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Implications of phytochemicals in snakebite management: Present status and

future prospective
Article in Toxin Reviews · December 2013

DOI: 10.3109/15569543.2013.854255
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Toxin Rev, Early Online: 1–24

! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/15569543.2013.854255
REVIEW ARTICLE
Implications of phytochemicals in snakebite management: present

status and future prospective
Nanjaraj A. N. Urs1, M. Yariswamy1, Vikram Joshi1, A. Nataraju2, T. V. Gowda1, and B. S. Vishwanath1
1
Department of Studies in Biochemistry, University of Mysore, Mysore, Karnataka, India and 2Department of Biochemistry, Mysore, Karnataka, India
Abstract Keywords
In spite of vast advances in healthcare services, treatment of snakebite still remains a challenge Herbal medicine, local toxicity, morbidity,
Toxin Reviews Downloaded from informahealthcare.com by B. S. Vishwanath on 12/21/13
to medical fraternity, because of unresolved complications of severe local tissue damage and Snakebite, venom enzymes
consequential physical disabilities. Though anti-venom therapy reduces mortality, is ineffective
against local tissue damage. In vitro and in vivo studies demonstrated that several alkaloids, History
flavonoids, polyphenols, terpenoids, saponins, sterols, glycosides, etc., from herbal medicines
effectively neutralized local tissue damage induced by venom toxins/enzymes. This review Received 29 May 2013
emphasizes the interplay of venom toxins/enzymes in local toxicity and their neutralization Revised 6 October 2013
using phytochemicals. Further, approaches using phytochemicals and anti-venoms are Accepted 7 October 2013
reviewed for better management of snakebite. Published online 16 December 2013
Abbreviations: AIPLAI: Azadirachta indica PLA2 inhibitor; CK: creatine kinase; ECM: extracel-
lular matrix; LDH: lactate dehydrogenase; PLA2: phospholipase A2; PLs: phospholipids; SVMPs:
For personal use only.
snake venom metalloproteases; SVSPs: snake venom serine proteases; VRV-PL-VIIIa: basic
phospholipase A2 from Vipera russelii venom; WSG: Withania somnifera glycoprotein
Introduction degenerative symptoms still remains a challenge to the

medical fraternity and scientific community. Though plant-
Plant extracts have been the source of remedy for various
based medicines are extensively used to treat snakebite
clinical abnormalities from the time immemorial. Over three-
victims, still there is/are no molecule(s) identified to neutral-
quarters of the world population relies mainly on plant-based
ize snake venom toxicity completely. Studies from
medicines for the primary health care (Bhau, 2012). More
several laboratories, including ours, have shown promising
than 30% of the entire plant species has been used for
results in neutralizing local toxicities like edema, hemorrhage,
medicinal purposes. The medicinal properties of herbal
and tissue necrosis using phytochemicals (Kini &
extracts are attributed to the presence of diverse classes of
Gowda, 1982a; Mahadeswaraswamy et al., 2011a,b; Sekar
bio-active molecules, many of which have attained the level
et al., 2003; Vishwanath & Gowda, 1987). Based on the
of drugs (Upadhyay, 2011). Phytochemicals are employed
available literature, this review is written to highlight the
for the treatment of hypertension, cardiovascular disorders,
strategies for management of snakebite using plant-derived
cancer, neuronal disorders, inflammation, diabetes, malaria,
therapeutics as a supportive therapy to anti-venom
influenza, arthritis, and severe pain (Li et al., 1999; Pandey
administration.
et al., 2011). A list of drugs derived from phytochemicals
Snakebite is a serious medical emergency in tropical
used against wide array of clinical disorders is given in
and sub-tropical regions of the world, especially in the rural
Table 1. These phytochemicals are retained in their native
zones. The victims are mainly farmers and the labor class.
form or derivatized prior to use as a drug formulation. It has
Venom injected into the victim following the bite causes
been estimated that in developed countries such as United
serious debilitating and life-threatening effects eventually
States, plant drugs contribute as much as 25% of the total
resulting in morbidity and mortality. In spite of higher
drugs used in the therapeutics, while in fast developing
mortality rates resulting from snakebite, the emphasis in this
countries such as China and India, the contribution is as
review is given to understand the unresolved complications of
much as 80% (Kiran Kumari et al., 2012). In spite of the
venom-induced local tissue damage and resulting morbidity.
extensive use of plant-based therapeutics in treatment of an
array of clinical conditions, snakebite and associated
Morbidity due to snakebite
Address for correspondence: Prof. B.S. Vishwanath, PhD, Department of Morbid symptoms of envenomation by viperid and crotalid
Studies in Biochemistry, University of Mysore, Manasagangotri,
Mysore – 570 006, Karnataka, India. Tel: +91-0821-2512471. E-mail: snakes vary in extent and presentation. The symptoms range
vishmy@yahoo.co.uk from local swelling, ptosis, gangrene, coagulopathy to severe
2 Nanjaraj A. N. Urs et al. Toxin Rev, Early Online: 1–24
Table 1. Drugs derived from phytochemicals used against clinical disorders.
No Clinical disorders Drugs derived from phytochemicals

