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Natural Toxins and Their Therapeutic Potential

Natural Toxins and Their Therapeutic Potential

Indian Journal of Experimental Biology Vol. 48, March 2010, pp. 228-237

Review Article

Natural and their therapeutic potential

V K Kapoor G H G Khalsa College of Pharmacy, Gurusar Sadhar, Ludhiana 141 104, India

Plants have been extensively investigated for exploring their therapeutic potentials, but there are comparatively scanty reports on drugs derived from animal kingdom, except for hormones. During last decade, the toxins that are used for defense by the animals, have been isolated and found useful tools for physiological and pharmacological studies, besides giving valuable leads to drug development. Toxins with interesting results have been isolated from the of snakes, , , snails, lizards, frogs and . The present review describe about some toxins as drugs and their biological activities. Some fungal, bacterial and marine toxins have also been covered in this article.

Keywords: Animal , Fungal toxin, Natural toxin, Therapeutic use,

Natural toxins, whether derived from , fungi, stereoisomers, is the most active coronary marine organism, snails or animals have played a vasoconstrictor acting through interaction with calcium significant role directly or indirectly in drug channels. Palytoxin is the most poisonous non- development. The first of the angiotensin converting proteinaceous substance has been isolated from enzyme (ACE) inhibitor captopril owes its discovery zoanthid coral Palythoa toxica . It is used as a to venom of the poisonous Brazilian viper, Bothrops physiological tool to evaluate anti-anginal juraraca. Bakhle 1 has reported that peptides from the chemotherapeutic agent. Toxins like betrachotoxins , Brazilian viper venom inhibit the activity of ACE , , have not only given new leads, present in cell-free extracts of dog lung. Captopril but have given impetus to neurophysiology and emerges 2,3 as a drug used in the management of pharmacology by acting as pharmacological tools. hypertension, and in heart failure after myocardial Molecular aspects of electrical excitability in nerve, infarction. Exendin-4, a peptide isolated from the skeletal muscle and cardiac cell can be elucidated with venom of gila monster, Heloderma suspectum , a the help of natural toxins. The present communication species of poisonous lizard from North America presents an account of recent advances made in natural exhibits a significant amino acid homology with toxins and their role in drug development. glucagon-like peptide 1 (GLP-1) secreted from intestinal L-cells. Extendins are carboxy-amidated toxins peptides containing 39 amino acid residues. Extendin- Fungal toxins Among the toxins obtained from 4 stimulated insulin secretion in vitro and is a potent different fungi are the most documented of 4 agonist of the GLP receptor . Studies in diabetic mice all . Aflatoxins are closely related group of have shown long-lasting reduction of blood glucose secondary metabolites produced by flavas concentration following once daily injection. and A. parasiticus . Improper storage of crop products Synthetic extendin-4 (exenatide) was licensed in 2005 often results in their by these for the treatment of type-2 diabetes in combination toxicogenic moulds. Thus, aflotoxins have been with metformin and/or sulphonylureas when either reported to naturally occur in plants, corns, seed, 5 drug, alone or in combination, is inadequate . groundnuts and peppers, etc. There are four naturally Palytoxin 6,7 , one of the most complicated natural occurring aflotoxins (B 1, B 2, G 1 and G 2). Chemically, product with sixty four chiral centres and seven aflotoxins are fluorescent compounds characterized by double bonds allowing a large number of a dihydrofuran or tetrahydrofuran moieties fused to a substituted heterocycle. The aflotoxins are ______listed as known human 8, B (1) Telephone: 0172-2632496; 1 Fax: 01624-275469 being one of the most potent environmental Email: vikkuips @yahoo.com and carcinogens known. KAPOOR: NATURAL TOXINS & THEIR THERAPEUTIC POTENTIAL 229

H C CH3 O 3 O O O O O

O H3C O O O CH3 O O Cl H3C

(2) (1) Fig. 1 Structure formulae of compounds ( 1) and ( 2)

Mycotoxins 9 produced by species, deadliest nerve known throughout history. It represented by , zearalenones and is estimated that an oral dose of 70 µg or inhalation of also affect animal and human health and a hundredth of that amount is enough to lethally possess divergent biological activities. a an average adult and most dreaded as β-resorcylic acid lactone, is reported to have biological weapon 14 . The toxin blocks the release of hyperestrogenic activity in mice 10 . A, from presynaptic nerve terminals roquefortine and are some of the toxicants of causing a generalized paralysis of the muscle resulting genus associated with human and animal in death. Its name is derived from “botulus”, Greek disease 11 . Griseofulvin (2) a toxicant from P. for sausage, the linked to many outbreaks of griseofulvum is used as antifungal drug. Panigrahi 12 15 . Botulin toxin has been used as an has reviewed the mycotoxins of the genus Alternana investigational agent for the study of synaptic and discussed their toxic activities. neurotransmission. Besides, it has proven to be an A mention may be made of amanitin and extremely useful therapeutic agent for clinicians to , the cyclopeptide toxins from the poisonous treat various gastrointestinal smooth muscle disorders. . Amanitin is mixture Its use in the treatment of achalasia is well of α-, β-, γ-amanitin and . α-Amanitin, which documented 15 . Botulin A and B have been approved is the major constituent, is 10-20 times more toxic for clinical use. Recently, use of in than phalloidin. Development of cyclosporin A the treatment of chronic anal fissures has been (ciclosporin A) as an immunosuppressive drug has reviewed 16 . Relief of post-radiotherapy masticatory been traced back to the stimulus derived from the first spasms 17 , and inducement of certicospinal excitability highly-active cyclopeptides from Amantia changes in a population of patients with limb . spasticity 18. Algal toxins Anatoxins represent first Marine toxins A mention has already been made present in fresh-water blue-green alga Anabaena flos- of palytoxin, a highly poisonous toxin from zoanthid aquae . Anatoxin-a is the strongest agonist known for coral Palythoa toxica used as a physiological tool. the nicotinic 13 . Despite its Other marine toxins of medicinal interest are apparent structural dissimilarity to the natural didemnins which are depsipeptides extracted in 1978 transmitter acetylcholine, the physiological effects of from a Caribbean tunicate (sea squirt) of the genus the toxin are identical with those of acetylcholine. Trididemnum 19 . Although more than nine didemnins Anatoxin-a is about 30 times more potent than (A-E, G, X and Y) have been isolated from the extract (carbamylcholine). of Trididemnum solidum , it is didemnin B (3) that Bacterial toxins The anaerobic bacterium possesses the most important biological activities 20 . botulinum produces a family of potent- Didemnin B is a strong antiviral agent active against neurotoxins collectively called as botulin toxins. both DNA and RNA viruses like Herpes simplex virus Seven serologically distinct types are known type 1, and a strong immunosuppressant that shows designated as botulin A, B, C, D, E, F and G. some potential in skin graft 21 . It shows strong activity Botulinum toxin has long been known as one of the against murine leukemia cells. It has undergone phase 230 INDIAN J EXP BIOL, MARCH 2010

