that can be healed by the
active ingredients of turmeric.
Botanical name: Curcuma longa; Family: Zingiberaceae, the ginger
family. Turmeric is a sterile plant and does not produce any seeds.
The plant grows up to 3-5 ft tall and has dull yellow flowers. The
underground rhizomes or roots of the plant are used for medicinal
and food preparation. The rhizome is an underground stem that is
thick and fleshy ringed with the bases of old leaves. Rhizomes are
boiled and then dried and ground to make the distinctive bright
yellow spice, turmeric.
Turmeric History
Probably originating from India, turmeric has been used in India for
at least 2500 years. It is most common in southern Asia and
particularly in India. Turmeric was probably cultivated at first as a dye
and later on it was used as cosmetic and as an auspicious and
aromatic food substance.
It possesses antiseptic, anti-inflammatory detoxifying properties as
well as carminative properties. Turmeric has a long history of
medicinal use in South Asia and was widely used in Ayurvedic,
Siddha and Unani systems.
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It is thought to be a hybrid selection and vegetative propagation of
wild turmeric (Curcuma aromatica), and some other closely related
species. It is native to India, Sri Lanka and the eastern Himalayas
Curcumin and Alzheimer’s disease
Worldwide, there are over 1000 published animal and human studies,
both in vivo and in vitro in which the effects of curcumin on various
diseases have been examined. Studies include epidemiological, basic
and clinical research on AD.
Epidemiological Studies
Various studies and research results indicate a lower incidence and
prevalence of AD in India. The prevalence of AD among adults aged
70-79 years in India is 4.4 times less than that of adults aged 70-79
years in the United States. Researchers investigated the association
between the curry consumption and cognitive level in 1010 Asians
between 60 and 93 years of age. The study found that those who
occasionally ate curry (less than once a month) and often (more than
once a month) performed better on a standard test (MMSE) of
cognitive function than those who ate curry never or rarely. [
Mechanism of action of curcumin on Alzheimer's disease
The process through which AD degrades the nerve cells is believed
to involve certain properties: inflammation, oxidative damage and
most notably, the formation of beta-amyloid plaques, and metal
toxicity.
Effects of Curcumin on Macrophages
A study conducted at UCLA found that curcumin may help the
macrophages to clear the amyloid plaques found in Alzheimer’s
disease.
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Macrophages play an important role in the immune system. They
help the body to fight against foreign proteins and then effectively
clear them. The AD patients, whose macrophages were treated with
curcumin, when compared with patients whose macrophages were
not treated with curcumin, showed an improved uptake and ingestion
of the plaques. Thus, curcumin may support the immune system to
clear the amyloid protein.
Curcumin on glial cells
Recent histological studies reveal the presence of activated microglia
and reactive astrocytes around A-beta plaques in brains from patients
with AD. The chronic activation of microglia secretes cytokines and
some reactive substances that exacerbate A-beta pathology.
So neuroglia is an important part in the pathogenesis of AD.
Curcumin has a lipophilic property and can pass through all cell
membranes and thus exerts its intracellular effects. Curcumin has
anti-proliferative actions on microglia. A minimal dose of curcumin
affects neuroglial proliferation and differentiation.
Trials, showed that curcumin dose dependently stops the
proliferation of neuroglial cells, by differentiate into a mature cell or
undergo apoptosis. It inhibits neuroglial cells proliferation dose
dependently (i.e.) higher the concentration, the greater the inhibition.
It has shown to decrease the glutamine synthetase (GS) assay, a
marker enzyme for astrocytes. The overall effect of curcumin on
neuroglial cells involves decreased astrocytes proliferation, improved
myelogenesis and increased activity and differentiation of
oligodendrocytes.
Curcumin as an Anti Inflammatory in Alzheimer's
One of the important pathogenesis in Alzheimer’s disease is the
chronic inflammation of nerve cells. Several studies have
demonstrated the associated inflammatory changes such as
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microgliosis, astrocytosis and the presence of pro-inflammatory
substances that accompany the deposition of amyloid-β (Aβ) peptide.
Patients with the prolonged use of certain nonsteroidal antiinflammatory (NSAID) drugs such as ibuprofen have been shown to
have a reduced risk of developing the symptoms of AD; however, the
chronic use of NSAID can cause a toxic effect on the kidneys, liver
and GI track.
