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��ࡱ�>��	������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������	��e�bjbj�V�V	.��<�<�n����������������������\YD�I78�.������� 6"6"6"6"6"6"6$�8�#;�F6�������F6�����7&.&.&.������ 6&.� 6&.&.V�4@�5�����p�doM���&5670I7 5x�;�,�;�5�;��5t��&.�����F6F6�-j���I7�������������������������������������������������������������������������;����������	�:	Herbs Used Against Radition Induced Neurobehavioral Alterations
Rajesh Arora, Damodar Gupta, Jyoti Sharma*, Atlar Singh Dhakar, Manish Adhikari
Department of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences (INMAS), New Delhi, India
*Email for correspondence: Sharma_jy@yahoo.com


INTRODUCTION
 �A common way to study behavior is to simply observe it happening. We subconsciously learn how others behave in different situations by observing what they do. You can also purposely observe and study the behavior of people, animals and plants. From this observed behavior, you can try to make some generalizations to find out the exactly what happens and why.� The study of behavior is not only the study of effect of radiation on brain but it is the combined effect of various biochemical changes occur by the neurotoxic effect of ionizing radiation.
Ionizing radiation in today�s world is like a double edged sword. Humans are exposed to ionizing radiations during diagnostic, therapeutic and industrial purposes. Apart from these humans also get exposed to ionizing radiations during air and space travel, background radiation nuclear accidents, and use of electronic devices. Nuclear terror attacks are not distant possibility, therefore it is essential to protect humans from ionizing radiations by pharmacological intervention. Recently, focus of radiation protection has shifted to test the radioprotective potential of plants and herbs in the hope that one day it will be possible to find a suitable pharmacological agent/s that could protect humans against the deleterious effects of ionizing radiation in clinical and other conditions as well as during nuclear terror attack. Majority of plant and herbs described in this review have medicinal properties and are being used in traditional Ayurvedic or Chinese systems of medicine to treat various ailments in humans. Most of these plants and herbs certainly have potential as radioprotectors of future. They protect against the radiation-induced behavioral alteration. Fractionation guided evaluation may result in the development of ideal radioprotector/s in the near future


NEED OF BEHAVIORAL RADIOPROTECTOR
�A common way to study behavior is to simply observe it happening. We subconsciously learn how others behave in different situations by observing what they do. You can also purposely observe and study the behavior of people, animals and plants. From this observed behavior, you can try to make some generalizations to find out the exactly what happens and why.� At organisimic level Ionizing  Radiation effect behavior of an organism in various aspect like it cause taste avoidance, memory loss, anxiety, hypertension, performance decrement etc.
SOME OF CHEMICALS USED AS BEHAVIORAL RADIOPROTECTOR :
Dexamethazone
Odansteron


DISADVANTAGES

PLANTS USED AS RADIOPROTECTOR 

Gingko biloba
Gingko biloba leaves, was found to be effective in patients with vasogenic edema observed after irradiation of the brain [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B14" 14]. It has been reported to protect against the clastogenic factors from plasma of human subjects exposed to irradiation [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B15" 15]. Treatment of recovery workers from the Chernobyl accident site was found to be effective when an oral dose of 40 mg/day of G. biloba was given 3 times daily for 2 months [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B16" 16]. 

Centella asiatica
Aqueous extract of Centella asiatica reduced the adverse effect of low dose irradiation in Sprague Dawley rats by inhibiting radiation-induced body weight loss and conditioned taste aversion [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B17" 17]. Similarly, it has been found to protect against the radiation-induced weight loss in mice exposed to 8 Gy �-radiation [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B18" 18].

