Abstract
The use of ionizing radiation, which is the cornerstone of cancer treatment, is compromised by the radiosensitivity of normal tissues. A chemical that can give selective benefit to the normal cells against the deleterious effects of ionizing radiation has been a long-sought goal. However, most of the compounds studied have shown inadequate clinical application owing to their inherent toxicity, undesirable side effects, and high cost. Studies carried out in the past 2 decades have shown that some of the classical Indian Ayurvedic drugs (Amritaprasham, Ashwagandha Rasayana, Brahma Rasayana, Chyavanprasha, Narasimha Rasayana, and Triphala Churna) possess radioprotective effects. In the current review, an attempt is made to summarize the radioprotective observations of these Ayurvedic drugs and the mechanisms responsible for the radioprotective effects.
Introduction
The effective use of ionizing radiation is compromised by the side effects resulting from the sensitivity of the bordering normal tissues. Accordingly, the use of compounds that can protect normal tissues against radiation injury has been a long-sought goal as in addition to protecting the normal tissue it will also permit use of higher doses of radiation to obtain better cancer control and possible cure. 1 Since the discovery by Patt et al 2 that pretreatment with cysteine protected rats against X-ray-induced mortality, several compounds have been synthesized and tested for their radioprotective properties. The sulfydryl compounds were found to be good radioprotectors but unfortunately their inherent toxic effects at their optimal protective doses were a major deterrent to their clinical use.3,4
Herbal drugs offer an alternative to synthetic compounds and are considered either nontoxic or less toxic 3 and experimental studies have shown that the Ayurvedic drugs Amritaprasham,5-7 Ashwaganda Rasayana,5-7 Brahma Rasayana,6-14 Chyavanaprasha, 14 Narasimha Rasayana,5-7 and Triphala15-18 possess radioprotective effects. In the current review, for the first time an attempt is made to summarize these observations with emphasis on the plausible reasons responsible for the radioprotective effects.
Traditional Ayurvedic Drugs With Radioprotective Effects
Ayurveda (in Sanskrit Ayur means life, and Veda means knowledge) the traditional Indian system of medicine, is one of the world’s oldest medical systems. 3 The concept and treatment principles of Ayurveda are different from that of the modern medicine. Whereas modern medicine is evidence based and makes use of a distinct well-defined chemical entity for treatment, emphasis in Ayurveda is mainly on disease prevention and promotion of good health by following proper lifestyle and by adopting measures of rejuvenation.19,20
According to the Ayurvedic system of medicine, the body is composed of tridosha, known as Vata, Pitta, and Kapha, the psychophysiological principles that regulate various functions in the body. Vata governs functions associated with the movement and communication. Pitta governs functions associated with metabolism, digestion, and transformation. Kapha governs the structure and cohesion of the body. For optimal functioning of the body, the 3 doshas need to be in a state of equilibrium with each other and its alterations affect the normal functions and health of the individual. The balance in tridosha is highly sensitive and is susceptible to variation because of age, environmental changes (diurnal, nocturnal, and seasonal modifications) and altered lifestyle (changes in food habits, physical activity).19-21
Exposure to ionizing radiation alters the balance and leads to the irreversible changes in the tridoshas that are visible as radiation sickness and when severe causes mortality. 15 The classical Ayurvedic drugs Amritaprasham,5-7 Ashwaganda rasayana,5-7 Brahma Rasayana,6-14 Chyavanaprasha, 14 Narasimha Rasayana,5-7 and Triphala,15-18 which belong to Rasayana group of drugs in Ayurveda (drug that imparts rejuvenating effects to the cell and tissues) are reported to possess radioprotective effects and are addressed in this review.