01 Bronchial inflammation Thymol
02 Cancer Taxol, vincristine, vinblastine, etiposide, teniposide, Topotecan
03 Diabetes mellitus Metformin
04 Genital and perianal warts Catechin
05 Gouty arthritis Colchicine
06 Hypertension and cardiovascular disorders Papaverine, reservatrol, reserpine, digitoxin
07 Influenza Shikimic acid
08 Malaria Quinine, Artemisinin
09 Neuronal disorders (Alzheimers disease, Parkinson’s disease, Dementia) Apomorphine, L-Dopa, galantamine, physostigmine
10 Pain Morphine
11 Tyrosinemia Leptospermone, nitisinone
Figure 1. Local toxicities of venomous snakebite.
mouth bleeding, hemorrhagic edema, and widespread loss of culminating in the destruction of both sarcoplasmic reticulum
skeletal muscle integrity. This loss in musculoskeletal integ- and muscle fibrils of skeletal muscles. The symptoms of
rity results in severe discharge of blood and exposure of myotoxicity include muscle pain, tenderness, weakness,
underlying bony tissue (Figure 1) (Gutiérrez et al., 2009; elevated serum creatine kinase levels, and myoglobinuria,
Lomonte et al., 1990; Selistre et al., 1990). Another major which is often associated with renal alterations and
hazard of tissue injury following envenomation is the hyperkalemia (Azevedo-Marques et al., 1985; Reid, 1975;
hypovolemic shock secondary to massive fluid shifts, par- White, 1995).
ticularly apparent in younger children in whom this compli- Snake venom toxins, apart from tissue damage, cause
cation is lethal (Montecucco et al., 2008). hemostatic disturbances by interfering with coagulation
cascade or platelet functions. Venom toxins exerting their
action towards coagulation cascade possess both pro-coagu-
Pathophysiological alterations induced
lant and anticoagulant properties. Pro-coagulant venom toxins
by snake venom
cause intravascular clotting, by rapid conversion of soluble
Hemorrhage is the characteristic local symptom of viperid fibrinogen to insoluble fibrin clot, which poses the risk
envenomation resulting from depletion of proteins and of blockage of blood flow to vital organs (Lu et al., 2005).
glycosaminoglycans in extracellular matrix (ECM) and base- The anti-coagulant venom toxins hydrolyze fibrinogen, ren-
ment membrane of blood vessels. Such blood vessels become dering the blood incoagulable (Kumar et al., 2011).
fragile and are susceptible for rupturing, resulting in hemor- Irrespective of the effect, venom toxins promote excessive
rhage (Serrano & Maroun, 2005). Hypoxic state induced by bleeding from the vital organs (cerebral hemorrhage is very
hemorrhage leads to the onset and progression of myotoxicity fatal – 20% of people who die after snakebite have cerebral
DOI: 10.3109/15569543.2013.854255 Phytochemicals in snakebite management 3
Figure 2. Mechanism of action of snake venom hyaluronidases.
hemorrhage). Specific snake venom toxins also interfere in facilitates enhanced diffusion of venom toxins from bitten site
platelet function, either promoting or inhibiting the process of to target organs. Hence, hyaluronidases are appropriately
platelet aggregation (Yamazaki & Morita, 2007). In addition called as ‘‘spreading factors’’ (Girish et al., 2004b). Snake
to hemostatic alterations, snake venom toxins, particularly venom hyaluronidases are not only involved in local tissue
phospholipase A2 (PLA2), target neuromuscular junctions/ damage but also play a crucial role in increasing the efficacy/
synapse, causing neurotoxicity. Neurotoxins reported from potency of other major venom toxins such as PLA2 and
snake venom act either at pre-synaptic cleft or post-synaptic proteases by facilitating them to reach systemic circulation.
cleft (Hodgson & Wickramaratna, 2002). Apart from indu- The products released by hyaluronidases are also suspected
cing local toxic symptoms and neurotoxicity, snake venom to participate in inflammatory responses (Figure 2;
PLA2s are known to induce cardiotoxicity, nephrotoxicity, Kemparaju & Girish, 2006).
and lung hemorrhage (Cher et al., 2005; de Morais et al.,
2013; Uma & Gowda, 2000). Snake venom phospholipases A2
Snake venom toxins responsible for Snake venom phospholipases A2 (PLA2s) are multi-toxic
pathophysiological alterations enzymes that act locally as well as systemically to induce
wide range of pathophysiological alterations in the victim
The wide range of local and systemic manifestations of snake (Gowda & Middlebrook, 1994; Gutiérrez & Ownby, 2003).
venom results from the concomitant action of enzymatic and PLA2s with Asp49 at the active site are catalytically active.
non-enzymatic toxins. Upon envenomation, these complex They hydrolyze the ester bond at Sn-2 position of phospho-
toxins simultaneously exert their action towards various tissue lipids present in plasma membrane of various cells, including
systems, leading to complications of local and systemic erythrocytes, to induce plasma membrane lesions and direct
toxicity. The major venom enzymes that are responsible for hemolysis, respectively (Burke & Dennis, 2009). Further,
local and systemic complications are hyaluronidases, lysophospholipids released as a result of catalytic activity act
phospholipase A2, and proteases. In addition, there are as surfactants, which in turn rupture the erythrocyte mem-
toxins such as L-amino acid oxidases, phosphodiesterases, brane causing indirect hemolysis (Richard & Edward, 1987).
and nucleotidases, which exhibit lesser toxicity by themselves The unique ability of PLA2 to target a specific organ or tissue
but can potentiate the progression of the damage caused is because of their high affinity binding to specific receptors
by major hydrolytic enzymes of snake venom, for instance by independent of the catalytic site. Upon binding to the target,
causing hemostatic disturbances (Fox, 2013). they induce pharmacological effects either via or independent
of their catalytic activity (Kini, 2003).
Snake venom hyaluronidases
Snake venom PLA2s also affects neurons at pre-synaptic
Venomous bite leads to introduction of toxins into the or post-synaptic cleft to cause neurotoxicity. Pre-synaptic
victim. The reach of toxins to the target sites is assisted by neurotoxins from snake venom reported till date are mostly
endoenzymes such as hyaluronidases or peptides like mela- PLA2 or PLA2-containing protein complex. They bind to
tonin present in the venoms (Kemparaju & Girish, 2006). receptors or lipid domains in the motoneuron plasma
Snake venom hyaluronidases are the major enzymes that are membrane at the neuromuscular junction and alter membrane
responsible for degradation of hyaluronic acid (glycosami- functions. The resulting loss of membrane potential allows
noglycans) of ECM and connective tissues surrounding the large influx of Ca2þ from the extracellular medium. Such
blood vessels, capillaries, and smooth muscles resulting in altered membrane promotes exocytosis of synaptic vesicles
the loss of structural integrity of the target organs. This loss (Montecucco et al., 2008). Thus, pre-synaptic neurotoxicity
involves enzymatic activity as well as interaction of the toxin 1994). The inflammatory mediators such as prostaglandins,
with intracellular proteins affecting the cycling of synaptic thromboxanes and prostacyclins are formed enzymatically
vesicles in the axon terminals of vertebrate motoneurons from arachidonic acid (Bonventre, 1992; Mayer & Marshall,
(Pungercar & Krizaj, 2007). 1993). Prostaglandins play an important role in the onset and
PLA2s from snake venom exerting their action on skeletal progression of inflammatory reactions by regulating various
muscles are referred to as myotoxic PLA2. These can be an events, initially contributing to inflammation in the enve-
Asp49 catalytically active variant or PLA2 homologue devoid nomed region and subsequently in the surrounding tissues.
of enzymatic activity, e.g. Lys49 PLA2 analogue (Maraganore The lipid hydroperoxides formed from arachidonic acid
et al., 1984), which is catalytically inactive (Scott et al., 1992; metabolism by lipoxygenase enzymes (5-, 12-, and 15-
Ward et al., 2002). Enzymatically active myotoxins cause lipoxygenases) also serve as mediators of inflammation
hydrolysis of membrane phospholipids, whereas enzymati- (Teixeira et al., 2003).
cally inactive myotoxins act via perturbation of the membrane Snake venom PLA2s also exhibit hemostatic disturbances.
and hence, in both the cases, alteration of membrane structure These enzymes inhibit blood coagulation by hydrolyzing pro-
occurs. Perturbation of membrane results in the alteration coagulant phospholipids (PLs). Some PLA2s show higher
of membrane potential leading to unrestrained exchange affinity towards anionic PLs. Therefore, the anticoagulant
of ions such as Ca2þ from extracellular medium. Increased nature of these PLA2s could be due to their competition
cytosolic Ca2þ concentration induces hypercontraction of with coagulation factors for binding to PLs and not necessar-
myofilaments. The Ca2þ uptake by mitochondria results ily due to the lipid hydrolysis (Lu et al., 2005). Venom PLA2
in mitochondrial swelling and disorganization of cristae, also affects platelet functions by different mechanisms.
which causes a severe impairment of mitochondrial function One group of PLA2 induces platelet aggregation by cleaving
(Montecucco et al., 2008). Further, the Ca2þ-dependent platelet membrane PLs. Another group of PLA2 inhibits
proteinases (calpains) and cytosolic PLA2 are over-activated. platelet aggregation via the cleavage products (Kini, 2003).
They degrade cytoskeletal components affecting the mechan- Few venom PLA2 have biphasic effects; the first phase is
ical integration of the tissues (Montecucco et al., 2008). reversible aggregation and the second phase is an inhibitory
The inflammatory events evoked by PLA2 are primarily effect on platelet aggregation. The aggregating effect may be
associated with enzymatic activity that release arachidonic due to the formation of thromboxane and the inhibition
acid and lysophospholipid. Arachidonic acid is a precursor for may be due to effects of cleaved products of arachidonic acid
the biosynthesis of several lipid mediators of inflammation metabolism. Effects on platelets may also be independent
(Bonventre, 1992; Mayer & Marshall 1993). Lysophospolipid of enzymatic activity and it may be partially mediated
enters inflammatory pathway through platelet activating by dramatic change in the cytoskeleton structure (Figure 3)
factor, lipoprotein-A, and endocannabinoids (Krug et al., (Kini & Evans, 1990).
Figure 3. Mechanism of action of snake venom phospholipase A2. PLA2: phospholipase A2; Asp49: Aspartate49; Lys49: Lysine49; PAF: platelet
activating factor; LPA: lipoprotein-A.
Snake venom proteases are known to contribute significantly to the toxic effects
of venoms. Individually, the contributions of peptide toxins
Snake venoms, particularly of viperid and crotalid snakes,
