INTRODUCTION:

Antioxidants are substances that inhibit oxidation reaction. Oxidation of molecules may lead to formation of free radicals that can start chain reactions and ultimately result in cell damage or death. Antioxidants will terminate these chain reactions by eliminating the free radical intermediates and hence they are referred as Reducing agents. Free Radicals are toxic metabolites of Oxygen which are lethal to living cells.¹ Hydroxyl radical, hydrogen peroxide, superoxide anions are together known as Free radical intermediates

Mechanism by which Reactive Oxygen Species causes tissue damage is DNA damage,

Lipid peroxidation, Protein damage, Oxidation of Antiproteases and Stimulation of Pro infective cytokine release by monocytes and macrophages.

Tertiary butyl hydroquinone, Propyl gallate, Butylated hydroxyl anisole, Butylated hydroxytoluene is some of the synthetic antioxidants that are commonly used.

Antioxidants are important for maintaining health .Oxidative stress occurs when antioxidant defense system is inadequate, which in turn causes lipid, protein and carbohydrate damage. Best sources being fruits and vegetables followed by nuts, grains, meat, poultry, fish. Phytochemicals (Phenolic compounds); Flavanoids which are compounds that give colour to vegetables, fruits, flowers and leaves. Catechins, active antioxidants in green and black tea, Lycopene present high in tomatoes, employed in the prevention of chronic diseases especially cancer and Zeaxantin present in spinach are the best source of natural antioxidants

Some of the antioxidants act as enzymes as they catalyze the oxidation of other molecules. Eg: Superoxide dismutase, Glutathione peroxidase, Glutathione reductase, Catalase, Glutathione transferase. Glutathione is a cysteine containing peptide .It has antioxidant properties because if the presence of Cysteine moiety which acts as a reducing agent.

Antioxidants help in free radical scavenging .Vitamin E protects polyunsaturated fatty acids against oxidation and cell membranes from damage by free radicals .Vitamin C Scavenges free radicals intracellularly, works along with Vitamin E. Beta-Carotene is the eliminator of uncharged oxygen which is harmful to cells whereas Selenium forms active site of antioxidant enzymes².

Minerals like Selenium, Copper, Iron, Zinc and Manganese, Vitamins like Vitamin E, Vitamin B and Vitamin C acts as antioxidants.³

Antioxidants like Melatonin can cross cell membranes and blood brain barrier. It is called suicidal antioxidants because once it is oxidized it cannot be reduced or reversed back to its previous state.^{3, 4}

Antioxidants inhibit oxidation reaction and scavenge free radicals ,preventing cell damage.

Vitamin E, Beta carotene, Vitamin C, Lycopene, Lutein, Flavanoids are best examples of antioxidants

The mechanism by which the antioxidants bring about their actions are,

1) Chain breaking mechanism – Primary/Natural antioxidants donate electrons to free radicals

2) Removal of Reactive Oxygen Species and Reactive Nitrogen Species

There is formation of superoxide by loss of electrons. The free radicals initiate chain reaction which results in formation of more free radicals in the cell membrane. As a result of this there is cell membrane damage. Anti oxidants inhibit oxidation reaction; neutralizes free radicals.

ANTIOXIDANTS AS THERAPEUTIC AGENTS:

The antioxidants are used for prevention of coronary artery disease by preventing atherosclerosis, sickle cell anaemia, Alzheimer’s disease, Diabetes ,premalignant oral lesions and many more.

PREVENTION OF CORONARY ARTERY DISEASE:

Antioxidant therapy may helpful in the prevention of Atherosclerosis and thereby the clinical complications like Myocardial Infarction, Coronary artery disease. Oxidation of circulating lipoproteins by free radicals especially Low density Lipoprotein may cause atherosclerosis. Enzymatic and Non enzymatic Nutrient antioxidants protect lipoprotein from oxidation in the intracellular and extracellular compartments respectively. Vitamin E plays a critical role in oxidation resistance followed by Vitamin C which helps in defending oxidative stress. Vitamin E has been proved efficient in preventing mortality from Cardiac diseases.^{3, 5}

SICKLE CELL ANAEMIA:

In Sickle cell anemia, abnormal hemoglobin (HbS) is known to have high affinity for red cell membrane. The sickle cells are susceptible to lipid peroxidation and there is an increased glutathione peroxidase activity and low catalase activities .This indicates that unbalanced antioxidant system can be harmful.³Alpha lipoic acid and acetyl –L-carnitine are used for the treatment of systemic inflammation in sickle cell anemia according to recent studies.