Curcumin has a potent anti-inflammatory effect. Through its various
anti-inflammatory effects, it may have a role in the cure of AD.
Curcumin inhibits Aβ-induced expression of Egr-1 protein and Egr-1
DNA-binding activity in THP-1 monocytic cells. Studies have shown
the role of Egr-1 in amyloid peptide-induced cytochemokine gene
expression in monocytes. By inhibition of Egr-1 DNA-binding
activity by curcumin, it reduces the inflammation. The chemotaxis of
monocytes, which can occur in response to chemokines from
activated microglia and astrocytes in the brain, can be decreased by
curcumin.
Curcumin is found to inhibit cyclooxygenase (COX-2),
phospholipases, transcription factor and enzymes involved in
metabolizing the membrane phospholipids into prostaglandins. The
reduction of the release of ROS by stimulated neutrophils, inhibition
of AP-1 and NF-Kappa B inhibit the activation of the proinflammatory cytokines TNF (tumor necrosis factor)-alpha and IL
(interleukin)-1 beta.
Overall, curcumin decreases the main chemical for inflammation and
the transcription of inflammatory cytokines. Curcumin inhibits
intracellular IL-12 p40/p70 and IL-12 p70 expression. The exposure
to curcumin also impaired the production of pro-inflammatory
cytokines (IL-1, IL-6 and TNF-). These studies indicate a potent
inhibitor of pro-inflammatory cytokine production by curcumin and
it may differ according to the nature of the target cells.
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Curcumin as an Anti-oxidant
Curcumin inhibits the activity of AP-1, a transcription factor involved
in expression of amyloid, which is linked to AD. Curcuminoids are
proven to have strong antioxidant action demonstrated by the
inhibition of the formation and propagation of free radicals. It
decreases the low-density lipoprotein oxidation and the free radicals
that cause the deterioration of neurons, not only in AD but also in
other neuron degenerative disorders such as Huntington’s and
Parkinson’s disease.
In one study, curcuma oil (500 mg Kg(-1) i.p.) was given 15 min
before 2 h middle cerebral artery occlusion, followed by 24 h reflow
in rats. This significantly diminished the infarct volume, improved
neurological deficit and counteracted oxidative stress.
A study conducted at Nanjing Medical University (China) showed
that a single injection of curcumin (1 and 2 mg/kg, i.v.) after focal
cerebral ischemia/reperfusion in rats significantly diminished the
infarct volume, improved neurological deficit, decreased mortality
and reduced the water content in the brain.
Curcumin has powerful antioxidant and anti-inflammatory properties;
according to the scientists, these properties believe help ease
Alzheimer’s symptoms caused by oxidation and inflammation. A
study conducted at Jawaharlal Nehru University (India) demonstrated
that the administration of curcumin significantly reduced lipid
peroxidation and lipofuscin accumulation that is normally increased
with aging. [It also increased the activity of superoxide dismutase,
sodium-potassium ATPase that normally decreased with aging.
In another study, curcumin has been shown to protect the cells from
betaA insult through antioxidant pathway. Curcumin protects brain
mitochondria against various oxidative stresses. Pre-treatment with
curcumin protects brain mitochondria against peroxynitrite (a
product of the reaction of nitric oxide with superoxide) a potent and
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versatile oxidant that can attack a wide range of cells in vitro by direct
detoxification and in vivo by the elevation of total cellular glutathione
levels.
Curcumin on Haemoxygenase Pathway
Natural antioxidant curcumin has been identified as a potent inducer
of hemoxygenase, a protein that provides efficient cytoprotection
against various forms of oxidative stress. By promoting the
inactivation of Nrf2-keap1 complex and increased binding to no1ARE, curcumin induces hemoxygenase activity. The incubation of
astrocytes with curcumin at a concentration that promoted
hemoxygenase activity resulted in an early increase in reduced
glutathione, followed by a significant elevation in oxidized
glutathione content. Glutathione is an important water-phase
antioxidant and essential cofactor for antioxidant enzymes protecting
the mitochondria against endogenous oxygen radicals. Its level
reflects the free radical scavenging capacity of the body. GSH
depletion leads to tissue damage due to lipid peroxidation and
oxidative damage.