towards local toxicity are not highlighted. But, they are
are rich sources of proteases which belong to serine and
known contributors to the systemic toxicity of snake venoms.
metalloprotease super-family. Snake venom proteases are
Several of them have been shown to be associated with other
hemostatically active and exert their effect towards coagula-
components of the venom to form complex toxins implicated
tion system, platelet aggregation, fibrinolytic system, and
in local toxicity (Fox, 2013). The task of treating progressive
vascular system (Kini, 2005). Further, these hemostatic
tissue damage and resulting physical disabilities due to
disturbances contribute to the progression of local manifest-
snakebite is still a challenge to the medical practitioners due
ations such as hemorrhage and myonecrosis, leading to an
to ineffectiveness of anti-venoms and lack of awareness in the
exaggerated response.
victim regarding the snake encountered (Alirol et al., 2010).
A number of snake venom serine proteases (SVSPs) show
Further, bare minimum facilities available in most hospitals
fibrin(ogen)olytic (thrombin-like) activities, which are not
in India make the treatment insufficient and lead to secondary
susceptible to hirudin or heparin and perhaps to most
complications (Cruz et al., 2009).
endogenous serine protease inhibitors, and form abnormal
fibrin clots interfering with hemostasis (Costa et al., 2010).
Drawbacks of hospital management: hope for
Some of them have kininogenase (kallikrein-like) activity,
alternative/augmentative therapy
releasing hypotensive bradykinin. In addition, SVSPs specif-
ically activate factor V, protein C and plasminogen (Matsui Presently, the only known remedy available in hospitals for
et al., 2000). treatment of snakebite is the polyvalent anti-venom. In spite
Snake venom metalloproteases (SVMPs) are zinc-depend- of its ability to neutralize the systemic toxicity induced by
ent enzymes of varying molecular mass. In comparison to venom, it fails to protect the victim from venom-induced local
SVSPs, they show pronounced effect on coagulation cascade tissue destruction (Girish & Kemparaju, 2011). Moreover,
and exhibit strong pro-coagulant effect. In continuation, anti-venom being a heterogeneous mixture of proteins is
they deplete plasma fibrinogen, causing abnormal bleeding liable to cause sensitivity reactions, which include: (a) Type I
at later stages of envenomation. Apart from their strong – Early anaphylactic reactions (within 5–180 min of anti-
interference in blood coagulation, SVMPs induce hemor- venom injection); (b) Type II – Pyrogenic reactions (within
rhage. The degradative effect of SVMPs towards ECM and 1–-2 h of treatment; (c) Late (serum sickness) reactions
basement membrane proteins make the blood vessels vulner- (within 1–12 days after treatment). Therefore, anti snake
able for rupturing (Escalante et al., 2011). Further, investi- venom usage in the treatment of snakebite remains partially
gations have revealed their involvement in the pathogenesis satisfactory (Kumar et al., 2010).
of myonecrosis, skin damage, edema and inflammation. Thus, The limitations and complications of anti-venom has
metalloproteases are important players in the pathogenesis entrusted scientific community with the task of exploring
of venom-induced local tissue damage (Aung et al., 2010). alternate/augmentative strategies such as use of plant-based
SVMPs-induced pathologies may be the direct effect of medicines for snakebite management (Gomes et al., 2010).
venom proteases or the indirect effect from SVMP-mediated The use of plant-based medicines for snakebite has
alterations, primarily hemorrhage (Figure 4). gained popularity based on the available evidences from
In addition to enzymatic toxins, non-enzymatic peptide folk healers, who have employed single plant extract or
toxins such as myotoxins, neurotoxins, and cytotoxins combination of several plant extracts as anti-dotes for
Figure 4. Mechanism of action of snake venom proteases. SVSPs: snake venom serine proteases; SVMPs: snake venom metalloproteases;
BM: basement membrane; EC: endothelial cell.
snakebite (Hasson et al., 2010). Although folk practitioners plant extract constitutes numerous phytochemicals, only a few
might not have the knowledge of the components present in of them neutralize venom toxicity. The result is low efficacy
the venom, they have developed multi-plant preparations in neutralizing the toxicity, whereas the purified biomolecules
through the knowledge passed on from ancestors to mitigate may have high potency of action. Direct interaction of the
the symptoms that arose by snakebite. A single plant biomolecule with venom toxin helps in reducing toxicity and
contains heterogeneous class of organic compounds, which hence increases the survival time of experimental animals/
may act individually or in combination to reduce the spread victims of snakebite. Hence, pure compounds isolated from
of toxin or dissociate the toxin complexes and reduce venom plants and their derivatives are gaining popularity over crude
potency or neutralize the venom toxicity as a whole. extracts in venom research. For example, Alam et al. (1994)
For example: the activities of extracts of Eclipta prostrata and Alam and Gomes (1998b) have reported the efficient
L. (Asteraceae) are due to three active components – neutralization of Russell’s viper venom by root extract of
wedelolactone (coumestan), sitosterol, and stigmasterol Indian medicinal plant Sarsaparilla (Hemidesmus indicus
(sterols). Individually, these compounds are less effective, R. Br.). They have also isolated active component, 2-hydroxy-
but in combination they efficiently reduce the toxicity 4-methoxy benzoic acid (Hydroxy anisic acid) and demon-
of differently acting snake venom toxins (Mors et al., 1989). strated neutralization of venom toxicity in animal model.
The extracts prepared from individual plant or isolated Hydroxy anisic acid, a phenolic compound, is found also in
compound(s) from same plant are less effective compared to Pimpinella anisum. The extracts from these plants are
the combined extracts of different plants in the treatment extensively used to treat Russell’s viper bite and associated
of snakebite (Gomes et al., 2010). Complex venoms appear ailments (Alam & Gomes, 1998a). In spite of the observed
to require combination of plant extracts (complex prepar- corrosive nature of hydroxy anisic acid, it is used in effective
ations) for treatment of toxicity. In fact, in some hospitals management of Russell’s viper bite. On the other hand, anisic
in India, doctors treat snakebite cases by combination of acid which lacks phenolic hydroxyl is non-corrosive and
anti-venom and plant extracts. In this regard, plant-based non-toxic. Anisic acid also neutralizes lung hemorrhage
medicines have been proved invaluable and are being used induced by a PLA2 VRV-PL-VIIIa of Russell’s viper venom
extensively to treat various toxic effects of snakebite (Sekar et al., 2003).
(Hasson et al., 2010). Therefore, it may be proposed that The root extract of a South American plant ‘‘Cabeca de
treatment of snakebite should include drugs/enumerating Negra’’ was available for plantation workers in Amazon
agents that act simultaneously on the toxicity induced Jungle as an oral antidote against snake and spider poisoning.
by snake venom. Hence, the extracts ought to be complex Nakagawa et al. (1982) isolated two potent snake venom
in their composition, among which some phytochemicals antidotes, cabenegrin A-I and A-II, from aqueous ethanol
may have fruitful interaction with venom toxins. Such an extract of ‘‘Cabeca de Negra.’’ In view of this unique activity,
interaction can lead to modification of toxins, thereby Ishiguro et al. (1982) successfully carried out synthesis of
reducing the toxicity and consequently the extent of tissue these compounds, by retaining the core portion of molecule
damage (Gomes et al., 2010). cabenegrin A-II and adding the substituent groups.
Although such poly-herbal preparations are used to treat Furthermore, special classes of iso-flavonoids possessing
snakebite by traditional healers, there are insufficient two contiguous benzofuran and benzopyran rings were
scientific evidences available in literature. Systematic inves- isolated from roots of Harpalyce brasiliana and they are
tigations are warranted to understand the extensive use of identified to be pterocarpanes (cabenegrin A-I and A-II).
poly-herbal preparations in treatment of snakebite. However, Among these pterocarpanes, 40 -dehydroxycabenegrin A-I,
such preparations are already in use in rural setup of isolated from a plant is used in the north-east of Brazil to
developing countries, with no reports of adverse effects treat snakebite. The derivatives of H. brasiliana inhibited
(Gomes et al., 2010). myotoxic, proteolytic, and PLA2 activities of Bothrops
Based on the available information, efficient strategies jararacussu venom. Da Silva et al. (2004) demonstrated
should be devised to investigate the usefulness of phyto- the improved anti-venom properties of pterocarpanes
chemicals and poly-herbal preparations in pre-clinical and through the synthesis of a bioisoster, where the prenyl
clinical settings following artificial envenomation. These group of pterocarpanes has been replaced with a benzyl
strategies should further promote phytochemicals and poly- group.
herbal preparation towards pre-clinical and clinical trials The folk medicinal plant Withania somnifera
along with the currently employed anti-venom therapy. (Ashwaganda) is used in Ayurvedic medicine for treatment
In addition, suitable models (cell/animal) should be developed of various ailments, including snakebite. Aqueous extracts of
for timely evaluation of plant isolates/extracts effectiveness this plant have been reported to neutralize toxic effects of
towards neutralization of venom toxin. Based on the available Indian spectacled cobra (Naja naja) venom (Lizano et al.,
literature, a list of plant(s) extract(s) and isolated pure 2003). Machiah et al. (2006) have isolated W. somnifera
compounds used in snake venom neutralization are listed in glycoprotein (WSG) from W. somnifera, which inhibits
Tables 2 and 3. hyaluronidase activity, a spreading factor present in the
snake venoms which aids spreading of toxins. Further, they
have also demonstrated its interaction with a post-synaptic
Phytochemicals in snakebite management
neurotoxic PLA2 leading to neutralization of its toxicity.
Plant-based preparations are of immense value in the treat- Gymnema sylvestre, a valuable medicinal plant belonging to
ment of snake venom–induced complications. Although the Asclepiadaceae, is native to Indian sub-continent, tropical
Table 2. Plant extracts used against snakebites.
No Plant Inhibition of toxicity References