II human clinical trials against adrenocarcinoma of presynaptic phospholipase A 2 , consists of kidney 22 , advanced epithelial ovarian cancer 22 and two dissimilar polypeptide chains (chains A and B) metastatic breast cancer 21 . Unfortunately, it has shown cross-linked by an interchain disulphide bond. The high and anaphylactic reactions in patients larger chain contains 120 amino acid residues, the resulting in terminating the trials 24 . smaller chain contains 60 residues. It has been suggested that both A and B chains are indispensable Animal toxins parts of β- for inducing the facilitation of spontaneous synaptic currents frequency with Venomous animals possess a wide range of toxins 27 for predation and defense. It is difficult to Xenopus nerve-muscle cultures . Recently, it has comprehend the exact number of venomous species or been indicated that both A and B chains possess the the number of toxins they produce. A number of capability to induce vesicle leakage, and reduction of interchain disulphide bond markedly releases this venomous animals and their toxins have been 28 investigated to explore their biological activities and ability from intact β-bungarotoxin molecule . therapeutic potential. Among the animal, toxins of The venom of Vipera russelli produces alterations snake, , , snail, lizard, frog, fish and in general behavioral pattern, reduction in insect have been described as follows. spontaneous motility, hypothermia, potentiation of 29 Snake toxins  is a mixture of both hypnosis, analgesia, and muscle relaxation . proteinaceous and non-proteinaceous components. Cobrotoxin isolated from the venom of Taiwan Protein components comprise enzymes, polypeptides cobra, naja atra , has been first reported 30, 31 to and proteins. These toxins are reported to exhibit a have anti-nociceptive effect which has been, in a later variety of pharmacological activities such as study, attributed to one of the six neurotoxins. Four myotoxic, neurotoxic, hypotensine, haemolytic, cardiotoxins have been isolated from Naja naja atra platelet-aggregation inhibition, anticoagulant, venom and their amino acid sequences have been inflammatory, and bactericidal. Use of determined 32-34 . The cardiotoxins have been found to snake venom in different pathophysiological be comprise 60 amino acid residues. King cobra, conditions has been mentioned in Ayurveda, Ophiophagus hannah , found in India, Mayanmar, homoeopathy and folk medicine. Snake venom Thailand, Malaysia, China, Japan and the contains several neurotoxic, cardiotoxic, cytotoxic, Philippines 35 is the largest venomous snake in the nerve growth factor, lectins, disintegrins, world. At least six α-neurotoxins have been isolated haemorrhagins and many enzymes 25 . from king cobra venom, of which four have been Venom of Southeast Asian banded snake, sequenced. They have been reported to act post- Bungarus multicinctus yields several proteinaceous synaptically with similar biological properties to factions of which α-bungarotoxin and β-bungarotoxin H C 3 O are the important ones. α-Bungarotoxin is a single HO H3C polypeptide chain of molecular weight of about 8,000 kDa containing 74 amino acid residues with 5 O H3C CH disulphide bridges. It is a post-synaptic neuron toxin 3 with -like action that binds selectively and O NH CH3 irreversibly to acetylcholine receptor sites, producing O neuromuscular blockade resulting in skeletal muscle R N O NH H3C paralysis. α-Bungarotoxin is used as a most reliable H pharmacological tool to study neuromuscular CH3O O O O O blockage. Its slow rate of dissociation makes it an CH3 excellent ligand for labeling, for affinity purification, N and for pharamacological analysis of acetylcholine N receptor. It is also a selective antagonist of the α-7 nicotinic acetylcholine receptor in the brain, and as CH3 such has applications in neuroscience research. A R= Lac-Pro-N-Me-L-Leu monoclonal antibody specific for α-bungarotoxin has (3) 26 been prepared . β-Bungarotoxin, the main Fig. 2Structure formula of compound ( 3) KAPOOR: NATURAL TOXINS & THEIR THERAPEUTIC POTENTIAL 231