ALZHEIMER’S DISEASE–A NEURODEGENERA-TIVE DISORDER:

It is characterized by neuronal and synaptic loss, extracellular Beta Amyloid protein deposition and intracellular deposits-NeuroFibrillary Tangles (NFTs) in the brain. Brain tissues are exposed to Oxidative Stress- imbalanced synthesis of Reactive Oxygen Species (ROS) and Antioxidative defense system. Glutathione plays an important role by scavenging the ROS. Preventive antioxidants are vital for protection of neurons against oxidative damages. Vitamin E, Vitamin C, Vitamin B decrease free radical mediated damage in neuronal cells and inhibits dementia. Vitamin E reduces Beta Amyloid protein and Plaque deposition whereas Vitamin C and Carotenoid inhibits lipid peroxidation. Thioctic acid is a powerful antioxidant which can recycle other antioxidants thereby preventing accumulation of lipid peroxidation products. Metabolic, Mitochondria –directed antioxidants and treatment with Vitamin E, Vitamin C are found to show certain positive effects. ^{5, 6}

CANCER AND ANTIOXIDANT THERAPY:

Alpha–Tocopherol succinate (Vitamin E) inhibits the growth of cancer cells at low concentrations and caused cell death at higher concentrations .Anticancer effect of Vitamin-C is extensive as it kills highly proliferating cancer cells directly.Lanthanides are considered to be an anticancer agent. Green tea is found to be effective in case of leukoplakia .Major advantage of Antioxidants is that it do not interfere with Chemotherapy .It may decrease the side effects experienced by the patient during treatment with chemotherapy that cause free radicals especially those produced by doxorubicin which may cause damage to heart. ^7,8

ACUTE CENTRAL NERVOUS SYSTEM INJURY:

Oxidative stress contributes to Ischemic or Hemorrhagic stroke. Free radicals may cause damage to cellular components which may lead to cell necrosis or apoptosis due to poor antioxidant defense system .Brain injury may increase the Glutamate level; produce Reactive Oxygen Species resulting in destruction of parenchyma . Therefore antioxidants treatment may improve the neurological outcome. ⁹

ACQUIRED IMMUNODEFICIENCY SYNDROME:

HIV infection is characterized by severe immunological and metabolic abnormalities .Glutathione is the main intracellular defense against oxidative stress and it also helps in protecting the cell from the harmful effects of free radical intermediates. This is the reason why GSH Replacement Therapy came into existence for HIV infection. ^{10, 11}

DIABETES:

Oxidative stress is produced under diabetic conditions and it leads to tissue damage. Lipoic acid is a powerful and versatile antioxidant used to prevent Diabetes. Combined antioxidants therapy or antioxidants with anti-inflammatory agents are used in Diabetic patients with albuminuria as per some studies. N- Acetyl -L-cysteine [NAC], vitamins C, Vitamin E, and alpha lipoic acid is beneficial in the treatment. Intraperitoneal glucose tolerance test revealed that the treatment with NAC retained glucose-stimulated secretion of insulin and decreased blood glucose levels. ¹²

USE OF ANTIOXIDANTS IN DENTISTRY

Prevention from occurrence of premalignant oral lesions and recurrence of secondary lesion. Production of ROS in excess by hyper reactive peripheral blood neutrophils is found out to be a cause of Oxidative stress in Periodontitis . Ascorbic acid is said to be effective in gingivitis. Therefore Antioxidant therapy could be beneficial. ^13,14

Table 1: Antioxidants and their uses

S. NO	ANTIOXIDANTS USED	DISEASE CONDITION	REFERENCE
1	Vitamin E,Vitamin C	CORONARY ARTERY DISEASE	A.A. Hamid et al, Gutter et al
2	Alpha lipoic acid and acetyl –L-carnitine	SICKLE CELL ANAEMIA	A.A. Hamid et al
3	Thioctic acid	ALZHEIMER’S DISEASE	Gutter et al
4	Lanthanides, lycopene	CANCER	Blot et al
5	N- acetyl-L-cysteine (NAC) , Vitamins C and E	DIABETES	Hideaki et al

1)Vitamin E and Vitamin C guards cell membranes from damage and scavenges free radicals ,primarily used in the treatment of coronary artery disease 2) A balanced anti oxidant system including alpha lipoic acid and acetyl-L-carnitine can prevent damage by increasing the production of oxygen free radicals 3)Thioctic acid prevents the accumulation of lipid peroxidation products that occurs during Alzheimer’s disease 4)Metal based drugs which has antioxidant properties are nowadays used in the treatment of cancer like lanthanides and lycopene has anti-carcinogenic and aniti-mutagenic activities 5) NAC, Vitamins C and E are found to decrease blood glucose level