Beta-Amyloid Plaques
The most prominent characteristic feature in AD is the presence of
beta-amyloid plaques. These plaques are basically an accumulation of
small fibers called beta amyloid fibrils. Because the deposition of
beta-amyloid protein is a consistent pathological hallmark of brains
affected by AD, the inhibition of A-beta generation, prevention of Abeta fibril formation, destabilization of pre-formed A-beta would be
an attractive therapeutic strategy for the treatment of AD.
Surprisingly low doses of curcumin given over longer period were
actually more effective than high doses in combating the
neurodegenerative process of AD. At higher concentration, curcumin
binds to amyloid beta and blocks its self assembly. The key chemical
features in amyloid beta are the presence of two aromatic end groups
and any alterations in these groups has profound effect on its activity.
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Because of the lipophilic nature of curcumin, it crosses the blood
brain barrier and binds to plaques. Curcumin was a better A-beta 40
aggregation inhibitor and it destabilizes the A-beta polymer.
In ‘in vitro’ studies, curcumin inhibits aggregation as well as
disaggregates to form fibrillar A-beta 1-40. Curcumin-derived
isoxazoles and pyrazoles bind to the amyloid beta peptide (A beta)
and inhibit amyloid precursor protein (APP) metabolism. Curcumin
crosses the blood-brain barrier as demonstrated by multi-photon
microscopy and reduces the existing senile plaques. In another study,
curcumin has been shown to increase the phagocytosis of amyloidbeta, effectively clearing them from the brains of patients with AD.
Metal Chelation
Studies showed that metals can induce A-beta aggregation and
toxicity and are concentrated on brain of Alzheimer’s patients.
Chelators’ desferroxamine and cliquinol have exhibited antiAlzheimer’s effects.
A study at Capital University Beijing demonstrated the toxicity of
copper on neurons. A greater amount of H 2 O 2 was released when
copper (2)-A (beta) 1-40 complexes were added to the xanthene
oxidase system. Copper was bound to A (beta)1-40 and was observed
by electron paramagnetic resonance spectroscopy. In addition,
copper chelators could cause a structural transition of A (beta). There
was an increase on beta sheet as well as alpha-helix when copper was
introduced.
Another study reveals that copper and zinc bind A-beta inducing
aggregation and give rise to reactive oxygen species. There was a
conformational change from beta sheet to alpha helix followed by
peptide oligomerization and membrane penetration, when copper
(or) zinc is added to A-beta in a negatively charged lipid environment.
Brain iron deregulation and its association with amyloid precursor
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protein plaque formation are implicated in the pathology of AD.
Curcumin, by interaction with heavy metals such as cadmium and
lead, prevents neuro-toxicity caused by these metals. The intraperitoneal injection of lead acetate in rats in the presence of curcumin
was studied microscopically. The results show lead-induced damage
to neurons was significantly reduced in rats injected with curcumin.
A study at Chinese University of Hong Kong showed that by using
spectrophotometry, the curcumin effectively binds to copper, zinc
and iron. In addition, curcumin binds more effectively with redoxactive metals such as iron and copper than the redox-inactive zinc. It
is suggested that curcumin suppresses inflammatory damage by
preventing metal induction of NF-kappa.
Cholesterol Lowering Effect
High-fat diets and increased blood cholesterol are linked to increased
amyloid plaques by the intracellular accumulation of cholestryl esters.
Researchers believe that by inhibiting cholesterol formation and
decreasing serum peroxides, curcumin might exert beneficial effects
on AD.
Safety
Oral bioavailability
Curcumin has poor bioavailability because curcumin readily
conjugated in the intestine and liver to form curcumin glucuronides.
In a clinical trial conducted in Taiwan, serum curcumin
concentrations peaked one to two hours after an oral dose. Peak
serum concentrations were 0.5, 0.6 and 1.8 micromoles/L at doses of
4, 6 and 8 g/day respectively. It is also measured in urine at a dose of
3.6 g/day. Absorption is poor following ingestion in mice and rats.
38% to 75% of an ingested dose of curcumin is excreted in the feces.
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Absorption appears to be better with food. Curcumin crosses the
blood brain barrier and is detected in CSF.
Side Effect
No apparent side effects have been reported thus far. GI upset, chest
tightness, skin rashes, swollen skin are said to occur with high dose.
A few cases of allergic contact dermatitis from curcumin have been
reported.