a. Elapid snakebites
01 Andrographis paniculata (Nelabevu) Acanthaceae Increases the survival time of mice against Naja naja Premendran et al. (2011)
02 Allium sativum (Garlic) Amaryllidaceae Prophylactic action of Cobra venom in rats Rahmy & Hemmaid (2001)
03 Annona senegalensis (African custard-apple) Annonaceae Hyperthermia of Naja nigricollis in rats Adzu et al. (2005)
04 Hydrocotyle javanica (Java pennywort) Apiaceae Increase in survival time of mice against Naja nigricollis Kumarapppan et al. (2011)
05 Luffa aegyptiaca (Luffa) Cucurbitaceae Proteolytic activity of Naja nigricollis Ibrahim et al. (2011)
06 Mucuna pruriens (Velvet bean) Fabaceae Protection against Naja sputatrix depression Fung et al. (2012)
DOI: 10.3109/15569543.2013.854255
07 Pentace burmanica (Burmese-mahogany) Malvaceae Lethality of Naja kaouthia venom Pithayanukul et al. (2005)
08 Schumanniophyton Indian cobra cardiotoxin Houghton et al. (1992)
Magnificum (Idumuje) Rubiaceae
09 Diodia scandens (Ivory coast) Rubiaceae Life-prolonging effect Martz (1992)
10 Clerodendrum viscosum (Glory tree) Verbenaceae RBC lyses induced by Naja naja venom Lobo et al. (2006)
11 Curcuma zedoaria (Zedoary) Zingiberaceae Naja naja siamensis cobra venom inhibition activity by ELISA Daduang et al. (2005)
b. Viperid snakebites
01 Crinum jagus (Crinum) Amaryllidaceae Increases survival time, reduces myonecrosis and hemorrhage of Echis ocellatus Ode & Asuzu (2006)
02 Anacardium occidentale (Cashew) Anacardiaceae PLA2, protease, and hyaluronidase and edema, hemorrhage, and myotoxic effects Ushanandini et al. (2009)
and lethality of Daboia russelii
03 Mandevilla illustris Apocynaceae Basic PLA2 and crotoxin and prolonges survival time of Crotalus durissus terrificus Biondo et al. (2004)
venom
04 Strophanthus hispidus (Ghana) Apocynaceae Prolonged the clotting time of blood treated with Echis carinatus venom Houghton & Skari (1994)
05 Mandevilla velutina Apocynaceae Myotoxic activity and edema of Crotalus durissus terrificus venom Hemorrhage of Biondo et al. (2003)
Bothrops alternatus, Bothrops moojeni and Bothrops pirajai
06 Eclipta prostrate (False daisy) Asteraceae Lethal activity and partial hemorrhagic activity of Calloselasma rhodostoma Pithayanukul et al. (2004)
Rats paw edema, granuloma in rat and hemorrhage in mice induced by Gloydius Chen et al. (2005)
brevicaudus, Gloydius shedaoensis, Gloydius ussuriensis and Deinagkistrodon
acutus
07 Mikania glomerata (Guaco) Asteraceae Edema of Crotalus durissus terrificus and hemorrhagic activity of Bothrops venoms Maiorano et al. (2005)
08 Echinacea purpurea (Snakeroot) Asteraceae Enhancement of antibody and immune cell response for Bothrops asper venom Chaves et al. (2007)
09 Mikania glomerata (Guaco) Asteraceae Aqueous extract along with antivenom influenced faster recovery from Cortalid Floriano et al. (2009)
venom induced sedation
10 Artemisia campestris (Field wormwood) Asteraceae Significantly neutralized Macrovipera lebetina viper venom in mice Memmi et al. (2007)
11 Andrographis paniculata (Nelabevu) Acanthaceae and Aristolochia Hemorrhagic, edema and lethal activity of Daboia russelii and Echis carinatus Meenatchisundaram et al. (2009)
indica (Indian birthwort) Aristolochiaceae venoms
12 Hemidesmus indicus (Indian Sarsaparilla) Apocynaceae and Pluchea Lethality and hemorrhagic activity of viper venoms Alam et al. (1996)
indica (Indian camphorweed) Asteraceae
13 Bixa orellana (Achiote) Bixaceae Edema-forming, defibrinating and coagulant effects of Bothrops asper venom Núñez et al. (2004)
14 Schizolobium parahyba (Brazilian fern tree) Caesalpinioideae Lethality and hemorrhage of Bothrops alternates and Bothrops moojeni Vale et al. (2008)
Hemorrhagic and myotoxic activities of Bothrops pauloensis and Crotalus durissus Mendes et al. (2008)
terrificus venoms
15 Acalypha indica (Indian acalypha) Euphorbiaceae Lethality, hemorrhage, necrotizing and mast cell degranulation in rats Shirwaikar et al. (2004)
16 Croton urucurana (Sangra - d’agua) Euphorbiaceae Hemorrhagic activity in rat Esmeraldino et al. (2005)
17 Tamarindus indica (Tamarind) Fabaceae PLA2, protease, hyaluronidase, L-amino acid oxidase and 5’-nucleotidase; edema, Ushanandini et al. (2006)
hemorrhage and myotoxic effects and lethality of Daboia russelii
18 Butea monosperma (Palash) Fabaceae Hyaluronidase activity and hemorrhage of Daboia russelii Tarannum et al. (2012)
19 Pentaclethra macroloba (Pracaxi) Fabaceae Partial inhibition of myotoxic, hemorrhage, and edema activities of Bothrops da Silva et al. (2005)
jararacussu
20 Mucuna pruriens (Velvet bean) Fabaceae Myotoxic, cytotoxic and coagulation activities of Echis carinatus Aguiyi et al. (2001)
(continued )
7
8
Table 2. Continued
No Plant Inhibition of toxicity References