cabrotoxin. Hannalgesin, a long-chain α-neurotoxin isolated perfused rat kidney method has been described from the venom of king cobra, exhibits analgesic to evaluate the renal effects of B. jararacussu myotoxin activity in mice 36 . It produces analgesia at a dose of I and II 45 . Myotoxins I and II have antibacterial effect 16-32 ng/g (ip) without causing any neurological or against Xanthomonas axonopodis.pv.passiflorae , a muscular deficits. The analgesic effect was blocked gram negative bacteria. The venom of Chinese pit by both naloxone and L-NG-nitroarginine methyl viper, Zhaoermia mangshanensis, exhibits coagulant ester (inhibitor of NO synthase) suggesting the activity on bovine and human fibrinogen and human possible involvement of opioid and plasma, high phosphodiesterase and arginine ester systems, respectively, in anti-nociceptive pathway. hydrolytic activity, and moderate to low L-amino acid From Indian king cobra venom a lethal neurotoxin oxidase, kallikrein, caseinolytic, phospholipese A 2, protein (Toxin CM36) has been isolated. It exhibits haemorrhagic acid myotoxic activities. The major toxin Ca 2+ dependent and produced from the venom named zhasermiatoxin has been irreversible blockade of isolated chick biventer isolated and found to be a homodenia with momomeric cervicis and nerve phrenic nerve diaphragm 37 . mass of 13,972 kDa, and consists of 121 amino acids 46 A novel short toxin (composed of 60-62 amino acid residues cross-linked by seven disulphide bridges . residue) has been isolated from the venom of Envenomation by snake poisonous snake bite monocellate cobra Naja kaouthia found in Yunnan causes a variety of symptoms which depend on the province of South-West China 38 . family to which the snake belongs. For example, The venom of South American rattle snake, snakes of viperidae family usually cause oedema, Crotalus durissus terrificus , has been investigated. A haemorrhage and myonecrosis; in severe cases neurotoxin crotamine which a single polypeptide permanent tissue loss, disability or amputation may chain of 42 amino acids with three disulphide bridges result. Natural resistance (immunity) against snake venom has been reported in hedgehog 47 , mongoose 48 has been shown to induce myonecrosis, and has been 49 used as a tool to study distribution in and opossum . In most cases, the resistance of the muscle fiber membrane 39 . Crotamine is also several animals to snake venom can be explained by the presence of protein factors in the blood which reported to produce analgesic effect at lower doses 50 without any apparent in vivo toxicity. The anti- inhibit the activity of important toxic compounds . nociceptive effect of crotamine is about 30-fold These proteins are either metalloproteinase inhibitors higher than that of morphine and has been (antihaemorrhagic factors) or PLA 2 inhibitors demonstrated to involve both central and peripheral (antineurotoxic and/or antimyotoxic factors). A mechanisms 40 . A review on crotamine giving current state of art of protein inhibitors of toxic PLA 2s derived from snake and mammalian blood and plants additional information on the biological activity of 51 crotamine has appeared 41 . Another study reveals that has been discussed . A special mention is made on a the factors with an apparent molecular weight less newly described glycoprotein PLA 2 inhibitor from than 3000 daltons from the venom of Crotalus Withania somnifera , which exhibits anti-myotoxic durissus terrificus causes an anti-nociceptive effect in and anti-oedema properties against a multi-toxic PLA 2 mice which is possibly mediated by opioid from Indian cobra. These proteins have therapeutic 42 potential in the snake envenomations. Recently, receptors . Subsequently, it has been shown that the 52 anti-nociceptive effect of venom involves, atleast Chatterjee and co-workers have reported that whole partially, a cascade of molecular events involving δ- seed extract of Strychnos nux vomica effectively and κ-opioid receptors 43 . neutralizes Daboia russelli venom induced lethal, Batroxobin, an enzyme derived from the venom of haemorrhage, defibrinogenating, PLA 2 enzyme Naja kaouthia Bothrops atrox (a pit viper found in Southern and activity and venom induced lethal, Central America), has thrombin-like properties 44 . It is cardiotoxic, neurotoxic, PLA 2 enzyme activity. The haemostatic in low doses and acts as a blood seed extract also potentiated polyvalent snake venom anticoagulant at higher does. Bite of Bothrops antiserum action in experimental animals. An active jararacussu , a snake found in Southeast-Brazil, compound (SNVNF) has been isolated. causes increase in myoglobin urea and acute renal Scorpion toxins Scorpions have been used in failure. Many mechanisms have been suggested to Chinese system of medicine for amelioration of a explain the mechanism of anal failure. Recently, number of diseases. Whole scorpions, scorpion sting 232 INDIAN J EXP BIOL, MARCH 2010

or their extracts have been found to be effective in that co-agatoxin IVA from the venom of funnel web treating some neural diseases such as apoplexy, spider, Agelenopsis asperta , enhances the agonist- epilepsy, facial paralysis, hemiplegia besides being induced tail flick anti-nociception when co- used to soothe the nerves and relieve pains caused by administered spinally with both morphine and meningitis, cerebral palsy and rheumatism 53,54 . clonidine suggesting use of the toxin in opioid