Hippophae rhamnoides 
Oral administration of a Hippophae rhamnoides fruit juice concentrate to rats before or after irradiation increased life span, restored the 11-oxycorticosteroid level in the blood and weight of isolated adrenals, and also normalized their basal activity and response to (ACTH) (corticotropin) under in vitro conditions [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B19" 19]. Hydroalcoholic extract of berries of H. rhamnoides also protected mice against �-radiation-induced mortality, decline in endogenous colony forming unit (CFU), micronuclei formation and various other hematological parameters [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B20" 20  HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B22" 22].
Osmium sanctum
The radioprotective property of Osimum sanctum was first reported by Jagetia et al. [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B23" 23] against the radiation-induced mortality, thereafter studies by Uma Devi and her coworkers established its radioprotective efficacy by evaluating mouse survival, spleen colony assay, and chromosome aberrations in mouse bone marrow cells. Apart from these osmium has been reported to protect against radiation-induced lipid peroxidation and reduction in glutathione concentration [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B24" 24,  HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B25" 25].
Panax ginseng
The radioprotective efficacy of ginseng (Panax ginseng) has been reported by several workers [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B26" 26� HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B30" 30]. Ginseng treatment caused recovery of thrombocyte and erythrocyte counts in blood after irradiation [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B31" 31]. The whole extract of ginseng and the relative protective effects of various fractions (carbohydrate, protein and saponins) have been evaluated. The results showed that the water-soluble whole extract of ginseng provided best protection against radiation induced damage in C3H mice, whereas isolated protein and carbohydrate fractions were less effective, the saponin fraction was ineffective [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B32" 32]. Similar results were obtained by Kim and coworkers, who found that whole ginseng extract and its fractions increased endogenous spleen colony formation in irradiated mice and also reduced apoptosis in jejunal crypt cells [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B27" 27]. The radioprotective effect of ginseng root extract on testicular enzymes (acid and alkaline phosphatases and lipid peroxidation) has also been reported [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B28" 28].
Podophyllum hexandrum
Podophyllum. hexandrum has been reported to protect against radiation-induced mortality, gastrointestinal damage and embryonic nervous system of developing mice [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B20" 20,  HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B33" 33� HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B35" 35]. It has also been reported to protect against radiation-induced decline in glutathione-S-transferase, superoxide dismutase in the liver and intestine of irradiated mice [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B36" 36]. Effect of 2.0 Gy gamma-dose delivered to rats in uterous 17th day of gestation was studied to monitor the radiation induced retardation of neurophysiological development in postnatal young ones. Rhizome of Podophyllum hexandrum which has been well documented for mitigating radiation injuries in adult mice was attempted for modifying radiation damage. Rats were observed from postnatal day 1 to 25 for the age of the appearance of physiological markers (pinna detachment, inscisor's eruption, eye opening) and acquisition of reflexes (surface righting, visual placing, reflex suspension, negative geotaxis). In irradiated groups there was a significant weight reduction in mother rats and offsprings throughout the experimental period. There was radiation-induced delay in the appearance of pinna detachment but not in eye opening and inscisor's eruption. Appearance of the reflexes were also delayed due to irradiation. Preirradiation administration of the extract of Podophyllum hexandrum (i.p., 200 mg/kg/b.w.) mitigated radiation induced postnatal physiological alterations. These studies have implications in protection against damage (in utero) due to planned radiation exposure.