Amritaprasham
According to Ayurveda, regular intake of Amritaprasham early morning is supposed to improve strength, stamina, and to retard aging.20,21 It is also advocated for the treatment of fever, cough, bronchial asthma, burning sensation, and seminal abnormalities such as azoospermia, oligospermia, erectly dysfunction, and menstrual disorder. It is indicated in urinary disorders, hemorrhoids, gastrointestinal disorders, epistaxis, anorexia, thirst, vomiting, and loss of consciousness. It is supposed to improve strength and provide hemopoetic stimulatory action.20,21
Preclinical studies have shown that the administration of Amritaprasham reduced the radiation-induced loss of body weight and arrested the decrease in the weight of liver, kidney, and spleen of mice. Treatment with Amritaprasham caused a 35.5%, 56.73%, and 40% decrease in serum glutamate pyruvate transaminase (GPT), serum lipid peroxide, and hepatic lipid peroxide levels, respectively, on day 2 and 54.67%, 40%, and 60% decrease in serum GPT, serum lipid peroxide, and hepatic lipid peroxide levels, respectively, on day 7 postirradiation. 6
Ashwagandha Rasayana
Ashwagandha Rasayana is accredited to be a bhalya (drug that improves strength) and vajikara (aphrodisiac). 21 Regular consumption is believed to retard senescence, rejuvenate the reproductive organs, and increase fertility in both men and women.20-23 With respect to radiation protection, Vayalil et al 6 have shown that the oral feeding of Ashwagandha Rasayana to mice at 50 mg/kg body weight for 28 consecutive days prevented the radiation-induced emaciation and decrease in the organ weight when compared with the irradiated controls. It also inhibited radiation-induced increase in serum GPT levels and lipid peroxidation levels. 6
Brahma Rasayana
Brahma Rasayana is a brain-specific geriatric drug and its regular consumption is supposed to promote mental clarity, improve resilience to mentally demanding chores, and improve memory and cognition. It is also supposed to reduce the symptoms of ageing such as wrinkling and graying of hair. 13 Animal studies have shown that feeding Brahma Rasayana protected mice from radiotoxic effects, reduced the loss of organ (spleen liver and kidney) and body weight, decreased the levels of serum and liver lipid peroxides, alkaline phosphatase, and GPT. 6 Clinical studies have also shown that oral administration of Brahma Rasayana increased the levels of lymphocytes and neutrophils in cancer patients undergoing radiotherapy. 13 Leukopenia, neutropenia, lymphopenia, and the level of serum lipid peroxidation were decreased, suggesting its benefit. 13
Chyavanaprasha
Chyavanaprasha is a polyherbal preparation made of more than 65 plants is one of the oldest and most popular Ayurvedic preparations. It is named after its inventor sage Chyavana and the first documented evidence of this formulation is observed in the principal Ayurvedic text Charak Samhita where it is advocated to treat kasa (cough), svasa (dyspnea), kshaya (consumption), svarabheda (voice problems), and hrdroga (cardiac problems). 20 Because of this it is also termed as the elixir of life. Chyavanaprasha is supposed to be an anabolic agent and its regular consumption is believed to give health benefit to people of all ages and health.20,24
Chyavanaprasha also possess radioprotective effects and administering graded doses of hydroalcoholic extract (5-80 mg/kg body weight) for 5 consecutive days by intraperitoneal route before exposure to supralethal dose of γ-radiation (10 Gy) protected animals against the radiation-induced sickness and mortality. 14 The best effect was observed at 15 mg/kg, where the highest survival of 58.33% was observed on day 30 postirradiation. The chyavanaprasha extract was nontoxic up to a dose of 6 g/kg body weight suggesting it to be safe and devoid of systemic toxicity. 14 Studies have shown that Chyavanaprasha decreases the carbon tetrachloride–induced liver damage in rats 25 and that it reduces the ascites and solid tumor volume of tumor-bearing animals, which then concomitantly increases their life span. 26 Intake of Chyavanaprasha (20 grams) twice a day for 2 months by bidi smokers, decreased their coughing, increased their appetite, and helped them gain body weight. 27
Narasimha Rasayana
Ashtangahridayam, one among the major ancient Ayurvedic treatise by Acharya Vagbhata describes the Narasimha Rasayana in detail and it is said to be of use in reversing aging, improving immune function, and increasing sexual vigor and potency.20,21 Feeding mice with 50 mg/kg body weight of Narasimha Rasayana consecutively for 5 days prior to, and for a month after, radiation arrested the radiation-induced deleterious effects. Treatment with Narasimha Rasayana increased the body weight and the organ weights of the recipient mice. 6 It also decreased the levels of radiotoxic biochemical endpoints and the levels of serum and tissue lipid peroxides, serum alkaline phosphatase, and GPT. 6
Triphala
Triphala churna, which in Sanskrit means 3 fruits, is made of Terminalia chebula Retz, Terminalia bellerica Roxb, and Phyllanthus emblica Linn or Emblica officinalis gaertn and is an important Ayurvedic formulation. The ancient Indian physicians used Triphala for many ailments but most importantly for gastrointestinal disorders such as dyspepsia, poor food assimilation, cleansing of colon, constipation, gastrointestinal tract, and colon tonifier. 20 Triphala has been reported to cause weight loss and to be useful in anemia, jaundice, constipation, cough, asthma, fever, chronic ulcers, leucorrhea, and pyorrhea.20,28 Preclinical studies have shown that Triphala is a potent free radical scavenger and possesses antioxidant, anti-inflammatory, antipyretic, analgesic, antibacterial, antimutagenic, adaptogenic, anticancer, and hypoglycemic effects. 15
Triphala is observed to exert radioprotective effects when administered through both intraperitoneal15,16 and oral routes. 17 Jagetia et al 15 have observed that administration of aqueous extract of Triphala (5-20 mg/kg) by the intraperitoneal route for 5 consecutive days prior to supralethal dose of 10 Gy γ-radiation protected mice against radiation sickness and mortality. 15 The best protection was observed for 10 mg/kg Triphala as nearly 60% survival was observed at the end of the study period of 30 days postirradiation. 15 The optimum radioprotective dose of 10 mg/kg Triphala was found to be 1/28 of the LD50 dose 280 mg/kg body weight and caused a dose reduction factor of 1.15. 16 Animal studies have also shown that oral feeding of Triphala powder for 14 consecutive days, 7 days prior to and 7 days after exposure to lethal dose of 7.5 Gy of whole-body γ-radiation. Triphala was ineffective when administered only after irradiation thereby indicating its benefit to be only when exposure to radiation is planned. 17 Recently, Yoon et al 18 also observed that administering Triphala (1 and 1.5 g/kg/d orally for 10 consecutive days) protected rats against the single fraction of 12.5Gy γ-irradiation-induced acute intestinal mucosal damage.