Scorpion venom contains a large number of dependent/tolerant patients 65 . isolated biologically active substances such as peptide toxins from South American tarantula Psalmopoeus with different in-channel specificities, enzymes, cambridgei selectively blocks acid-sensitive ion nucleotides, lipids, mucoproteins, biogenic , channels or H +-gated cationic channels 66 . The glycosaminoglycans and histamine 55 . Injection of channels have been reported to play an important role scorpion venom can induce the secretion of in pathological conditions such as brain ischemia or inflammatory mediators such as bradykinin, platelet epilepsy. activating factor, prostaglandins, leucotriens, Snail toxins Among the numerous marine cytokines and 5-hydroxytryptamine that contribute to animals cone snails (Family Cnidae; genus Conus ) pain response 56 . have been investigated extensively to explore their Anti-nociceptive activity has been demonstrated by therapeutic potential. Cone snails are predators that scorpion venoms and their peptide toxins 53,57-59 . An live in tropical and sub-tropical waters. Cone snail antitumour-analgesic peptide from Bothus martense toxins named are primarily used to stun, venom shows strong inhibitory effect on both visceral immobilize and kill prey, although they could be used and somatic pain and also antitumour activity on for defensive purposes also. The toxins derived from E. ascites tumour and S-180 fibrosarcoma cells 54 . cone snails are currently being investigated for the Scorpion β-toxins have also been used as treatment of chronic pain, epilepsy, cardiovascular pharmacological tools in the study of voltage- diseases, psychiatric and movement disorders 67 . activated Na + channels 60,61 . A 25 amino acid peptide co- MVIIA Indian red scorpion, Mesobuthus tamulus , venom isolated from venom of Conus magus has been shown causes cardiac abnormalities like acute myocarditis, to inhibit neuropathic pain responses and induces less cardiac dysrhythmia (achy arrhythmias, tolerance than morphine 68 . A synthetic co-conotoxin bradyarrythmias) and various degrees of heart block. MVII, ziconotide (PRIAL), has been approved by Recently, it has been shown that the venom induces FDA of US for the treatment of severe pain 69 . activation of muscarinic receptors by enhanced Conantokintokin G, a 17 amino acid peptide from C. activity via Gi-guanylyl cyclase mediated geographus , has been reported to be a novel cell-signaling pathways in producing atrial rate therapeutic agent for the treatment of pain 70 . Co- changes 62 . Vasosensory responses elicited by Indian conotoxin GVIA 71 , Contulakin-G72 from C. red scorpion venom have been compared with geographus ; and co-conotoxin from C. catus 73 have capsaicin (which also evokes vasosensory refluxes)- also been reported to have promising anti-nociceptive induced responses. It has been shown that intraarterial activity. Biologically active T-1-conotoxin 74 , and a V- injection of scorpion venom produces prolonged conotoxin-like peptide 75 from venoms of C. spurious cardiorespiratory alterations as compared to and C. austini , respectively, have also been reported. capsaicin-induced responses 63 . Sodium channel modulating activity in S-conotoxin

Spider toxins Spider toxins comprise isolated from C. amadis , an Indian marine snail, has been reported 76 . polypeptides with molecular weights ranging from 4 to 10 kDa, which function as neurotoxins. The Lizard toxins Mention has already been made of pharmacology and biochemistry have been reviewed the gila monster, Heloderma suspectum , native to the by Rash and Hodgson 64 , who have classified toxins South-Western United States and North-Western from spider venom affecting; glutamatergic Mexico. From the venom of the lizard Goke et al. 4 neurotranmission; voltage-sensitive calcium channel; have reported exendin-4, a glucagons-like peptide. voltage dependent Na + channel; K + channel; and The lizard hormone is almost half identical to a chloride channel. Also classified are toxins which similar hormone in the human digestive tract, called stimulate transmitter release and toxins blocking post- glucagon-like peptide-1 (GLP-1), that increases the synaptic cholinergic receptors. It has been reported production of insulin when blood levels are KAPOOR: NATURAL TOXINS & THEIR THERAPEUTIC POTENTIAL 233

high. Insulin helps to move sugar from the blood into frog skin of Phyllomedusa species. Dermorphine (5) other body tissues where it is used for energy. which is a heptapeptide chain shows high affinity for Exendin-4 remains effective much longer than human re-opioid receptors 78 . Several peptides related to hormone. A synthetic exendin-4 named exenatide has dermorphin have also been reported 79 . Like µ-opiates been prepared and marketed as Byetta which has been agonists, dermorphins produce anti-nociception, approved by the Food and Drug Administration of US catalepsy, rigidity and sedation. Intrathecal in April 2005 to treat type-2 diabetes in patients who administration of dermorphins in humans has shown are not able to control their high blood sugar with 100 times greater potency than morphine 80 . three other medications, metformin, sulphonylurea or Deltorphins and related peptides isolated from the thiazolidenedione. Another long-acting GLP-1 mimic frog skin have also been found to exhibit high braglutide is in advanced clinical development 5. selectively for δ-opiate receptors 81 and produce analgesia in laboratory and humans. From Heloderma horridum , a Mexican headed lizard, exendin-3 has been isolated with interesting A comprehensive review on the bioactive biological activity 77 . Structurally related peptides molecules such as peptides, proteins, steroids, known as helospectin and helodermin have also been alkaloids and opioids isolated from various isolated from venom of these species. skins has appeared. Potent therapeutic activities like Frog toxins Number of potent bioactive antibacterial, antifungal, antiprotozoal, antidiabetic, compounds of interesting structures have been isolated antineoplastic, analgesic and sleep inducing properties from frog skin. More than hundred toxins have been have been discussed which provide potential clue towards new drug development 82 . identified from the skin secretions of frogs of genus Dendrobates and Phyllobates . From the latter genus, Fish and mollusc toxins The two toxins which are toxins like and with probably the most widely used tools both by + novel structure have been isolated which have given electrophysiologists and by biochemists to study Na impetus to neurophysiology and pharmacology besides channel are tetrodotoxin (6) and saxitoxin. giving new leads in synthetic organic chemistry. Tetrodotoxin is obtained from ovary and liver of Batrachotoxins (4) are potent cardiotoxic and many species of fish of family Tetradoxtidae, neurotoxic steroidal alkaloids found in certain species specially the globe fish, Spheroides rubripes . of South American poison-dart frogs of genus According to Ishikawa Health Service Association, Phyllobates . The name has been derived from the Japan, tetrodotoxin is nearly 100 times more Greek word “betrachas” meaning frog.

Bactrachotoxin, generally classified as a neurotoxin, O CH3 has marked effects on cardiac muscles which are H3C similar to cardiotoxic effects of digitalis. Acting on O peripheral nervous system, it causes activation of Na + HO CH3 channels. Batrochotoxin kills by permanently N N H H3C blocking nerve signal transmission. It is used as a H3C biochemical tool for the study of Na + channel.

Batrachotoxin R, bathachotoxinin A and O O homobatrachotoxinin are the other members of the family. Histrionicotoxin is a piperidine alkaloid isolated from the skin of poisonous arrow frog HO Dentrobates histrionicus . It causes non-competitive H inhibition of receptors. It is used as (4) biochemical probe for neuromuscular transmission. Fig. 3Structure formula of compound ( 4) Another neurotoxin isolated from the skin secretions of the Columbian poison-dart frogs D. histrionicus and D. occulater is gephyrotoxin. Like the previous H-Ty 2-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH 2 toxins, it also effects neuromuscular transmission.