21 Galactia glaucescens Fabaceae Prevented the neuromuscular paralysis of Crotalus durissus. terrificus venom on Dal Belo et al. (2008)
mouse phrenic nerve-diaphragm preparation
22 Dipteryx alata Vogel (Almendro) Fabaceae Neurotoxicity and myotoxicity of Bothrops jararacussu venom in mouse phrenic Nazato et al. (2010)
nerve-diaphragm preparation
23 Casearia mariquitensis (zapatero) Flacourtiaceae Pulmonary hemorrhage of Bothrops neuwiedi metalloproteases. Izidoro et al. (2003)
24 Casearia sylvestris (Guacatonga) Flacourtiaceae Proteolytic activity and hemorrhagic activity Bothrops venoms Borges et al. (2001)
25 Casearia sylvestris (Guacatonga) Flacourtiaceae Myotoxic activity of Bothrops venom; edema of Bothrops moojeni and Bothrops Borges et al. (2000)
Nanjaraj A. N. Urs et al.
jararacussu; Prolonged survival time of mice Raslan et al. (2002)

Hemorrhagic and myotoxic activities caused by crude venoms and toxins
26 Nectandra angustifolia (Bebeeru) Lauraceae Hemolytic and coagulant activities of Bothrops neuwiedi diporus Torres et al. (2011a)
27 Bauhinia forficate (Orchid Tree) Leguminosae Clotting and fibrinogenolytic activities of Bothrops and Crotalus venoms Oliveira et al. (2005)
28 Gloriosa superba (Flame lily) Colchicaceae Strychnos nux-vomica Neutralized the rattlesnake venom lethality in mice model Samy et al. (2007)
(Nux Vomica) Loganiaceae
29 Hibiscus aethiopicus (Hibiscus) Malvaceae Cytotoxicity of C(2)C(12) muscle cells, Rabbits, guinea pigs and hemorrhage of egg Hasson et al. (2010)
embryo treated with Echis ocellatus venom
30 Morus alba (White mulberry) Moraceae Proteolytic and hyaluronolytic activities; edema, hemorrhage and myonecrotic Chandrashekara et al. (2009)
activities of Daboia russelii
31 Musa paradisiaca (Banana) Musaceae PLA2, myotoxicity, hemorrhagic activity and lethality of Crotalid venoms Borges et al. (2005)
32 Sapindus saponaria (Wingleaf soapberry) Sapindaceae PLA2 of Bothrops jararacussu lacerda, Bothrops moojeni hoge, Bothrops alternates da Silva et al. (2012)
duméril and Crotalus durissus. terrificus
33 Solanum campaniforme (Palotalillo) Solanaceae Myotoxicity, hemorrhage and skin necrosis of Bothrops pauloensis Torres et al. (2011b)
34 Vitis vinifera (Grape) Vitaceae Protease, hyaluronidase; edema, hemorrhage and myonecrosis of Indian Daboia Mahadeswaraswamy et al. (2008,
russelii and Echis carinatus 2009)
c. Elapid and viperid snakebites
01 Guiera senegalensis (Moshi medicine) Combretaceae Reduces the mortality rate induced by Echis carinatus and Naja nigricollis in mice Abubakar et al. (2000)
02 Mimosa pudica (Touch-me-not) Fabaceae Hyaluronidase and protease of Naja naja, Daboia russelii and Echis carinatus Girish et al. (2004a)
Neutralize the Naja kaouthia venom on pre-incubation with MPT Ambikabothy et al. (2011)
Naja kaouthia, Ophiophagus hannah, Bungarus candidicus, Bungarus fasciatus, Vejayan et al. (2007)
Calloselasma rhodostoma
03 Parkia biglobosa (African locust bean) Fabaceae Completely blocked the hemorrhagic activity and increased survival time of Naja Asuzu & Harvey (2003)
nigricollis and Echis ocellatus
04 Mucuna pruriens (Velvet bean) Fabaceae Neutralization of lethality of Asiatic cobra (Naja) venoms Tan et al. (2009)
Phospholipase activity and fibrinolytic activity of cobra and krait venoms Meenatchisundaram & Michael
(2010)
05 Vitex negundo (Chaste Tree) Lamiaceae and Emblica officinalis Lethality, inflammatory activity of Daboia russelii and Naja kaouthia and Alam & Gomes (2003)
(Indian gooseberry) Phyllanthaceae hemorrhage of Daboia russelii
06 Camellia sinensi (Tea) Theaceae PLA2, proteases, hyaluronidase, L-amino acid oxidase, hemorrhagic and the Pithayanukul et al. (2010)
dermonecrotic activity of Naja naja kaouthia and Calloselasma rhodostoma
d. Miscellaneous
01 Achyranthes aspera (Prickly Chaff Flower) Amaranthaceae Recommended in the treatment of snakebite Sheikh Saeed Ahmad (2007)
Nerium odorum Soland (French willow) Apocyanaceae The root is used as an antidote to snake venom. Sheikh Saeed Ahmad (2007)
Anagallis arvensis (Scarlet pimpernel) Primulaceae Antidote to snake venom
02 Apuleia leiocarpa (Garapa) Anti snake venom property Ruppelt et al. (1991)
Caesalpiniaceae and Casearia sylvestris (Guacatonga) Flacourtiaceae
03 Jatropha curcas (Physic Nut) Euphorbiaceae Acts as antidote against snake venom Thomas et al. (2008)
04 Humirianthera ampla (Kiwifruit) Icacinaceae Ethnopharmacological use against snake venom Luiz et al. (2007)
05 Leucas aspera (Leucas) Lamiaceae Antidote to snake venom Srinivasan et al. (2011)
06 Pittosporum neelgherrense (Pittosporum) Pittosporaceae An effective antidote to snakebite (Kani and Malapandaram tribes of Kerala) Shyamal et al. (2006)
Table 3. Phytochemicals used against snakebite.
No Plant Phytochemical Activity inhibition References