Tinospora cardifolia
Oral administration of an aqueous extract of guduchi, Tinospora cordifolia has been reported to increase the survival of mice exposed to radiation [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B37" 37]. Treatment of mice with hydroalcoholic extract of Tinospora cordifolia has been found to protect against the radiation-induced micronuclei formation and oxidative stress and decline in the mouse survival, spleen CFU and hematological parameters [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B38" 38].
Emblica officinalis
The fruit pulp of Amala, Emblica officinalis (EO) has been reported to increase the survival and inhibit radiation-induced weight loss in mice [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B39" 39]. Phyllanthus amarus has been reported to protect against the radiation-induced decline in white blood cells (WBC), superoxide dismutase, catalase, glutathione-S-transferase, glutathione peroxidase, and glutathione reductase [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B40" 40].
Amaranthus paniculata
Daily oral administration of 800 mg/kg body weight (b. wt.) of Rajgira (Amaranthus paniculatus) leaf extract for 15 consecutive days before whole body exposure to �-radiation protected mice against the radiation-induced lethality with a dose reduction factor of 1.36. It increased endogenous spleen colony forming units and spleen weight without any side effects or toxicity. Rajgara extract also arrested radiation-induced lipid peroxidation and the decline in reduced glutathione in the liver and blood of mice [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B41" 41].
Piper longum
The ethanolic extract of Piper longum (pippali) fruits was found to protect mice against the radiation-induced decline in WBC, bone marrow cells �-esterase positive cells and GSH. Pippali extract also reduced the elevated levels of glutathione pyruvate transaminase (GPT), alkaline phosphatase (ALP), lipid peroxidation (LPO) in liver and serum of irradiated animals [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B42" 42].
Syzigium cumini
 Syzigium cumini Linn. Skeels also known as Eugenia cumini (family Myrtaceae), and has been reported to posses several medicinal properties in the folklore system of medicine [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B43" 43]. The micronucleus study of radioprotective effect of dichloromethane and methanol (1:1) extract of jamun (SCE) in human peripheral blood lymphocytes (HPBLs) ascertained its radioprotective potential, where 12.5 �g/ml SCE was found to reduce the micronuclei up to a maximum extent. In vivo evaluation further established its radioprotective activity where it was found to reduce radiation-induced sickness, gastrointestinal and bone marrow deaths [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B7" 7,  HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B44" 44]. Not only leaf but the hydroalcoholic extract of jamun seeds (JSE) also exhibited a greatest protective effect at 80 mg/kg JSE. The JSE was more effective when administered through the intraperitoneal route at equimolar doses than the oral. The JSE treatment protected mice against the gastrointestinal as well as bone marrow deaths with a DRF of 1.24 [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B45" 45].
Mentha arvensis
Pudina or Mint (Mentha arvensis Linn., Family Lamiaceae), a plant, native of Japan, is used as a food seasoner, household remedy, and for industrial purposes [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B46" 46]. Treatment of mice with 10 mg/kg b. wt. of chloroform extract of mint (Mentha arvensis Linn) protected against the radiation-induced sickness, gastrointestinal and bone marrow deaths with a DRF of 1.2. Further it was non-toxic up to a dose of 1000 mg/kg b. wt., the highest drug dose that could be tested for acute toxicity [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B47" 47]. Pre-treatment of mice with leaf extract of another species of pudina, i.e. Mentha piperita has been reported to protect mice against the radiation-induced decline in hematological constituents, serum phosphatase, endogenous spleen colonies formation, spleen weight, goblet cells/villus section and chromosomal damage [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B48" 48� HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B50" 50].
Menthe spicata
Mentha spicata a well known herb for gastro protective properties in traditional system of medicine has ben shown to protect against radiation induced lethality, and recently its constituents have been found to possess calcium channel antagonizing properties. It is also used to examined the radioprotective e-fficacy, particularly in mitigating radiation induced conditioned taste aversion(CTA), which has been proposed as a behavioral endpoint that is mediated by the toxic effect of gamma radiation on peripheral systems, primarily the gastrointestinal system. Intraperitoneal administration of mentha spicata            -1hour  2 Gy of gamma radiation was found to render significant radioprotection against CTA (p<0.05) by blocking the saccharin avoidance  response within 5 post-treatment observational days, with the highest saccharin intake being observed on day 5.