The chronic use of curcumin can cause liver toxicity. For this reason,
turmeric products should probably be avoided by individuals with
liver disease, heavy drinkers and those who take prescription
medications that are metabolized by liver. Curcumin was found to be
pharmacologically safe in human clinical trials with doses up to 10
g/day. A phase 1 human trial with 25 subjects using up to 8000 mg
of curcumin per day for three months found no toxicity from
curcumin.
Interaction
Curcumin is said to interact with certain drugs such as blood thinning
agents, NSAIDs, reserpin. Co-supplementation with 20 mg of
piperine (extracted from black pepper) significantly increases the
bioavailability of curcumin by 2000%.
Contraindication
Curcumin is not recommended for persons with biliary tract
obstruction because it stimulates bile secretion. It is also not
recommended for people with gallstones, obstructive jaundice and
acute biliary colic. Curcumin supplementation of 20-40 mg has been
reported to increase gallbladder contractions in healthy people.
Human
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Epidemiological studies have shown that prevalence of AD is 4.4
lower amongst Indian Asians as compared to people of western
origin. Dementia incidence in western countries and East Asian
countries were lower than that of Europe.
Clinical -Vivo: Blood from six patients with AD and three healthy
controls was taken and the macrophage cells were isolated. After
treatment of macrophages with curcuminoids, Aβ uptake by
macrophages of three of the six AD patients was found to have
significantly increased.
Conclusion
Several unanswered questions remain:
• What is the one main chemical property of curcumin that can
be exploited in treating AD?
• What is the role of curcumin in other neurological disorders
such as Parkinson’s, Huntington’s and other dementias?
• How does curcumin interact with neuronal plaques? Is it
effective only as a food additive? Would it be effective when
used alone or with other anti inflammatory drugs?
Based on the main findings detailed above, curcumin will lead to a
promising treatment for Alzheimer’s disease. The recent review paper
of John Ringman also supports some of the abovementioned
properties of curcumin in AD; however, large-scale human studies
are required to identify the prophylactic and therapeutic effect of
curcumin.
Vitamin D + Curcumin May Help Clear Amyloid Plaques
UCLA scientists have found that vitamin D, together with a chemical
found in turmeric spice called curcumin, may help stimulate the
immune system to clear the brain of amyloid beta, which forms the
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plaques considered the hallmark of Alzheimer's disease.
The early research findings, which appear in the July issue of the
Journal of Alzheimer's Disease, may lead to new approaches in
preventing and treating Alzheimer’s by utilizing the property of
vitamin D3 - a form of vitamin D - both alone and together with
natural or synthetic curcumin to boost the immune system in
protecting the brain against amyloid beta.
Vitamin D3 is an essential nutrient for bone and immune system
health; its main source is sunshine, and it is synthesized through the
skin. Deficiencies may occur during winter months or in those who
spend a lot of time indoors, such as Alzheimer’s patients. It is
expected that vitamin D3 and curcumin, both naturally occurring
nutrients, may offer new preventive and treatment possibilities for
Alzheimer’s disease.
Using blood samples from nine Alzheimer's patients, one patient
with mild cognitive impairment and three healthy control subjects,
scientists isolated monocyte cells, which transform into macrophages
that act as the immune system’s clean-up crew, traveling through the
brain and body and gobbling up waste products, including amyloid
beta. Researchers incubated the macrophages with amyloid beta,
vitamin D3 and natural or synthetic curcumin.
The team discovered that curcuminoids enhanced the surface binding
of amyloid beta to macrophages and that vitamin D strongly
stimulated the uptake and absorption of amyloid beta in macrophages
in a majority of patients.
Previous research by the team demonstrated that the immune genes
MGAT III and TLR-3 are associated with the immune system’s
ability to better ingest amyloid beta. It was shown that there are two
types of Alzheimer’s patients: Type 1 patients, who respond
positively to curcuminoids, and Type II patients, who do not.
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Since vitamin D and curcumin work differently with the immune
system, we may find that a combination of the two or each used
alone may be more effective - depending on the individual patient.
Curcumin has been used for thousands of years as a medicinal
preparation made from turmeric or as turmeric powder used as a
preservative and coloring agent in foods (yellow curry powder).
Curcumin was isolated as the major yellow pigment in turmeric, a
pure chemical (diferulomethane).