A special mention is made of dermorphine and (5) related peptides isolated from the South American Fig. 4Structure formula of compound ( 5) 234 INDIAN J EXP BIOL, MARCH 2010

Acknowledgement O The author is thankful to Ms Rajandeep Kaur Billing for help. OH O HO References NH2 O 1 Bakhle Y S, Conversion of angiotensin I to angeotensin II by N cell-free extracts of dog lung, Nature , 220 (1968) 919. H 2 Cushman D W & Ondetti M A, History of the design of N HO H captopril and related inhibitors of angiotensin converting HO enzyme, Hypertension , 17 (1991) 589. 3 Smith C G & Vane J R, The discovery of captopril, FASB , 17 OH (6) (2003) 788. 4 Goke R, Fehmann H C, Linn T, Schmidt H, Krause M, Eng J & Goke B, Extendin-4 is a high potency agonist and Fig. 5Structure formula of compound ( 6) truncated extendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin- secreting β-cells, J Biol Chem , 268 (1993) 19650. poisonous than . Saxitoxin is a neurotoxin 5 Furman, B L, Current and future incretin-based therapies for produced by certain species of marine dinoflagellates the treatment of diabetes, Pharmaceut J , 282 (2009) 521. Gonyaulax catenella or G. tamarensis . The toxins are 6 Moore R E & Bartolini G, Structure of palytoxin, J Amer used in biochemical research. Chem Soc , 103 (1981) 2491.

A mention may be made of urotensin I, a straight- 7 Shimizu Y, Structural chemistry: complete structure of palytoxin elucidated, Nature , 302 (1983) 212. chain peptide of 38 amino acids isolated from many 8 IARC, some naturally occurring substances: Food items and fish. It is reported to produce a sustained hypotension constituents, heterocyclic aromatic amines and mycotoxins, in most mammalian species. A myotoxin (TmC4- in IARC Monographs on the evaluation of carcinogenic risks 47.2) from the toadfish Thalassophzyne maculosa has to humans , vol. 56, (Lyon, France) 1993. 83 9 Szathmary C I, Mirocha, C J, Palyusik M & Pathre S V, been reported to depolarize skeletal muscle fibres . Identification of mycotoxins produced by species of A sting of the fish, Scatophagus argus , an Indian Fusarium and obtained from Eastern Europe, venomous edible spotted butterfish produces Appl Environ Microb , 32 (1976) 579. tremendous local pain, severe swelling, rise of body 10 D’Mello J P F, Macdonald A M C & Placinta C M, Fusarium temperature, throbbing sensation, etc. From the spine mycotoxins, in A handbook of plant and fungal toxicants , edited by JPFD’Mello (CRC Press, Boca Raton) 1997, 287. extract of the fish a haemorrhagic protein toxin (SA- 11 Pitt J I & Leistner L, Toxigenic Penicillium species, in HT) has been isolated with molecular weight of 18.1 Mycotoxins and animal , edited by J E Smith and R S kDa 84 . The toxin produces severe haemorrhage on Henderson (CRC Press, Boca Raton) 1991, 81. stomach wall, but is devoid of cutaneous 12 Panigrahi S, toxins, in A handbook of plant and haemorrhage. SA-HT significantly increases plasma fungal toxicants , edited by JPFD’Mello (CRC Press, Boca Raton) 1997, 319. plasmin, serum MDA level and decreases SOD level 13 Spivak C E, Witkop B & Albuquerque E X, Anatoxin-a: A indicating the possible involvement of novel, potent agonist at the nicotine receptor, Mol cyclooxygenase and lipooxygenase pathway. Detailed Pharmacol, 18 (1980) 384. pharmacological studies on the sting extract of the 14 Arnon S S, Schechter R, Inglesby T V, Henderson D A, butterfish have also been carried out 85 . Barlett J G, Ascher M S, Eitzen E, Fine A D, Hauer J, Layton M, Lillibridge S, Osterhalom M T, O’ Tool T, Parker G, Perl Honey bee toxins From the venom (opitoxin) of T M, Russel P K, Swerdlow D L & Tonal-K, Botulinum honey bee Apis mellifera , a 18 amino acid polypeptide toxin as a biological weapon: medical and public health neurotoxin apamin has been isolated. It is used management, J Am Med Assc , 285 (2001) 1059. primarily in biomedical research to study the 15 Zhao X & Pasricha P R, Botulinium toxin for spastic GI disorders: A systematic review, Gastrointest Endoscop, 57 electrical properties of small conductance Ca 2+ + (2003) 219. activated K channels (SK channels). Apamin binds to 16 Medhi B, Rao R S, Prakash A, Prakash O, Kaman L & these channels in the brain and spinal cord and Pandhi M, Recent advances in the pharmacotherapy of inhibits them 86 . Apamin as a SK channel blocker has chronic anal fissures: An update, Asian J Surg , 31 (2008) therapeutic applications on the peripheral cells (e.g. 15A. 17 Alepuz J E, Sandoval G B, Blanco S A, Costa J & Valls- the insulin releasing cells of the pancreas) and on the Sole, J, Relief of post-radiotherapy masticatory spasms with where there is evidence for a botulinum toxin, Abstracts of the 13 th European Congress of role of SK channels in memory processes 87 . Clinical Neurophysiology, (TUO22) 119 (2008) S18. KAPOOR: NATURAL TOXINS & THEIR THERAPEUTIC POTENTIAL 235