a. PLA2 inhibitors
01 Rauwolfia serpentine (Sarpagandha) Apocynaceae Ajmaline, Reserpine and Serpentine PLA2 of Naja naja Bhat (1991)
02 Aristolochia indica (Indian birthwort) Aristolochic acid PLA2 and Edema-inducing activity of Daboia Vishwanath & Gowda (1987)
Aristolochiaceae russelii
03 Betula alba (Silver birch) Betulaceae Betulin and betulinic acid Venom PLA2 activity Bernard et al. (2001)
04 Cordia verbenacea (Cordia) Boraginaceae Rosmarinic acid Paw edema induced by Bothrops jararacussu venom Ticli et al. (2005)
DOI: 10.3109/15569543.2013.854255
(BthTXs)
05 Tragia involucrate (Indian Stinging Nettle) 2,4 dimethyl hexane, 2 methylnonane, Venom and PLA2 neutralization in mice Samy et al. (2008, 2012)
Euphorbiaceae 2,6 dimethyl heptane
06 Glycine max (Soybean) Fabaceae Genistein Naja naja phospholipase-I and RV-PL-V induced Dharmappa et al. (2010)
mouse paw edema
07 Casearia sylvestris (Guacatonga) Flacourtiaceae Ellagic acid PLA2 and PLA2 induced myotoxicity and edema of da Silva et al. (2008)
Bothrops jararacussu
08 Vitex negundo (Chaste tree) Lamiaceae Tris (2,4-di-tert-butylphenyl) phosphate Daboia russelii PLA2 induced rat paw edema Vinuchakkaravarthy et al. (2011)
(TDTBPP)
09 Sideritis mugronensis Lamiaceae Hypolaetin-8-glucoside Snake venom PLA2 Alcaraz & Hoult (1985)
Marchantia berteroana (Umbrella liverwort) Hypolaetin Isoscutellarein Kaempferol
Marchantiaceae
Phegopteris connectilis (Long Beech Fern)
Thelypteridaceae
10 Azadirachta indica (Neem) Meliaceae AIPLAI (A. indica PLA2 inhibitor) PLA2 of Naja naja, Naja kaouthia and Daboia Mukherjee et al. (2008)
russelii
11 Phytolacca americana (American pokeweed) Oleanolic acid PLA2 of Daboia russelii (VRV-PL-V) and Naja naja Dharmappa et al. (2009)
Phytolaccaceae (NN-PL-I) & mouse paw edema
12 Piper umbellatum (Cow-foot leaf) Piperaceae 4-nerolidylcatechol PLA2 and myotoxic and edema-inducing activities Núñez et al. (2005)
Piper peltatum (Santa Maria Plant) Piperaceae of Bothrops asper venom
13 Fagopyrum esculentum (Buckwheat) Polygonaceae Rutin Efficiently inhibited PLA2-II from both Daboia Lindahl & Tagesson (1997)
russelii and Crotalus atrox. Weak inhibition of
PLA2-I of Naja naja
14 Ampelozizyphus amazonicus (Ampelozizyphus) Ursolic acid, betulin, betulinic acid Snake venom PLA2 Rosas et al. (2007)
Rhamnaceae
15 Malus domestica (Apple) Rosaceae Ursolic acid (3beta-hydroxy-urs-12-en- PLA2 and PLA2 induced mouse paw edema Daboia Nataraju et al. (2007)
28-oic acid) russelii and Naja naja
16 Atropa belladonna (Belladonna) Solanaceae Atropene PLA2 of Naja naja Basavarajappa (1992)
17 Thea sinensis (Tea) Theaceae Melanin PLA2 of contortrix laticinctus, Agkistrodon halys Hung et al. (2004)
blomhoffii, and Crotalus atrox.
18 Curcuma longa (Turmeric) Zingiberaceae Turmerin protein Cytotoxicity, edema and myotoxicity of Naja naja Chethankumar & Srinivas (2008)
19 Acalypha indica (Indian acalypha) Euphorbiaceae Acalyphin, Chlorogenic acid, Daboia russelii PLA2 Nirmal et al. (2008)
Pueraria lobata (Kudzu) Fabaceae Stigmasterol, Curcumin and Tectoridin
Glycine max (Soybean) Fabaceae
Phyllostachys edulis
(Bamboo) Poaceae
Curcuma longa (Turmeric) Zingiberaceae
20 Sponge Manoalide PLA2 of Cobra venom Lombardo & Dennis (1985)
21 Vegetable oils, followed by nuts and seeds including Alpha-tocopherol Membrane stabilizing effect against viper venom Mukherjee et al. (1997)
whole grains PLA2
(continued )
9
10
Table 3. Continued
No Plant Phytochemical Activity inhibition References

b. Protease inhibitors
01 Pimpinella anisum (Anise) Apiaceae Anisic acid Lethal action of Daboia russelii; Echis carinatus; Alam & Gomes (1998a)
Naja kaouthia; Ophiophagus hanna.
02 Hemidesmus indicus (Indian sarsaparilla) 2-hydroxy-4-methoxy benzoic acid (Root Lethal and hemorrhagic activity of Daboia russelii Alam & Gomes (1998b)
Apocynaceae extract) venom in rabbits.
03 Tabernaemontana catharinensis (Milkwood) 12-methoxy-4-methylvoachalotine Reduced lethal and myotoxic activities of Crotalus Batina Mde et al. (2000)
Apocynaceae durissus terrificus
04 Eclipta prostrata (False daisy) Asteraceae Wedelolactone, Sitosterol, Stigmasterol Myotoxicity of Crotalus durissus terrificus Mors et al. (1989)
05 Baccharis trimera (Carqueja) Asteraceae Neo-clerodane diterpenoid Hemorrhage, Fibrinogen and caseinolytic activities Januário et al. (2004)
of class P-I and III metalloproteases of Bothrops
neuwiedi and Bothrops jararacussu
06 Argusia argentea (Octopus bush) Boraginaceae Rosmarinic acid (RA) from methanol Fibrinogenolysis, digestion of type IV collagen Aung et al. (2010)
extract activity of Trimeresurus flavoviridis
07 Glycyrrhiza glabra (Licorice) Fabaceae Glycyrrhizin Reduced venom-induced bleeding, thrombus for- Assafim et al. (2006)
mation & thrombus weight of Bothrops jararaca
08 Pentaclethra macroloba (Pracaxi) Fabaceae Triterpenoid saponins named macrolobin- Hemorrhagic, fibrin(ogen)olytic, and proteolytic da Silva et al. (2007)
A and B activities of class P-I and P-III metalloproteases
of Bothrops neuwiedi and Bothrops jararacussu
09 Davilla elliptica Dilleniaceae Myricetin, quercetin and amenthoflavone Anti-hemorrhagic potential of against Bothrops Nishijima et al. (2009)
Byrsonima crassa (Byrsonima) Malpighiaceae jararaca
Mouriri pusa (Puca) Melastomataceae
10 Filipendula ulmaria (Meadowsweet) Rosaceae Salicylic acid Hemorrhagic activity of Daboia russelii and Echis Alam & Gomes (1998a)
carinatus
11 Curcuma longa (Turmeric) Zingiberaceae ar-Turmerone Hemorrhagic activity of Boyhrops jararaca and Ferreira et al. (1992)
lethal effect of Crotalus durissus terrificus
12 Gallnuts 3, 4, 5-tri-hydroxy benzoic acid, the Proteolytic activity of Daboia russelii and purified Mahadeswaraswamy et al. (2011a)
Gallic acid (GA) hemorrhagic complex
c. Hyaluronidase inhibitors
01 Mimosa pudica (Touch-me-not) Fabaceae b-3-(3-hydroxy-4-oxopyridyl) a-amino- Hyaluronidase activity Mahadeswaraswamy et al. (2011b)
propionic acid, the mimosine DR Hyal-II potentiated myotoxicity of VRV-PL-VIII
myotoxin and hemorrhagic activity
02 Hydrangea macrophylla (Bigleaf hydrangea) hydrangenol derivatives (BT-1 and BT-2) Hyaluronidase activity Kakegawa et al. (1988)
Hydrangeaceae
03 Flavonoid aglycones Apigenin, luteolin and kaempferol Hyaluronidase activity and delayed the venom action Kuppusamy & Das (1991)
in mice.
04 Tannin N-(cis-3,4 dimethoxycinnamoyl) anthra- Hyaluronidase activity Kakegawa et al. (1985)
nilic acid
d. PLA2 and Protease inhibitors
01 Hemidesmus indicus Indian sarsaparilla) Lupeol acetate Defibrinogenating and PLA2 of Daboia russelii; Chatterjee et al. (2006)
Apocynaceae cardiotoxicity, neurotoxicity and respiratory
changes of Naja kaouthia
02 Pluchea indica (Indian camphorweed) Asteraceae Sitosterol and Stigmasterol Viper venom-induced defibrinogenation, and Cobra Gomes et al. (2007)
venom-induced PLA2 activity
03 Strychnos nux vomica (Nuxvomica) Loganiaceae SNVNF (ethanolic seed extract) Lethality, hemorrhage, edema of Daboia russelii; Chatterjee et al. (2004)
cardiotoxicity and neurotoxicity of Naja kaouthia
04 Emblica officinalis (Indian gooseberry) Pthalate like compound Viper and cobra venom induced lethal, hemorrhagic, Sarkhel et al. (2011)
Phyllanthaceae PLA2, cardiotoxic and neurotoxic activity
e. PLA2 and hyaluronidase inhibitors