Curcumin’s structure is similar to other plant pigments called
polyphenolics (chemicals containing multiple ‘phenol’ groups) which
often have potent anti-oxidant and anti-inflammatory properties and
associated health benefits. Many similar plant pigments are known as
potent antioxidants, for example, the pigments extracted from grapes
in red wine ( resveratrol), or in green tea (catechins) or in fruit juices
(blueberries, strawberries, pomegranates etc) typically contain
polyphenolic antioxidants and have been studied for their possible
medicinal or preventive value.
Of the many polyphenolics, curcumin is special for the following reasons:
Curcumin is the Asian version of aspirin. Our wonder drug aspirin
was originally purified from willow bark extracts that were used in
European and American Indian traditional medicines to control
inflammation. Eventually aspirin was synthesized by German
chemists as one of the most successful drugs in the Western medicine
cabinet. Today aspirin is used not only in pain remedies and other
analgesic applications, but to control minor fever and inflammation
and, at low doses, to prevent heart attack and stroke.
Curcumin has been used in traditional Indian (Ayurvedic) and
Chinese medicine for thousands of years largely because of its proven
efficacy in treating conditions with inflammation. They also used it in
foods as an effective food preservative, just as we use synthetic
additives like BHA. These ancient civilizations have vast trial and
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error experience with many different herbal remedies and food
preparations and they selected curcumin as a food additive and major
tool for medicinal use based on efficacy- not superstition.
Curcumin has proven to be a potent anti-carcinogen. Because of low
toxicity and great efficacy in multiple in vitro and in vivo cancer
models, curcumin has successively made it through the first stages
(Phase I) of clinical testing abroad and is currently in clinical trials at
several sites in the U.S. All of this work by many labs has provided
the basis to quickly and safely explore curcumin’s potential for
Alzheimer’s and other neurological diseases.
Curcumin has shown efficacy in many other pre-clinical culture and
animal models for diseases related to aging and chronic treatment
with related ‘curcuminoids’ have even been able to increase the
lifespan of mice.
Tests in several models for Alzheimer’s has found that it not only
reduces oxidative damage and inflammation (as expected), but also
reduces amyloid accumulation and synaptic marker loss and
promotes amyloid phagocytosis and clearance. Curcumin worked to
prevent synaptic marker and cognitive deficits caused by amyloid
peptide infusion and Abeta oligomer toxicity in vitro.
The Merck researchers also showed data suggesting that ADDL
binding to cultured primary hippocampal neurons leads to an
increase in phosphorylated tau in those neurons several hours later.
The investigators infused an antibody against the Aβ1-15 epitope into
the brains of Tg2576 mice and showed that this experimental passive
vaccination reduced not only the levels of Aβ oligomers but also of
phosphorylated tau and active GSK3β, one of the kinases known to
phosphorylate tau. In subsequent in-vitro and cell-based experiments,
Aβ42 oligomer preparations activated GSK3β. The A11 antibody,
which recognizes Aβ oligomers but not monomers or fibrils,
counteracted that activation.
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These findings strengthen an emerging realization that Aβ oligomers
act upstream of tau, and suggest that this might happen in part via
GSK3β. They also imply that if a safe and effective vaccine against
oligomeric Aβ could be found, it might have an indirect effect on the
tau arm of AD pathogenesis, as well.
Recent findings showing that docosahexenoic acid, or DHA – an
omega-3 fatty acid found in cold-water fish – dramatically slowed the
progression of Alzheimer’s disease in mice.
Promising results were obtained, using D3 alone or together with
curcumin. There is new hope that these two natural occurring
substances may help boost the immune system and thus clear the
brain of amyloid-beta, which forms plaque, therefore giving hope and
relief to Alzheimer’s patients.
These studies have shown that D3 and curcumin together have
reduced the oxidized damage to the brain and also decreased the
inflammation.
Types of AD
Scientists have found that two different groups of Alzheimer’s
patients reacted differently: Type 1 patients responded to the
curcumnoids and type 2 did not respond positively. These two types
of patient results depend on the genes MGATIII and TLR-3, which
allows the immune system to work properly and thus enables the
immune system to ingest amyloid-beta.