Mechanisms Responsible for the Radioprotective Effects
The exact mechanism of action responsible for the radioprotective effects of these Rasayana drugs is unknown. As these formulations contain many plants with diverse pharmacological properties with some of them possessing radioprotective effects (Table 1), it is logical to expect that myriad protective mechanisms are concomitantly operating (Figure 1). Some of the studied and reported mechanisms are explained in the following sections.
Composition of Various Traditional and Proprietary Herbal Drugs Reported to Possess Radioprotective Effects.
Biochemical targets responsible for radioprotective effects of the Ayurvedic Rasayana drugs (arrows up = increase; arrows down = decrease).
Free Radical Scavenging
Agents that can scavenge free radicals or reactive metabolites without affecting the outcome of the treatment would be beneficial to the host and can enhance the efficiency of the treatment. Studies have shown that the Triphala, Chyavanaprasha, and Brahma Rasayana possess free radical scavenging and antioxidant effects. In vitro studies suggest that Brahma Rasayana scavenged Fe2+-ascorbate and Fe3+-ADP-ascorbate–induced lipid peroxidation and scavenged the hydroxyl, superoxide, and nitric oxide generated in vitro. It also inhibited the phorbol myristate acetate–induced superoxide generation in mice peritoneal macrophages and nitrite production in peritoneal macrophages. 16 Triphala and Chyavanaprash have also been observed to scavenge nitric oxide in vitro. 29 Rasayana drugs are composite herbal formulations and many plants that are an integral part of Rasayana preparations possess free radical scavenging and antioxidant prpperties (Table 2).3,6,7,30-32
Plants With Various Pharmacological Properties That Are an Integral Part of the Rasayana Drugs.
Increase in Antioxidant Enzymes
Studies have shown that Triphala and Brahma Rasayana increase the levels of glutathione and antioxidant enzymes and protect against the oxidative stress.11,17,35 The administration of aqueous extract of the medicinal plants such as Aegle marmelos, Terminalia chebula, Emblica officinalis, which are an integral part of many Rasayana formulations, have been reported to effectively modulate the oxidative stress and enhance the antioxidant status in rodents.36-39
Antimutagenic Activities
There is increasing evidence that many phytochemicals, plants, and their compound formulations present in rasayana can act as inhibitors of mutagenesis and carcinogenesis.3,40,41 Studies by Yadav et al 27 have shown that consumption of Chyavanaprasha by bidi smokers decreased the genotoxic risk caused by mutagenic agents present in tobacco smoke. When compared with bidi smokers alone, consumption of Chyavanaprasha decreased the mitotic index, chromosomal aberrations, sister chromatid exchanges, and satellite associations. 27
Kaur et al 40 have reported that aqueous, chloroform, and acetone extracts of Triphala was observed to possess antimutagenic effects against both direct and indirect mutagens in the Ames histidine reversion assay. The results demonstrate that the extracts inhibited the mutagenicity induced by both direct- and indirect-acting mutagens, but the inhibition was greater for S9-dependent mutagens. 40 The acetone and chloroform extracts were observed to be better than the aqueous extracts in the TA98 and TA100 tester strains of Salmonella typhimurium. Maximum inhibition was observed for the acetone extract. 40
Triphala and its individual constituents are reported to prevent γ-radiation-induced DNA strand break formation in the plasmid DNA (pBR322) in vitro. 42 Feeding of triphala was also observed to inhibit the radiation-induced DNA strand breaks in leukocytes and splenocytes of mice exposed to whole-body irradiation of 7.5 Gy. 17 Furthermore, plants such as Ocimum sanctum, Podophyllum hexandrum, Phyllanthus amarus, Phyllanthus amarus, Moringa oliefera, Tinospora cordifoila, Mentha piperita, Syzygium cumini, Aegle marmelos, and Aphanamixis polystachya have been reported to inhibit radiation-induced DNA damage as evaluated by chromosomal aberration or micronucleus assay. 41
Inhibition of Lipid Peroxidation