01 Withania somnifera (Ashwaganda) Solanaceae Withania somnifera glycoprotein PLA2 and Hyaluronidase of Naja naja and Daboia Machiah et al. (2006);
russelii venom Machiah & Gowda (2006)
f. Phosphodiesterase inhibitors
01 Bridelia ndellensis (Babooni) Euphorbiaceae Quinovic acid glycosides Phosphodiesterase-I (Sigma P 4631) (EC 3.1.4.1) Mostafa et al. (2006)
02 Mitragyna stipulosa (Mitragyna) Rubiaceae Quinovic acid and its glycosides, alpha- Snake venom phosphodiesterase I Fatima et al. (2002)
amyrin, 3 beta-acetyl ursolic acid,
mixture of oleanolic and ursolic acid
and beta-sitosterol glucopyranoside
DOI: 10.3109/15569543.2013.854255
03 Symplocos Racemosa (Symplocos bark) Benzoyl salireposide and Salireposide Snake venom phosphodiesterase I Choudhary et al. (2004)
Symplocaceae
04 Symplocos racemosa (Lodhra) Symplocaceae Phenolic glycoside derivatives Snake-venom phosphodiesterase I Badoni et al. (2010)
0
g. 5 Nucleotidase inhibitors
01 Dong quai Vanillic acid 5’nucleotidase and anticoagulant effects of Naja Dhananjaya et al. (2006)
Angelica sinensis naja
Apiaceae
02 Jack-bean Concanavalin A (Con-A) 5’ nucleotidase of Naja naja, Naja kaouthia, Naja Dhananjaya et al. (2010)
Canavalia ensiformis melanoleuca, Naja naja sputatrix, Angkistrodon
Fabaceae halys blomhoffii, Bothrops asper
h. ATPase inhibitors
01 Gymnema sylvestre Potassium gymnemate Toxic ATPases of Daboia russelii and Naja naja Kini & Gowda (1982a,b)
(Gymnema)
Asclepiadaceae
i. Miscellaneous
01 Mangifera indica Pentagalloyl glucopyranose PLA2, hyaluronidase and L-amino acid oxidase of Leanpolchareanchai et al. (2009)
(Mango) Calloselasma rhodostoma and Naja naja Pithayanukul et al. (2009)
Anacardiaceae kaouthia venom
Caseinolytic and fibrinogenolytic activities of
Malayan pit viper and Thai cobra venoms
02 Ehretia buxifolia Ehretianone Anti snake venom activity against Echis carinatus Selvanayagam et al. (1996)
(Fukien Tea) venom in mice
Boraginaceae
03 Persimmon fruit Tannic acid Biological toxicities of Habu and Erabu snakes Homma et al. (1965)
Ebenaceae
04 Mucuna pruriens Multiform glycoprotein (gpMuc) Protect mice against E. carinatus, cobra, and krait Guerranti et al. (2004); Aguiyia
(Velvet bean) venoms. et al. (1999); Di Patrizi et al.
Fabaceae (2006)
05 Brongniartia podalyrioides and Brongniartia inter- () Edunol Reduced expected Bothrops atrox venom induced Reyes-Chilpa et al. (1994)
media mortality in mice
(Mexican snakeweeds)
Leguminosae
06 Schumanniophyton magnificum Schumanniofoside Reduced lethal effect of Naja melanoleuca venom in Akunyili & Akubue (1986)
(Idumuje) mice
Rubiaceae
07 Anisodus tanguticus Anisodamine Relieves venom induced microcirculatory and renal Li et al. (2009)
(Zang Qie) failure
Solanaceae
08 Cabeca de Negra South American plant Cabenegrin A-I and A-II from Aqueous Respiration, blood pressure and cardiac symptoms Nakagawa et al. (1982)
ethanolic extract of Bothrops atrox venom in dog

09 Cissus assamica Resveratrol (3,4’5- Chinese anti-snake venom property Yang et al. (1998)
11
(hong bei si chou) trihydroxytransstilbene)

Africa, and Australia. It is used as an antidote for snakebite. Chemical modification of phytochemicals
Gymnemic acids are the most abundant acidic glycosides
Among numerous plants that are reputed to neutralize
isolated from the leaves of this plant. Our previous investi-
the toxicities of snake venom, only a few are promising in
gations (Kini & Gowda, 1982a,b) have reported that toxic
neutralizing venom-induced toxicity by isolated compounds
ATPases from N. naja and V. russelii venoms can be
with or without chemical modifications. In some cases,
completely inhibited by potassium gymnemate. The
isolated compounds need minor modifications for better
Casearia sylvestris Sw. (Flacourtiaceae) is utilized as a
efficiency in their action. For example: ascorbic acid is a
folk medicinal plant in Brazil and all of Latin America to
natural antioxidant; as such it possesses very poor anti-venom
treat pathological conditions such as inflammation, micro-
properties, but when it is condensed with palmitic acid
bial infection, and snakebite. Studies have showed that
the resulting compound L-ascorbic acid-6-palmitate possesses
C. sylvestris aqueous extract can inhibit toxic effects caused
very good anti-venom properties. We have previously
by snake venoms or PLA2 isolated from different species
reported that the basic multi-toxic PLA2 VRV-PL-VIIIa
of Bothrops genus. Da Silva et al. (2008) have isolated
from V. russelii venom can be inhibited by L-ascorbic acid-
ellagic acid and its derivatives from aqueous extracts of
6-palmitate in vitro and VRV-PL-VIIIa induced mouse paw
C. sylvestris and demonstrated the inhibition of both venom
edema, myotoxicity, and lung hemorrhage in experimental
toxicity and the toxic PLA2 isolated from the Bothrops sp.
mice (Mohamed et al., 2011).
The presence of hydroxyls in the structure of ellagic acid at
position 3 or 30 increases the neutralizing ability towards toxic
Methodologies employed in snakebite

