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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 www.healthoracle.org 1 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. www.healthoracle.org 2 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. www.healthoracle.org 3 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 www.healthoracle.org 4 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. www.healthoracle.org 5 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 www.healthoracle.org 6 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. www.healthoracle.org 7 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 www.healthoracle.org 8 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. www.healthoracle.org 9 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 www.healthoracle.org 10 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 www.healthoracle.org 11 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. www.healthoracle.org 12 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 www.healthoracle.org 13 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. www.healthoracle.org 14 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. www.healthoracle.org 15 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 www.healthoracle.org 16 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. www.healthoracle.org 17 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 www.healthoracle.org 18 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 www.healthoracle.org 19 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. www.healthoracle.org 20 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. www.healthoracle.org 21 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. www.healthoracle.org 22 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 www.healthoracle.org 23 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 www.healthoracle.org 24 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. www.healthoracle.org 25