According to the UCLA team of researchers it is too early to be
recommended at this point or to say what dose should be
recommended. The fact of being able to use curcumin as an aide in
the prevention is extremely exciting. Curcumin is very inexpensive
and along with the necessity of D3, the cost to the patient could be
minimal.
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Some benefits of Curcumin are:
1. Prevention
for cancer
2. Anti-inflammatory properties
3. Cardiovascular benefits
4. Prevention of high cholesterol
5. Rheumatoid Arthritis benefits
6. Prevention of Alzheimer’s disease
7. Prevention of Multiple sclerosis
Vitamin D3 is a necessary part of any diet
Studies have shown that D3 should be an important part of any diet.
Vitamin D3 deficiency will cause such problems as cardiovascular
diseases, diabetes, osteoporosis, depression and gum diseases. All
these conditions contribute to dementia.
Vitamin D has become a subject of intense study as scientists find
more and more diseases that high levels of vitamin D seem to protect
against. Easily obtained by exposure to the sun and also available in
some foods, insufficient amounts of the nutrient have been linked to
major diseases.
Elderly villagers in India who consume lots of curry have one of the
world’s lowest rates of Alzheimer's disease. Now, a team of
researchers in California has discovered that combining curcumin
with vitamin D3 may prompt the immune system to mobilize against
amyloid beta, the substance that forms the plaques in the brain
characteristic of Alzheimer’s. So far, the investigators found evidence
of this effect in tests with blood samples from nine Alzheimer's
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patients, a patient with cognitive impairment and three healthy
controls. They incubated immune system cells called macrophages
which clean up waste products - including amyloid beta - with
vitamin D and curcumin. The study showed that curcumin boosted
the binding of amyloid beta to the macrophages and that vitamin D
strongly stimulated the uptake and absorption of amyloid beta in
macrophages.
The pain reduction side of curcumin’s abilities relate to how the
flavonoid deactivates inflammatory systems in the body. Specifically,
inflammatory cytokines – a major inflammation marker – are
modulated by the curcumin, as are MAPK pathways, another
significant inflammation ingredient
Women who have been subjected to hormone replacement therapy
after menopause tend to have higher risks of breast cancer after the
therapy. Although the practice has now been largely stopped, the
legacy of it continues. Turmeric, it turns out, also plays a role in
preventing this type of cancer development.
The menopausal-type breast cancers studied here develop due to an
over-abundance of progestin, a faux version of the hormone
progesterone that is sometimes given to women. Curcumin
significantly impacted the growth rate of these tumors. It can be
considered an excellent candidate for use as a chemo-preventive
agent in clinical trials involving postmenopausal women taking both
estrogens and progestins.
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Note how much smaller the curcumin tumors are...
In general, this study reinforces a battery of information showing
curcumin slows the growth of tumors by regulating a host of
different cell signaling pathways – essentially cutting off the
communication channels of the cancerous cells in such that tumors
cannot survive.
Along those same lines, curcumin has shown itself to act like a
MAOI drug – one of the most powerful classes of anti-depressant
drugs available. It blocks monoamine oxidase thereby preventing the
brain from breaking down dopamine (read the Nutrition Wonderland
break down on dopamine if you need help). This mechanism may
also help treat Parkinson’s disease, as they rely on similar mechanisms
in the brain.
The Absorption Problem
Curcumin suffers from a similar problem common to most
flavonoids we have looked at in the past: it just does not get absorbed into
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the bloodstream very effectively. In fact, its present at woefully small
amounts in the body. Even after consuming as much as 12g of
turmeric (which is a ton of turmeric), only trace amounts of curcumin
made it into the body. The only way to translate all this positive
research in the lab is to figure out a way to get more curcumin into
the body.
Plenty of researchers are working on this problem though. The
Human BioMolecular Research Institute is developing methods to
deal with the bioavailability issue. Synthetic curcuminoids, compounds
combine the medical benefits of curcumin with a better delivery
vehicle that survives the brutal GI tract that usually destroys natural
curcumin. Some of these synthetic methods employed by the HBRI
include nano-particle engineering, cutting edge work that may
overcome part of what holds back this herb today.
A more natural approach may also fix the turmeric absorption
problem. The addition of piperine (an active compound of black
pepper) enhances the anti-depressive effect of turmeric. Simply
adding together the compounds found in nature may multiply the
effect of turmeric by up to 2000% by allowing the body to absorb
more curcumin. .