18 Cicinelli P, Cosentino E, Pace L, Formisano R & Marciani M treatment of severe neurotoxic envenoming, Q J Med , 80 G, Botulin toxin A induces corticospinal excitability changes (1991) 751. in a population of patients with limbs spasticity, Abstracts of 36 Pu X C, Wong P T H & Gopalakrishnakone P, A novel the 13 th European Congress of Clinical Neurophysiology , analgesic toxin (hannalgesin) from the venom of king cobra (TUO23) 119 (2008) S18. (Ophiophagus hannah ), Toxicon , 33 (1995) 1425. 19 Rinehart K L Jr, Cook J C, Pandey R C, Gaudioso L A, 37 De P, Dasgupta S C & Gomes A, A lethal neurotoxic protein Meng H, Moore M L, Gloer J B, Wilson G R, Gritowsky R from Indian king cobra ( Ophiophagus hannah ) venom, E, Zierath P D & Shield L S, Biologically active peptides and Indian J Exp Biol , 40 (2002) 1359. their mass spectra, Pure Appl Chem , 54 (1982) 2409. 38 Meng Q-X, Wang W-Y, Lu Q-M, Jin Y, Wei J-F, Zhu S-W 20 Rinehart K L Jr, Gloer J B, Hughes R G Jr, Renis H E, & Xiong Y-L, A novel short neurotoxin, cobrotoxin C, from McGovren J P, Swynenberg E B, Stringfellow D A, Kuentzel monocellate cobra ( Naja kaouthia ) venom: Isolation and S L & Li L H, Didemnins: Antiviral and antitumor purification, primary and secondary structure determination, depsipeptides from a carribbean tunicate, Science , 212 and tertiary structure modeling, Comp Biochem Physiol Part (1981) 933. C, 132 (2002) 113. 21 Montgomery D W & Zukowski C F, Didemnin B: A new 39 Brazil O V & Fontana M D, Toxins as tools in the study of immunosuppressive cyclic peptide with potent activity in sodium channel distribution in the muscle fiber membrane, vitro and in vivo , Transpalation , 40 (1985) 49. Toxicon , 31 (1993) 1085. 22 Motzer R, Scher H, Bajorin D, Sternberg C & Bosl G J, 40 Mancin A C, Soares M, Andiroo-Escarso S H, Faca A M, Phase II trial of didemnin B in patients with advanced renal Green L J, Zuccolotto S, Pela I R & Giglio J R, The cell carcinoma, Inves New Drug , 8 (1990) 391. analgesic activity of crotamine, a neurotoxin from Crotalus 23 Cain J M, Liu P Y, Alberta D E, Gallion J J, Laufman L, durissus terrificus (South American rattle snake) venom: A O’Sullivan J, Weiss G & Bickers J N, Inves New Drug , 10 biochemical and pharmacological study, Toxicon , 36 (1998) (1992) 113. 1927. 24 Nuijen B, Bouma M, Manada C, Jimeno J M, Schellens J H 41 Oguiura N, Boni-Mitake M & Radis-Baptista G, New view M, Bult A & Beijnen J H, Anticancer Drug , 11 (2000) 793. on crotamine, a small basic polypeptide myotoxin from 25 Pal S K, Gomes A, Dasgupta S C & Gomes A, Snake venom South American rattle snake venom, Toxicon , 46 (2005) 363. as therapeutic agents, Indian J Exp Biol , 40 (2002) 1353. 42 Georgi R, Bernardi M M & Cury Y, Analgesie effect evoked 26 Kase R, Kitagawa H, Hayashi K, Tanoue K & Inagaki F, by low molecular weight substances extracted from Crotalus Neurtalizing monoclonal antibody specific for α- durissus terrificus venom, Toxicon , 31 (1993) 1257. bungarotoxin: Preparation and characterization of the 43 Picolo G, Cassola A C & Cury Y, Activation of peripheral antibody, and localization of antigenic region of α- ATP-sensitive K + channels mediates the anti-nociceptive bungarotoxin, FEBS Lett , 254 (1989) 106. effect of Crotalus durissus terrificus snake venom, Eur J 27 Liou J-C, Cheng Y-C, Kang K-H, Chu Y-P, Yang C-C & Pharmacol , 469 (2003) 57. Chang L-S, Both A chain and B chain of β-bungarotoxin are 44 Lochnit G & Geyer R, Carbohydrate structure analysis of functionally involved in the facilitation of spontaneous batroxobin, a thrombin-like serine protease from Bothrops transmitter release in Xenopus nerve-muscle cultures, moojeni venom, Eur J Biochem, 228 (1995) 805. Toxicon , 43 (2004) 341. 45 Barbosa P S F, Martins A M C, Havt A, Toyama D O, 28 Liu W-H, Kao P-H, Lin S-R & Chang L-S, Membrane- Evangelista J S A M, Ferreira D P P, Joazeiro P P, Beriam L damaging activity with A Chain and B chain of β- O S, Toyama M H, Fonteles M C & Monteiro H A S, Renal , Toxicon , 53 (2009) 262. and antibacterial effects induced by I and II 29 Dutta A S & Chaudhuri A K, Neuropharmacological studies isolated from Bothrops jararacussu venom, Toxicon , 46 on the venom of Viper russelli , Indian J Exp Biol , 29 (1991) (2005) 375. 937. 46 Mebs D, Kuch U, Coronas F I V, Batista C V F, Gumprecht 30 Chen R & Robinson S E, The effect of cholinergic A & Possani L D, Biochemical and biological activities of manipulations on the analgesic response to cobrotoxin in the venom of the Chinese pit-piper Zhaoermia mice, Life Sci ., 47 (1990) 1949. mangshanensis with the complete amino acid sequence and 31 Chen R & Robinson S E. The effect of on phylogenetic analysis of a novel Arg49 phospholipase A 2 cholinergic neurons in the mouse, Life Sci , 751 (1992) 1013. myotoxin, Toxicon , 47 (2006) 797. 32 Bhaskaran R, Huang C C, Tsai Y C, Jayaraman G, Chang D 47 Omori-Satoh T, Yamakawa Y & Mebs D, The K & Yu C, Cardiotoxin II from Taiwan cobra venom, Naja antihaemorrhagic factor, esinacin, from the European naja atra structure in solution and comparison among hedgehog ( Erinaceus europacus), a metalloprotease inhibitor homologous cardiotoxins, J Biol Chem , 269 (1994) 23500. of large molecular size possessing ficolin/opsonin P35 lectin 33 Bhaskaran R, Huang C C, Chang D K & Yu C, Cardiotoxin domains, Toxicon, 38 (2000) 1561. III from Taiwan cobra ( Naja naja atra ) determination of 48 Z-Q Yonaha K, Tomihara Y & Toyama S, Characterization structure in solution and comparison with short neurotoxins, of the antihaemorrhagic factors of mongoose ( Herpestes J Mol Bio , 235 (1994) 1291. edwardsii ), Toxicon , 32 (1994) 1459. 34 Chang L-S, Hunag H-B & Lin S-R, The multiplicity of 49 Neves-Ferreira A G C, Cardinale N, Rocha S L G, Perales J cardiotoxins from Naja naja atra (Taiwan cobra) venom, & Domont G B, Isolation and characterization of DM40 and Toxicon , 38 (2000) 1065. DM43, two snake venom metalloproteinase inhibitors from 35 Tin M, Rai M, Maung C, Tun P & Da W, Bites by the king Didelphis marsupialis serum, Biochem Biophys Acta , 1474 cobra ( Ophiophagus hannah ) in Myanmar: successful (2000) 309. 236 INDIAN J EXP BIOL, MARCH 2010

