Turmeric -Contemporary applications in medicine

Turmeric exemplifies a herb for which clinical applications have evolved over time. Until recently, this perennial herb, widely cultivated in tropical regions of Asia, particularly in India, was valued primarily as a commercial item for imparting a lively yellow color and also as a part of most curry powders. In India, the Bengal kind of Turmeric is preferred for dyeing purposes, and the Madras kind is preferred for flavouring purposes. The long established image of turmeric as a commercial dyestuff and component of curry 6 was partly responsible for overshadowing its importance as a medicinal herb.

The significance of turmeric in medicine has changed considerably since the discovery of the anti-oxidant properties of naturally occurring phenolic compounds.. The same ground dried rhizome of Curcuma longa, which has been used for centuries as a spice, food preservative and a coloring agent, has been found a rich source of phenolic compounds or curcuminoids7. Curcuminoids refers to a group of phenolics present in turmeric, which are chemically related to its principal ingredient, curcumin. Three main curcuminoids were isolated from turmeric: curcumin, demethoxycurcumin and bisdemethoxycurcumin. All three impart the hallmark yellow pigmentation to Curcuma longa plant, and particularly to its rhizomae.

Although the chemical structure of curcumin was determined by Lampe in 1910, it was only in the seventies and eighties that the potential uses of curcuminoid compounds in medicine have been studied. The ongoing laboratory and clinical research indicates that turmeric and its phenolics have unique anti-oxidant and anti-inflammatory properties8,10,11,12,13,14 . Their potential use in prevention of cancer and in the treatment of infection with human immunodeficiency virus (HIV) are also subjects of intensive laboratory and clinical research 15,16,9.

These interesting findings on curcuminoids, as well as concerns over toxicity of synthetic phenolic antioxidants such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), have further stimulated interest in natural phenolics for medicinal and food applications.

CURCUMINOIDS - PHARMACOLOGICAL ACTIONS INCLUDING PRECLINICAL AND CLINICAL EVALUATIONS:

The use of Curcuma longa to treat a variety of inflammatory, biliary and respiratory disorders, has generated scientific interest in the curative properties of the turmeric rhizome. Much of the work has focused on the use of dried extracts, the volatile oil and the active principles, the Curcuminoids.

Most researchers used alcoholic extracts of the rhizome. Their studies revealed a diversity of biological effects and initiated further research into the mechanism of these processes. A discovery of prime importance was the antioxidant property of curcumin, which is largely responsible for its wide range of pharmacological activity.

1. Antioxidant properties of turmeric and curcumin

During the physiological process of respiration, inhaled and tissue incorporated oxygen oxidizes cellular components and biomolecules. This process when tilted towards excessive activity by external factors, such as nutrition, or internal factors such as disease, results in the generation of oxidative products known as free radicals. These free radicals are highly reactive chemical molecules, which react with biological compounds causing tissue damage by a process called "free radical pathology".

The sequence of changes resulting from an injury (due to burns, thermal shock, radiation, etc.) are as follows89:

1. The sensation of pain.

2. Phagocyte activation and the production of damaging free radicals.

3. Arachidonic acid release and enzymatic peroxide formation.

4 Metal ion release from storage sites.

5. Release of heme protein which may react with peroxides to promote free radical damage.

6. Depletion of antioxidant defense mechanisms, such as GSH (glutathione) from the cells.

7. Oxidative stress.

The aging process exemplifies the cumulative result of deterioration of individual cells, tissues and organs, caused and promoted by free radicals. The human body has built-in mechanisms to counteract free radicals. These mechanisms are collectively known as the body’s antioxidant defense. Unfortunately, in most instances the antioxidant defense is gradually overwhelmed by the aging process or a disease or both. The inflammatory processes associated with microbial or viral infections and the progression of cancer are just a few disease conditions which contribute to depletion of the anti-oxidant defense system of the body. Therefore, it is important to preserve the body’s defenses against damages by free radicals. Some vitamins, minerals and natural compounds like phenols, flavonoids and carotenoids have the ability to counteract free radical pathology by scavenging or neutralizing the free radicals. These diversified groups of nutrients, micronutrients and food supplements belong to a category of biologically important substances known as antioxidants.

Curcuminoids are natural phenolic compounds, with potent antioxidant properties. Several research groups have recently provided convincing evidence for the antioxidant properties of curcuminoids. Both turmeric and curcuminoids inhibited generation of potent free radicals like superoxide and hydroxyl radicals 8. The antioxidant properties of curcumin in prevention of lipid peroxidation, another process that generates free radicals, is well recognized27,72.

In studies on spice principles as antioxidants in the inhibition of lipid peroxidation of rat liver microsomes, curcumin was found to be a potent antioxidant 8.

(Ref 8)

1. Vitamin E 2. Curcumin 3. Eugenol 4.Capsaicin

Amongst the spice principles tested, Curcumin showed the highest ability to prevent lipid peroxidation. Curcumin, in this study, was found to be eight times more powerful than Vitamin E.

The biological effects of curcuminoids to counteract free radicals, have been assessed in animal models with chemically induced inflammation and swelling. Inflammation is known to be associated with increased levels of lipid peroxides and free radicals, which are generated by the liver as well as by the inflammed site in the body. Lipid peroxidation is essentially a "free radical chain reaction" involving the following stages89:

1. Initiation

Hydrogen is abstracted from a polyunsaturated fatty acid side chain by a free radical species:

CH+R*------- C*+RH

C*+O2 ---------- -CO2*

2. Propogation

The fatty acid side chain peroxyl radical -CO2* attacks adjacent fatty acid side chains.

CO2*+-CH-------- -CO2H + -C*

The propogation continues, leading to accumulation of lipid peroxides in the membranes, destabilizing them and permitting the entry of damaging ions. Peroxyl radicals attack ions as well as membrane proteins. An antioxidant terminates the propogation of free radicals either by accepting and quenching them or by retarding the "initiation" step by reducing the generation of free radicals.

Examples of Free Radicals

Name Formula Formation / effect in vivo

Trichloromethyl CCl3* During metabolism of CCl4 in the liver and contributing to the toxic effects of this solvent.

Hydroxyl OH* Attacks all molecules in the human body
Peroxyl, alkoxyl RO2* , RO* Formed by several routes especially during the breakdown of organic peroxides.

Oxides of nitrogen NO*
NO2* Formed in vivo from the amino acid L-arginine. From cigarette smoke

Curcumin fed to the animals with chemically induced inflammation reduced levels of lipid peroxides, reduced inflammation, and as a result inhibited production of tissue damaging free radicals26,72. Also, under in vitro conditions, in tissue culture, rat and mouse liver cells incubated in the presence of micromolar concentrations of curcumin reduced the generation of lipid peroxides.26 Curcumin also prevented the oxidative damage and alteration of the DNA genetic material in cultured fibroblasts.71

A potential role of curcumin in preventing oxidative damage to the arterial wall has been studied. Cardiovascular disease is caused by the progressive narrowing of the arterial walls. This is essentially due to the deposition of cholesterol plaque resulting from high blood levels of oxidized cholesterol. Oxidition of blood cholesterol is evaluated in clinical studies by measuring blood levels of lipid peroxides. Administration of 500 mg of curcuminoids daily to healthy humans for seven days lowered levels of blood lipid peroxides by 33%, as well as levels of blood cholesterol by 29%. Authors of this study indicate a possible use of curcuminoids in the prevention of cardiovascular disease.18 The key data from this study are presented below:

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