effects (Da Silva et al., 2008).
management
Extracts of Aristolochia sp. were used as antidotes in
treating poisonous snakebite cases both in India and South Snakebite, a global health hazard, needs attention in terms
America. Our earlier studies (Vishwanath & Gowda, 1987) of effective treatment and better management to improve the
have shown that Aristolochic acid, an alkaloid isolated from health of the affected individuals and the society. This hard
the plant Aristolochia sp., interacts and inhibits major basic task should be a concerted effort from health officials and
PLA2 from V. russelii venom and edema induced by the scientific community, with co-operation from folk healers
toxin. The inhibitory potential of phytochemicals towards as well as utilization of advanced diagnostic techniques.
snake venom PLA2 has been confirmed by molecular The strategies for snakebite management can be categorized
interaction studies such as circular dichroism and X-ray as traditional approach, scientific approach, and combination
crystallography. Ursolic acid, oleanolic acid (triterpenoids) of both traditional and scientific approaches (Figure 5).
and genistein (isoflavone) interact with PLA2 to cause Irrespective of the approach, the task of snakebite treatment
apparent shift in far UV-CD spectra, indicating the direct has to be managed carefully for restoring the structural and
interaction of these inhibitors with PLA2 (Dharmappa et al., functional status of the affected tissue/organ.
2009, 2010; Nanda et al., 2007; Nataraju et al., 2007).
Similar to the CD spectral studies, co-crystallization of Traditional approach
inhibitors with PLA2 have also revealed the nature of
Innumerable plants are being used by tribal populations
interaction. Co-crystallization of anisic acid with PLA2
and folk healers across the world for treating complications
indicated the binding of anisic acid at the active site of
of snakebite. Folk healers/tribal populations usually depend
PLA2 (Sekar et al., 2003). Interaction studies in these
on multiple plants rather than a single plant source for the
directions will enable the understanding of structure-function
preparation of paste, extract, juice, or decoctions against
relationship of the venom proteins, which will lay a better
snakebite complications. Herbal preparations may include
foundation for deriving potent plant-based drugs against
whole plant, root, rhizome, stem, bark, tuber, gum, leaf,
snakebite.
flower, fruit, and seed. The route of administration is varied
Plant extracts and plant-derived bio-active components
depending on severity of symptoms of snakebite, which may
have also been reported to possess inhibitory action
be (a) external application of the plant paste or its sap on the
towards snake venom hyaluronidases. The aqueous root
bitten area; (b) oral administration of plant preparations which
extract of Mimosa pudica inhibits the hyaluronidase and
includes chewing of leaves or bark or drinking of plant
protease activities of Indian Viperid snake venoms
extracts, juices, or decoctions (Figure 5). Irrespective of the
(Girish et al., 2004a). Mimosine, a purified compound
route of administration, the treatment strategy is continued till
isolated from M. pudica inhibits in vitro hyaluronidase
the recovery (Makhija & Khama, 2010).
activity of V. russelii venom (Mahadeswaraswamy et al.,
2011b). Further, the studies detailing the molecular inter-
Scientific approach
actions of purified plant isolates provide different dimensions
for understanding the mechanism of action of venom toxins. The scientific approach of using medicinal plants against
For example, multi-toxins exert multiple toxic effects through snakebite has been adopted from the knowledge of folk
multiple active sites or domains and these sites may be medicine and in the last 30 years it has merited closer
overlapped or buried within the protein. In such instances, the scientific attention (Figure 5). The methodologies employed
interaction of purified plant isolate(s) not only can distinguish by various researchers around the world to scientifically
the pharmacological sites of toxins from each other but they validate the usage of medicinal plants against snakebite are
may also have the potentials of serving as remedy for specific as follows: (a) Plant extracts or purified compounds used in
toxicity. folk medicine have been orally administered to experimental
Figure 5. Methodologies employed in snakebite management. IP: intraperitoneal; IM: intramuscular; ID: intradermal.
animals prior and post envenomation to determine their myotoxicity, hematological alterations, cytotoxicity, and
antidote potentials; in some cases co-administration of lipid peroxidation followed by inhibition using plant-derived
extracts/isolates along with the venom is followed. (b) Plant bio-active components (Hasson et al., 2010; Shirwaikar
extracts/fractions have been extensively analyzed for the et al., 2004).
identification of phytochemicals, such as secondary metabol-
ites, peptides, and proteins, which are responsible for toxin Combination approach (future prospective)
neutralization. The phytochemicals and protein fractions that The use of herbal medicine in clinical practices utilizes the
are isolated, identified from plant sources, and demonstrated knowledge from folk healers, which is translated as augmen-
for their toxin neutralization potentials by various researchers tative therapy along with routinely employed conventional
under in vitro and in vivo conditions include acids (anisic treatment. Herbal preparations/isolates have been signifi-
acid, 2-hydroxy, 4-methoxybenzoic acid), alkaloids (ALPLAI, cantly reported for their action against venom-induced local
aristolochic acid, atropine), glycosides (benzoyl saliriposide), toxicity, although some medical practitioners/researchers
phenolics (4-nerolidylcatechol), protein (WSG, turmerin), argue that such compounds play a role even in controlling
pterocarpanes (Carbenegrin A-I and A-II), steroids systemic toxicity (increasing survival time of experimental
(b-sitosterol, stigmasterol, wedelolactone), tannin (ellagic animals). On the other hand, anti-venom therapy, the most
acid), and terpenoids (glycyrrhigin, gymnemic acid) accepted mode of treatment for snakebite has its own
[Table 3 and Figure 6]. Proteins from plant sources may limitations. Considering the limitations of herbal preparations
directly interact with snake venom toxins and neutralize them as well as anti-venom, a combined approach that includes
or they may help as adjuvant in the production of antibodies both herbal preparations and anti-venom will be helpful in
against snake venom toxins when administered along with effective management of snake venom-induced complica-
commercially available anti-venoms. (c) In vitro experiments tions. The approach exemplifies a fine balance between the
used till date for the neutralization studies of crude/purified necessity, efficacy, and adverse effects of both anti-venom
venom toxins mainly include enzyme inhibition studies, and herbal preparations in efficient treatment and better
which are carried out by pre-incubation (Tables 2 and 3; management of snakebite.
Figure 6]. (d) In vivo experimental designs used for venom
neutralization studies include lethality studies, local and
Concluding remarks
systemic hemorrhage (skin, lung), edema, myotoxicity, and
myonecrosis in rodents, rabbit, and porcine models (Alam & Plants have been serving as important sources of remedy
Gomes, 1998b; Kumarapppan et al., 2011). In early 1980s, for various life-threatening ailments including snakebite
dogs have been used for toxicity studies, but due to ethical complications. The extensive use of plants for snakebite
issues nowadays mice model is the only preferred model for management is attributed to presence of diverse phytochem-
lethality/toxicity studies. (e) Ex vivo experiments have been icals which play vital role in the neutralization of venom
demonstrated by researchers using isolated frog tissues, nerve toxins/whole venom in experimental animals. In most cases,
diaphragm preparations, and isolated erythrocytes for demon- they exert their action against venom toxins in a concerted
strating snake venom–induced cardiotoxicity, neurotoxicity, manner, but recent trend in venom research looks for pure
Figure 6. (A) Snake venom PLA2 inhibitors. (B) Snake venom protease inhibitors. (C) Snake venom hyaluronidase inhibitors. (D) Snake venom PLA2
and protease inhibitors. (E) Snake venom PLA2 and hyaluronidase inhibitor. (F) Snake venom 50 nucleotidase inhibitor. (G) Snake venom ATPase
inhibitor. (H) Snake venom phosphodiesterase inhibitors. (I) Whole venom inhibitors.
Figure 6. Continued.
compounds from plants to argue for their specificity phytochemicals to reduce the toxicity also needs careful
against venom toxins and to minimize the risk of adverse assessment to provide new insights for developing new
effects. In spite of extensive research in the field of medicinal strategies against snakebite complications. The precautious
plants to tackle the complications of snakebite, no plant- usage of herbal medicines based on the present know-
based drug is available as a potent therapeutic agent. ledge will help in providing a better care for snakebite
The importance of partial chemical modification of the victims.
16
DOI: 10.3109/15569543.2013.854255
17
18
DOI: 10.3109/15569543.2013.854255
19
Declaration of Interest Batina Mde F, Cintra AC, Veronese EL, et al. (2000). Inhibition of the
lethal and myotoxic activities of Crotalus durissus terrificus venom
The authors have no conflicts of interests to disclose by Tabernaemontana catharinensis: identification of one of the active
The authors acknowledge the financial assistance provided components. Planta Med 66(5):424–8.
Bernard P, Scior T, Didier B, et al. (2001). Ethnopharmacology and
by Department of Biotechnology (DBT), New Delhi bioinformatic combination for leads discovery: application to
(Order No. BT/43/NE/TBP/2010; Dated 14-03-2011) and phospholipase A(2) inhibitors. Phytochemistry 58(6):865–74.
Karnataka Fund for Infrastructure Strengthening in Science Bhat MK. (1991). Studies on the toxic phospolipases from the Indian
and Technology (K-FIST) of Vision Group of Science and cobra (Naja naja naja) venom and their detoxification by active plant
components. PhD thesis, University of Mysore, India.
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Implications of phytochemicals in snakebite management: Present status and

Article in Toxin Reviews · December 2013

Nanjaraj Urs A N Yariswamy Manjunath

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Vikram Joshi Nataraju Angaswamy

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Snake Venom Toxins and Haemostasis View project

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Toxin Rev, Early Online: 1–24

Implications of phytochemicals in snakebite management: present

Introduction degenerative symptoms still remains a challenge to the

Table 1. Drugs derived from phytochemicals used against clinical disorders.

No Clinical disorders Drugs derived from phytochemicals

Figure 1. Local toxicities of venomous snakebite.

Figure 2. Mechanism of action of snake venom hyaluronidases.

Table 2. Plant extracts used against snakebites.

No Plant Inhibition of toxicity References

No Plant Inhibition of toxicity References

jararacussu; Prolonged survival time of mice Raslan et al. (2002)

Table 3. Phytochemicals used against snakebite.

No Plant Phytochemical Activity inhibition References

No Plant Phytochemical Activity inhibition References

e. PLA2 and hyaluronidase inhibitors

ethanolic extract of Bothrops atrox venom in dog

(hong bei si chou) trihydroxytransstilbene)

Methodologies employed in snakebite

Br.). Toxicon 32(12):1551–7. mechanism, and signaling. J Lipid Res 50:S237–42.

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