50 Thwin M-M & Gopalakrishnakone P, Snake envenomation 67 McIntosh J M & Jones R M, Cone venom from accidental and protective natural endogenous proteins: A mini review of stings to deliberate injection, Toxicon , 39 (2001) 1447. recent developments (1991-1997), Toxicon , 36 (1998) 1471. 68 Bowersox S S, Gadbois T, Singh T, Pettus M, Wang Y X & 51 Lizano S, Domont G & Perales J, Natural phospholipase A 2 Luther R R, Selective N-type neuronal voltage-sensitive myotoxin inhibitor proteins from snakes, mammals and calcium channel blocker, SNX-111, produces spinal plants, Toxicon , 42 (2003) 963. antinociception in rat models of acute, persistent, and 52 Chatterjee I, Chakravarty A K S & Gomes A, Antisnake neuropathic pain, J Pharmacol Exp Therap , 279 (1996) venom activity of ethanolic seed extract of Strychnos nux 1243. vomica Linn, Indian J Exp Biol , 42 (2004) 468. 69 Hama A & Sogen J, Antinociceptive effects of the marine 53 Guan R J, Wang C G, Wang M & Wang D C, A depressant snail peptides conantokin-G and conotoxin MVIIA alone and insect toxin with a novel analgesic effect from scorpion in combination in rat models of pain, Neuropharmacology , Buthus martensii Karsch, Biochem Biophys Acta , 1549 56 (2009) 556. (2001). 70 Malmberg A B, Gilbert H, McCabe R T, & Basbaum A I, 54 Liu Y F, Ma R L, Wang S L, Duan Z Y, Zhang J H, Wu L J & Powerful antinociceptive effects of the cone snail venom- Wu C F, Expression of an antitumour-analgesic peptide from derived sub-type-selective NMDA receptor antagonists the venom of Chinese scorpion Buthus martensii Karsch in conantokins G and T, Pain , 101 (2003) 109. Escherichia coli , Protein Expr Purif, 27 (2003) 253. 71 Suh H W, Song D K, Choi S R, Huh S O & Kim Y H, 55 Zlotkin E, Miranda F & Rochat H, Chemistry and Differential effects of ω-contotoxin GVIA, nimodipine, pharmacology of Buthinae scorpion venoms, in Handbook of calmidazolium and KN-62 injected intrathecally on the anti- experimental physiology , Vol. 48, edited by S. Bettini, nociception induced by beta-endorphin, morphine and [D- (Springer, Heidelberg). 1978, 317 Ala2, N-Me Ph4, Gly-ol5] enkephalin administered 56 Correa M M, Sampio S V, Lopes R A, Mancusco L C, Cunha intracerebro ventricularly in the mouse, J Biol Chem , 282 O A, Franco J J & Giglio, J R, Biochemical and (1997) 961. histopathological alteration induced in rats by Tityus 72 Craig A G, Norberg T, Griffin D, Hoeger C, Akhtar M, serrulatus scorpion venom and its major neurotoxin Schmidt L, Low W, Dykert J, Richelson E, Navaro V, tityastoxin-1, Toxicon, 35 (1997) 1053. Maazella J, Watkins M, Hillyard D, Imperial J, Cruz L J & 57 Guan R J, Wang M, Wang D & Wang D C, A new insect Olivera B M, Contulakin-G, an O-glycosylated neurotoxin AngP1 with analgesic effect from the scorpion neurotensin, J Biol Chem , 274 (1999) 13752. Buthus martensii karsch: purification and characterization, J 73 Lewis R J, Nielsen K J, Craik D J, Loughnan M L, Adams D Peptide Res, 58 (2001) 27. A, Sharpe I A, Luchian T, Adams D J, Bond T, Thomas L, 58 Chen B & Ji Y, Antihyperanalgesia effect of Bmk AS, a Jones A, Matheson J L, -ater R, Andrews P R & scorpion toxin, in rat by plantar injection, Brain Res, 952 Alewood P F, Novel omega-conotoxins from Conus catus (2002) 322. discriminate among neuronal calcium channel subtypes, J 59 Goudet C, Chi C W & Tytgat J, An overview of toxins and Biol Chem , 275 (2000) 35335. genes from the venom of the Asian scorpion Buthus 74 Aguilar M B, Lezama-Monfil L, Maillo M, Pedraza-Lara H, martensii karsch, Toxicon , 40 (2002) 1239. Lopez-Vera E & de la Cotera E P H, A biologically active 60 Karbat I, Turkov M, Cohen L, Kahn R, Gordon D, Gure vitz hydrophobic T-1-conotoxin from the venom of Conus M & Frolow F, X-ray structure and mutagenesis of the spurious , Peptides, 27 (2006) 500. scorpion depressant toxin LqhIT2 reveals key determinants 75 Zugasti-Cruz A, Maillo M, Lopez-Vera E, Falcon A, de la crucial for activity and anti-insect selectively, J Mol Biol , Cotera E P H, Olivera B M & Aguilar M B, Amino acid 366 (2007) 586. sequence and biological activity of a V-conotoxin-like 61 Bosmans F, Martin-Eauclaire M-F & Tytgat J, Differential peptide from the worm-hunting snail Conus austini, effects of fine ‘classical’ scorpion β-toxins or rNa u 1.2a and Peptides, 27 (2006) 506. DmNav1 provide clues on species-selectivity, Toxicol Appl 76 Sudarslal S, Majumdar S, Ramasamy P, Dhawan R, Pal P P, Pharmacol , 218 (2007) 45. Ramaswami M, Lala A K, Sikdar S K, Sarma S P, Krishnan 62 Deshpande S B, Kanoo S & Alex A B, Bradycardia induced K S & Balaram P, Sodium channel modulating activity in a by Mesobuthus tamulus scorpion venom involves muscarinic δ-conotoxin from an Indian marine snail, FEBS Lett , 553 receptor-G-protein-coupled cell signaling pathways, Indian J (2003) 209. Exp Biol , 46 (2008) 229. 77 Raufman J P, Singh L & Eng J, Extendin-3, a novel peptide 63 Singh S K & Deshpande S B, Vasosensory responses elicited from Haloderma horridum venom, interacts with vasoactive by Indian red scorpion venom last longer than capsaicin- intestinal peptide receptors and a newly described receptor induced responses, Indian J Exp Biol , 46 (2008) 755. on dispersed acini from guinea pig pancreas. Description of 64 Rash L D & Hodgson W C, Pharmacology and biochemistry exendin-3(9-39) amide, a specific exendin receptor of spider venoms, Toxicon, 40 (2002) 225. antagonist, J Biol Chem , 266 (1991) 2897. 65 Mintz I M, Venema V J, Swiderek K M, Lee T D, Bean B.P 78 Broccardo M, Erspamer V, Falconieri-Erspamer G, Improta & Adams M E, P-type calcium channels blocked by the G, Linari G, Melchiorri P & Montecucchi P C, spider toxin w-aga-IVA, Nature , 355 (1992) 827. Pharmacological data on dermorphins, a new class of potent 66 Escoubas P, De Weille J R, Lecov A, Diochot S, Waldmann opioid peptides from amphibian skin, Br J Pharmacol , 73 R, Champigny G, Moinier D, Menez A & Lazdunski M, (1981) 625. Isolation of a tarantula toxin specific for a class of protonated 79 Barra D, Mignogna G, Simmaco M, Pucci P, Severini C, Na + channels, J Biol Chem, 275 (2000) 25116. Falconieri-Erspamer G, Negri L & Erspamer V, [D-Leu2]- KAPOOR: NATURAL TOXINS & THEIR THERAPEUTIC POTENTIAL 237