CONCLUSION:

The imbalance between reactive oxygen species and antioxidant defense system may damage DNA; Carbohydrates or proteins .Proper consumption of Antioxidants through diet and supplementation will remove free radicals from body, improve health and lower the risk of various diseases. Carotene, an antioxidant present in tomatoes effectively reduces Reactive Oxygen Species mediated diseases .Lycopene shows cardio protective, anti-inflammatory and anti- carcinogenic properties .Selenium derivatives can be used in the prevention of cancer and control of heart failure. Lipoic acid is a powerful antioxidant that aids protection against aging stroke, heart attack and cataracts because they suppress the action of free radicals in important organs like brain, heart and eyes .Antioxidants are used as food preservatives also. However, the therapeutic uses of antioxidants and their success in clinical practice needs to be determined further.

ACKNOWLEDGEMENT:

The author is grateful to the authors/editors of all those articles, journals and books from where the data for this article has been reviewed and discussed.

REFERENCES:

1 S.L. Nuttall, M.J. Kendall and U. Martin, Antioxidant therapy for the prevention of cardiovascular disease, Q J Med ;1999; 92:239-244

2 Neelu Shetti and Renuka Patil, Antioxidants : It's beneficial role against health damaging free radical ,World J Sci and Tech; 2011, 1(11) : 46-51

3 A.A Hamid, O.O Aiyelaagbe, L.A Usman , O.M. Ameen and A. Lawal ,Antioxidants : It's medicinal and pharmacological applications, ,2010,Afric J of Pure and Applied Chem ,4(8), 142-151.

4 Tan, Dun-Xian; Manchester, Lucien C.; Reiter, Russel J.; Qi, Wen-Bo; Karbownik, Malgorzata; Calvo, Juan R. . "Significance of Melatonin in Antioxidative Defense System: Reactions and Products". Neurosignals ; 2000, 9(3–4): 137–59

5 Gutter RG (1991). Antioxidants and ageing. Am. J. Clin. Nutr.Hail N, Cortes M, Drake EN, Spallholz JE (2008). Cancer chemoprevention: a radical perspective. Free Radic. Biol. Med., 45(2): 97-110.

6 Traber, Maret G.; Atkinson, Jeffrey. "Vitamin E, antioxidant and nothing more". Free Radic Biol and Med; 2007, 43 (1): 4–15.

7 Bjelakovic G, Nikolova D, Gluud LL, Simonetti, R.G; Gluud, C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA; 2007, 297(8): 842–857.8.

8. Ames B, Cathcart R, Schwiers E, Hochstein P. "Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis". Proc Natl Acad Sci USA; 1981 78 (11):685862.

9 Cheremisinoff NP, Performance properties of Plasters and elastomers. Handbook of Polymer science and technology : Marcel Dekker Inc,New York, 1989, Vol II

10 F.Staal, Antioxidant therapy for AIDS, Eur.J. Clin. Investig (2000) 30, 841±842.

11 Walmsley SL,Winn LM, Harrison ML, Uetrecht JP, Wells PG. Oxidative stress and thiol depletion in plasma and peripheral blood or lymphocyte from HIV infected patients:toxicological and pathological implications. AIDS, 1997,11:1689-97

12 Hideaki Kaneto, Yoshitaka Kajimoto, Jun-ichiro Miyagawa, Taka-aki Matsuoka, Yoshio Fujitani, Yutaka Umayahara, Toshiaki Hanafusa, Yuji Matsuzawa, Yoshimitsu Yamasaki, and Masatsugu Hori. Beneﬁcial Effects of Antioxidants in Diabetes, Diabetes,1999 48 :2398–2406.

13 D. Wei et al, lipid peroxidation levels,total oxidant status and superoxide dismutase in serum ,saliva and gingival crevicular fluid in chronic periodontitis patients before and after periodontal therapy ,Austr Dent J, 2010, 55:70-78

14 I.L.C .Chapple , Reactive Oxygen Species and antioxidants in inflammatory disease, J .Clin perio , 1997 ,24:287-296

International conference on harmonization (ICH) harmonized tripartite guideline for stability testing of new drugs substances and products Q1A (R2) aug-2003. Q1A (R2) Mar 2004.

Received on 04.08.2013 Modified on 15.09.2013

Research J. Pharm. and Tech. 6(12): Dec. 2013; Page 1426-1429