An Even Bigger Problem
With all of these benefits and the small bits of such promising
research, it may come as a surprise that so many of these findings are
preliminary in nature, especially since curcumin has been widely used
in Ayurvedic medicine for well over 4,000 years now. Part of the
answer is a fairly typical one in the 21st century world of science.
The LA Times published a piece last year that both strongly warns
against turmeric supplementation and offers an explanation to why so
little ‘actionable’ research has been done on the subject.
Big, expensive human trials of the compound have not been done
because drug companies cannot make money selling a curry spice.
Despite this, at least a dozen small clinical trials are underway around
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the world. It is believed that the compound shows great potential for
treating Alzheimer’s, inflammatory bowel disease, arthritis,
cardiovascular disease and other conditions caused by inflammation.
Turmeric and its flavonoid curcumin show massive therapeutic
benefits for all sorts of diseases and maladies. Inflammatory pain
from arthritis, elderly suffering from mental decline and women
genetically predisposed to cancer would appear to benefit from this
compound. But no doctor in his right mind would recommend such
a protocol until it was rigorously studied against the barrage of
unknown drug interactions, and, of course, amidst a minefield of
malpractice litigation.
We wait, for additional studies that will probably never come on the
scale required to elevate curcumin to the echelon of a true
pharmaceutical-type product. The advances are novel and interesting
but remain in a medical gray area until the structure of the medical
system is updated to take herbal medicine seriously.
Benefits of Turmeric enhanced by Black Pepper
Research has demonstrated anti-inflammatory, antioxidant, and anticancer properties of the spice turmeric and its constituent curcumin.
However, studies have also indicated that curcumin has a poor
bioavailability (absorption) when consumed orally due to its rapid
metabolism in the liver and intestinal wall.
Piperine, extracted from pepper, is a bioavailability (absorption) enhancer that
allows substances to remain in cells for longer periods of time.
What is piperine?
Piperine is a pungent compound found in the fruit of the plants in
the Piperaceae family, the most famous member of which is Piper
nigrum, black pepper and Piper longum (long pepper). It has a long
history of use in Ayurvedic medicine as a restorative and treatment.
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In 1998 researchers at St. John’s Medical College, Bangalore, India
combined piperine with curcumin to test the bioavailability
(absorption) of curcumin in rats and healthy human volunteers.
In rats the bioavailability was increased by 154%.
In the human volunteers, curcumin taken with 20 mg of piperine increased the
bioavailability (absorption)of curcumin by 2000%.
The researchers concluded that piperine enhances the serum (blood)
concentration, extent of absorption and bioavailability of curcumin in
both rats and humans with no adverse effects.
This means that a low dose of curcumin (or turmeric for that
matter) could have a greater effect in terms of health benefits when
combined with piperine than a large dose of curcumin or turmeric
would.
Putting black pepper on your food may be one of the easiest, most
economical ways to boost your overall health status. Piperine, the
main alkaloid from black pepper has been shown to substantially
increase the bioavailability of the nutrients in foods and supplements.
As the quality of food declines, it is increasingly important to your
health that the nutrients you consume are able to be used to
maximum efficiency by your body.
Piperine is able to increase bioavailability of many substances through
a number of mechanisms.
• It inhibits several enzymes responsible for metabolizing
nutritional substances,
• It stimulates amino-acid transporters in the intestinal lining,
inhibits removal of substances from cells so they continue to be
available for use over longer periods
• It decreases the intestinal activity allowing more of the
substances to enter the body in active form.
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The results of these actions are that substances reach, enter and
remain within their target cells for longer periods of time than would
normally be the case.
Piperine can turn a marginally effective therapeutic substance into a
highly effective one by increasing its bioavailability and intracellular
residency time. As an example, piperine can increase the
bioavailability of the cancer, inflammation and infection fighter,
curcumin, by twenty-fold.
Piperine favorably simulates the digestive enzymes of the pancreas,
enhances digestive capacity and significantly reduces gastrointestinal
food transit time. Black pepper or piperine treatment has also been
evidenced to lower lipid peroxidation in vivo and beneficially
influence the cellular status of organic sulfur compounds, antioxidant
molecules, and antioxidant enzymes in a number of experimental
situations of oxidative stress.