In vitro studies have shown that the both alcoholic and aqueous extracts of Rasayana inhibit enzymatic- and nonenzymatic-induced microsomal lipid peroxidation in a concentration-dependent manner.33,43 Triphala is also observed to decrease the radiation-induced lipid peroxidation in vitro. 32 Brahma Rasayana treatment decreased the radiation-induced increase in the serum lipid peroxidation in cancer treatment 13 and serum and liver lipid peroxidation in the chickens subjected to heat stress. 44 Studies also indicate that several botanicals such as Centella asiatica, Ocimum sanctum, Podophyllum hexandrum, Amaranthus paniculatus, Emblica officinalis, Phyllanthus amarus, Piper longum, Tinospora cordifoila, Mentha arvensis, Mentha piperita, Syzygium cumini, Zingiber officinale, Ageratum conyzoides, Aegle marmelos, and Aphanamixis polystachya protect against radiation-induced lipid peroxidation (Table 2). 41
Anti-Inflammatory Effects
Studies have shown that Rasayana drugs and some of their constituent plants are potent inhibitors of inflammation as shown by reduction in paw edema induced by carrageenan and various experimentally induced inflammatory reactions.45,46 They are also shown to alleviate rheumatoid arthritis. 47 Triphala is also reported was effective in preventing the Freund’s adjuvant–induced arthritis and inflammation in mice. 48 The effect was observed to be better than that of indomethacin and the levels of lysosomal enzymes, tissue marker enzymes, glycoproteins, and paw thickness were significantly altered in the Triphala group to near normal conditions. 48
Hemopoietic Stimulation
Studies suggest that the Rasayana drugs possess hemopoietic stimulatory function against cytotoxic effects of anticancer agents. Triphala, Brahma Rasayana, Narasimha Rasayana, Ashwaganda Rasayana, Amritaprasham Chayavanprasha have been observed to attenuate the radiation-induced damage to the hemopoietic system.6,7,15 The plants Acanthopanax senticosus, Embelica officinalis, Withania somenifera, Tinospora cordifolia, and Boerhaavia diffusa provide total-body radiation protection by stimulating hematopoiesis.3,41
Immune Modulation
Rasayanas are observed to possess immunomodulating effects and unlike the conventional agents activate immune system without altering other basic parameters of the body.6,7,48 Administering Rasayana to animals improved the total number of leukocytes, absolute number of polymorphonuclear cells and lymphocytes in the peripheral blood of mice without altering liver or kidney function.5-7,49 Clinical studies have shown that administration of Brahma Rasayana did not alter the total leukocyte, the white blood cell counts, and the ratios. An increase in the activity of lymphocytes and increase in serum granulocyte macrophage colony-stimulating factor were also observed. 13
Triphala has been reported to possess immunomodulatory activities and to stimulate the neutrophil functions in immunized rats and stress-induced suppression in the neutrophil functions. 50 Additionally, some of the medicinal plants that are an integral part of the Rasayana, such as Picrorhiza kurroa, Tylophora indica, Aconitum heterophyllum, Holarrhena antidysenterica, Tinospora cordifolia, and Ocimum gratissimum, are reported to improve the phagocytic function without affecting the humoral or cell-mediated immune system. 51 Plants possessing immunomodulating and immunostimulatory activities, for example, Podophyllum hexandrum, Hippophae rhamnoides, Viscum album, Ocimum sanctum, and Tinospora cordifolia, have also been reported to provide protection by increasing spleen colony-forming units.
Several triterpenoids such as glycyrrhizic acids, ursolic acid, and oleanolic acid possess immunopotentiating activity. 3 Studies have also shown that the phytochemicals glycyrrhizin and glycyrrhizic acid, present in Glycyrrhiza glabra increased cellular immunocompetence. 51 Tinospora cordifolia is suggested to activate macrophages and release granulocyte macrophage colony-stimulating factor activity, 52 whereas its active constituents syringin and cordiol are reported to enhance the humoral and cell-mediated immunity. 53 Reports also indicate that the plants such as Allium sativum and Ocimum sanctum, which also possess radioprotective effects, augment NK cells, whereas Aloe vera is shown to stimulate synthesis of interleukin-1 and tumor necrosis factor-α3,54,55 (Table 2).