deltorphin, a 17 amino acid opioid peptide from the skin of 83 Sosa-Rosales J I, D’Suze G, Salazar V, Fox J & Sevcik C, the Brazilian hylid frog, Phyllomedusa burmeisteri , Peptides , Purification of a mycotoxin from the toadfish 15 (1994) 199. Thalassophryne masculosa (Gunter) venom, Toxicon , 45 80 Negri L, Erspamer G F, Severini C, Petenza R L, Melchiorri (2005) 147. P & Erspamer V, Dermorphin related peptides from skin of 84 Karmakar S, Muhuri D C, Dasgupta S C, Nagchaudhuri A K Phyllamedusa bicolor and their amidated analogs activate & Gomes A, Isolation of a haemorrrhagic protein toxin (SA- two µ-opioid subtypes, which modulate antinociception and HT) from the Indian venomous butterfish ( Scatophagus catalepsy in the rat, Proc Natl Acad Sci , 89 (1992) 7203. argus Linn) sting extract, Indian J Exp Biol , 42 (2004) 452. 81 Kreil G, Barra D, Simmaco M, Erspamer V, Erspamer G F, 85 Muhuri D, Karmakar S, Dasgupta S C, Nagchaudhuri A K & Negri L, Severini C, Corsi R & Melchiorri P, Deltorphin, a Gomes A, Pharmacological studies on the venomous spotted novel amphibian skin peptide with high selectivity and butterfish ( Scatophagus argus Linn) sting extract on affinity for δ-opioid receptors, Eur J Pharmacol , 162 (1989) experimental animals, Indian J Exp Biol , 42 (2004) 461. 123. 86 Castle N A, Haylett D G & Jenkinson D H, Toxins in 82 Gomes A, Giri B, Saha A, Mishra R, Dasgupta S C, Debnath characterization of potassium channels, Trends in A & Gomes A, Bioactive molecules from amphibian skin: Neurosciences , 12 (1989) 59. Their biological activities with reference to therapeutic 87 Stocker M, Ca(+2)-activated K + channels: molecular potentials for possible drug development, Indian J Exp Biol , determinants and function of the SK family, Nature Rev 45 (2007) 579. Neurosci , 5 (2004) 758.

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