In addition to its effects on bioavailability, piperine has many other
actions in the body that include increasing beta-endorphins in the
brain, acting as an anti-depressant, increasing serotonin production,
boosting brain functioning, stimulating adrenal production, relieving
pain and asthma symptoms, stimulating melanin production,
decreasing ulcerations of the stomach, reducing stomach acid
production, and coordinating digestive tract contractions. It is highly
effective against colon cancer.
Other benefits of piperine
The journal Biometals reports a study involving cadmium, a well
known environmental carcinogen and immuno-toxicant that is
characterized by marked atrophy of the thymus and spleen
enlargement. Cadmium induces death in lymphocytes and alters
immune functions.
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Researchers tested the ameliorative effects to cadmium damage using
piperine, picrolivglycosides, and curcumin polyphenols. They found
that of the three herbals, piperine displayed maximum efficacy. All
the examined doses of piperine increased cell viability in a dose
dependent manner. Restoration of cell damage such as cytotoxicity,
oxidative stress and phosphatidylserine externalization was
potentiated with piperine. T and B cell phenotypes and cytokine
release were also mitigated best with piperine, rendering piperine the
compound of choice under immuno-compromised conditions.
In a study reported in the September edition of the journal Food and
Chemical Toxicology the effect of various doses of piperine was
determined. Results showed that piperine at all dosage ranges used in
the study possessed anti-depression like activity and cognitive
enhancing effects at all treatment durations. Researchers determined
that piperine is a functional food that improves brain functioning.
The medicinal properties of various compounds such as curcumin
cannot be well utilized because of poor bioavailability due to its rapid
metabolism in the liver and intestinal wall. In an older study reported
in Planta Medica, the effect of combining piperine, a known inhibitor
of hepatic and intestinal glucuronidation, was evaluated to determine
the bioavailability of curcumin in rats and healthy human volunteers.
When curcumin was given alone to the rats, moderate serum
concentrations were achieved over a period of 4 hours. When
piperine was added with the curcumin, the serum concentration of
curcumin increased for a 1-2 hour period. Time to maximum
concentration was significantly increased while elimination half life
and clearance significantly decreased. The bioavailability was
increased by 154%.
When curcumin was given alone to humans, serum levels were either
undetectable or very low. Addition of piperine produced much higher
concentrations from 0.25 to 1 hour following administration. The
bioavailability of curcumin when taken with piperine increased
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2000%.
A study reported in the September issue of Phychopharmacology was
designed to investigate the involvement of monoaminergic systems in
the antidepressant activity of curcumin and the effect of piperine as a
bio-enhancer to the biological effects of curcumin.
The researchers found that the enhanced curcumin dose dependently
inhibited the immobility period, increased serotonin, and inhibited
the monoamine oxidase enzymes. The compound also enhanced the
anti-immobility effect of sub-threshold doses of various
antidepressant drugs like fluoxetine, venlafaxine, or bupropion. The
combination of sub-threshold dose of enhanced curcumin and
various antidepressant drugs resulted in synergistic increase in
serotonin levels. The co-administration of piperine with curcumin
resulted in potentiation of pharmacological, biochemical, and
neurochemical activities. They concluded that the curcumin, piperine
combination proved to be a useful and potent natural antidepressant.
The summer issue of Clinical Laboratory Science reports a study to
determine if resveratrol from red grapes, cinnamaldehyde from
cinnamon, and piperine from black pepper have anti-proliferative
effects on colon cancer. Quantitative effects of each phytochemical
on concentration responses and time courses of proliferation of
cultured human colon cancer cells were assessed. The results showed
the phytochemicals each displayed anti-proliferative effects. Piperine
displayed a trend toward anti-proliferation at 24 hours and statistically
significant inhibition at 48 and 72 hours. Researchers concluded that
all three compounds offer significant anti-proliferative effects on
human colon cancer cells and provide protective effects against colon
cancer.
Using piperine
Piperine is generally consumed as a component of black pepper.
Adding black pepper to cooked foods, raw foods, and fresh juices is a
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good way to increase nutrient absorption. Black pepper spices up
almost all foods, even snacks like popcorn. It can be added to the
Budwig protocol used as a preventative and cure for cancer. It is
natural that the foods and the compound that makes their nutrients
so highly available go so well together.
Supplemental piperine should be taken along with meals for
maximum benefit.
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