Zingiber officinalis
The rhizome of Zingiber officinale, commonly known as ginger, is consumed daily worldwide as a spice and flavoring agent. The rhizome of ginger has been reported to possess diverse medicinal properties in the traditional Indian system of medicine, the Ayurveda, and it is widely used in several medicinal preparations [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B51" 51]. Administration of 10 mg/kg (i.p) or 250 mg/kg (orally) hydroalcoholic extract once daily, consecutively for 5 days was found to protect mice against the radiation-sickness, gastrointestinal as well as bone marrow deaths with a DRF of 1.15. Ginger has been reported to increase glutathione, reduce lipid peroxidation in vivo and scavenging of various free radicals in vitro [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B52" 52,  HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B53" 53].
Ageratum conzyoides
Ageratum conyzoides, (family: Asteraceae) is commonly known as Billy Goat Weed. It has been used in various parts of Africa, Asia and South America for curing various diseases. The study of various doses of alcoholic extract of Ageratum conyzoides, Linn. revealed that the best protective dose was 75 mg/kg and it reduced radiation-induced, sickness gastrointestinal as well as bone marrow deaths. A DRF was found to be 1.3. The radioprotective effect was due to scavenging of DPPH (1,1-diphenyl-2-picrylhydrazyl), free radical [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B54" 54].
Aegle marmelos
Aegle marmelos Correa, commonly known as bael, is a spinous tree belonging to family Rutaceae. It is grown throughout the sub-continents as well as Bangladesh, Burma and Srilanka [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B55" 55]. The hydroalcoholic extract of Aegle marmelos (AME) protected cultured HPBLs against the radiation-induced micronuclei at a concentration of 5 �g/ml. It was also reported to scavenge �OH, O2��, DPPH, ABTS�+ and NO (nitric oxide) radicals in vitro in a concentration dependent manner [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B56" 56]. The radioprotective efficacy of 15 or 250 mg/kg AME was further confirmed in animal studies where its intraperitoneal as well as oral administration has been found to protect mice against the radiation-induced sickness, gastrointestinal and bone marrow deaths and mortality giving a DRF of 1.2. It also protected mice against the radiation-induced lipid peroxidation and elevated GSH concentration in the liver, kidney, stomach and intestine at 31 days post-irradiation. Oral administration also protected mice against the gamma radiation-induced decline in erythrocytes, leukocytes, lymphocytes and clonogenicity of hemopoietic progenitor cells assessed by exogenous spleen colony forming assay. Pretreatment of mice with AME elevated the villus height and the crypt number accompanied by a decline in goblet and dead cell number [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B57" 57,  HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B58" 58]. Not only leaf but also the hydroalcoholic extract of Aegle marmelos fruit administered intraperitoneally at a dose of 20 mg/kg once daily, consecutively for five days found to protect mice against the radiation-induced sickness, gastrointestinal as well as bone marrow deaths with a DRF of 1.1 [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B59" 59].
Aphanamixis polystachya
Rohituka, Aphanamixis polystachya Wall. Parker [Amoora rohituka, Amoora aphanamixis (Roxb.) Wight & Arn.] is a member of the family Meliaceae. The ethyl acetate fraction of Aphanamixis polystachya at a dose of 7.5 mg/kg b. wt. before exposure to 1�5 Gy of whole body gamma-radiation significantly reduced the frequencies of aberrant cells and chromosomal aberrations like acentric fragments, chromatid and chromosome breaks, centric rings, dicentrics, exchanges and total aberrations at all post-irradiation scoring times. It also showed a concentration dependent scavenging of hydroxyl, superoxide, 2,2'-diphenyl-1-picryl hydrazyl (DPPH) radicals and the 2,2-azino-bis-3-ethyl benzothiazoline-6-sulphonic acid (ABTS) cation radicals in vitro. EAP treatment also reduced lipid peroxidation in bone marrow cells in a concentration dependent manner [ HYPERLINK "http://www.pubmedcentral.nih.gov/" \l "B60" 60].
Spinacia oleracea
the radioprotective efficacy of spinach
against radiation induced oxidative stress, since its leaves are rich in antioxidants
like carotenoids (lutein, �-carotene, zeaxanthin), p-Coumaric acid, ascorbic acid,
proteins, vitamins etc.

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