Adoptogenic and Antistress Properties
Oral administration of Triphala is reported to significantly prevent the noise-induced 56 and cold stress–induced 57 behavioral and biochemical abnormalities in albino rats. With regards to radiation-induced stress it is logical to expect that the adoptogenic properties of triphala may contribute, at least in part, to the observed radiation protection. Studies have shown that the Rasayana drugs such as Chyavanaprasha, Triphala, and Brahma Rasayana as well as the plants used in them such as Withania somnifera, Emblica officinalis, Asparagus racemosus, and Tinospora cordifolia also possess these effects (Table 2).3,30,33,34
Conclusions
Scientific studies carried in the recent past have shown that the Rasayana drugs Chyavanprasha, Triphala, Brahma Rasayana, Ashwagandha Rasayana, Narasimha Rasayana, and Amritaprasham are effective in preventing the toxic effects of ionizing radiation and physiologically attainable nontoxic doses. A combination of factors such as free radical scavenging, prevention of lipid peroxidation, inhibition of DNA damage, protection and rapid regeneration of bone marrow progenitors after cytotoxic therapy, and increase in or restoration of glutathione and antioxidant status of enzymes would have contributed to the radioprotective effects. With regard to radiation protection, all published studies with these Rasayana drugs have been carried out with animals and human studies are required.
With regard to the use of these individual rasayans in clinics as radioprotective agent, it is hypothesized that the organ-specific Brahma Rasayana and Triphala would be useful in brain and gastrointestinal cancers, whereas Amritaprasham, Ashwagandha Rasayana, Chyavanprasha, and Narasimha Rasayana would be useful in improving the overall health of the patient. However, for these to be of use in cancer treatment their selective radioprotective effects needs to be investigated. Suitable studies with tumor-bearing animals of different histological and metastatic potentiality are warranted as only then it will be of use in clinics. Studies are also required to understand the pharmacokinetic, pharmacodynamic, and safety issues of Rasayana at various doses and also the effects when administered for prolonged periods of time. Additionally, mechanistic studies with cultured mammalian cells (normal and neoplastic) are also required for understanding the effect of these drugs, the principal plants, and phytochemicals at molecular level. Furthermore, Rasayana formulations are polyherbal and their biological actions depend on the presence of bioactive compounds. It is a well known fact that the concentration of the bioactive compounds varies from place to place and the way in which the plants have been processed postharvesting in the preparation of Rasayana and that this affects the pharmacological action. In view of these observations, it is imperative to validate the uniformity of the herbal mixing and also the proportion by using standards and internationally accepted assays such as high-performance thin layer chromatography, ultra-high-performance liquid chromatography/ultraviolet spectroscopy/mass spectrometry, and reversed phase high-performance liquid chromatography.58,59
Rasayana drugs have been consumed by the habitants in the Indian subcontinent since time immemorial and this gives it an advantage over the synthetic drugs. The nontoxic nature of Rasayana drugs gives immense advantage as they can be easily recommended for human trials and at lesser costs when compared with their synthetic counterparts. Apart from applications in the clinics as an adjuvant in radiotherapy, Rasayana drugs can also be used as a radiation countermeasure agent in the management of nuclear incidents, for example, for the protection of defense personnel from nuclear weapon radiations, for protecting reactor workers and rescue crew, and protection of astronauts from cosmic rays against radiation-induced genomic instability and carcinogenesis. As there are no existing safe and effective synthetic radioprotectors, these studies are useful. Pilot studies should be initiated with personnel continuously exposed to low doses of radiation such as flight attendants and radiotherapy/nuclear medicine staff and technicians. Such study will give valuable information on the radioprotective effects of Rasayana drugs in humans and on the maximal permissible dose for optimal radioprotective effects.
These Rasayana drugs are of use in the treatment, prevention, and improvement of the quality of life of both healthy and diseased individuals, and their regular consumption may benefit humans against other age-related diseases and ailments. Most of these Rasayanas can be used regularly as a food for maintaining balanced mental and physical health. They may be used either alone or along with other modalities of treatment as an adjuvant. Their free radical scavenging, antioxidant, anti-inflammatory chemoprotective, chemopreventive, and immunomodulatory effects will also be of immense use in maintaining a healthy lifestyle and a disease-free life.
Footnotes
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.