Extraction and Medicinal application of snake venom For animal health

Antivenin plants used for treatment of snakebites in Uganda: ethnobotanical reports and pharmacological evidences

 

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Timothy Omara1,2*     , Sarah Kagoya3,4, Abraham Openy5, Tom Omute6, Stephen Ssebulime7, Kibet Mohamed Kiplagat8  and Ocident Bongomin9

 

 

 

Abstract

 

Snakebite envenomation is a serious public health concern in rural areas of Uganda. Snakebites are poorly documented  in Uganda because most occur in rural settings where traditional therapists end up being the first-line defense for treatment. Ethnobotanical surveys in Uganda have reported that some plants are used to antagonize

the activity of various snake venoms. This review was sought to identify antivenin plants in Uganda and some

pharmacological evidence supporting their use. A literature survey done in multidisciplinary databases revealed that

77 plant species belonging to 65 genera and 42 families are used for the treatment of snakebites in Uganda. The majority of these species belong to family Fabaceae (31%), Euphorbiaceae (14%), Asteraceae (12%), Amaryllidaceae (10%) and Solanaceae (10%). The main growth habit of the species is shrubs (41%), trees (33%) and herbs (18%). Antivenin extracts are usually prepared from roots (54%) and leaves (23%) through decoctions, infusions, powders, and juices, and are administered orally (67%) or applied topically  (17%). The most frequently encountered  species were Allium cepa, Carica papaya, Securidaca longipedunculata, Harrisonia abyssinica, and Nicotiana tabacum. Species with global reports of tested antivenom activity included Allium cepa, Allium sativum,  Basella alba, Capparis tomentosa, Carica papaya, Cassia occidentalis, Jatropa carcus, Vernonia cinereal, Bidens pilosa, Hoslundia opposita, Maytensus senegalensis, Securinega virosa, and Solanum incanum. There is need to identify and evaluate the antivenom compounds in the claimed plants.

 

Keywords: Antiophidic, Antivenin, Snakebite, Traditional medicine, Uganda

 

 

 

Introduction

Snake envenoming  is a global health  problem  and a jus- tification  for morbimortality and various socio-economic losses. A recent  conservative  global  estimate  points  that about  5.5 million  snakebite  cases  are encountered  every year causing about  2 million deaths  [1, 2]. Up to 500,000 of these cases are reported in Africa [3–5]. In 2002, 108 cases of snakebites  were reported  in Gulu Regional Hos- pital   (Uganda)   though   none   of  the   victims   died  [6].

 

 

* Correspondence: timothy.omara@agroways.ug; prof.timo2018@gmail.com;

prof.timo2018@mu.ac.ke

1Department of Chemistry and Biochemistry, School of Biological and

Physical Sciences, Moi University, Uasin Gishu County, Kesses, P.O.Box

3900-30100, Eldoret, Kenya

2Department of Quality Control and Quality Assurance, Product Development Directory, AgroWays Uganda Limited, Plot 34-60, Kyabazinga Way, P.O. Box 1924, Jinja, Uganda

Full list of author information is available at the end of the article

About  151 cases were reported  in neighboring  Kenya  in

1994 with 19% of these from venomous  snakes [7].

A recent  study  [8] in 118 health  facilities  throughout Uganda  revealed  that  only  4% of  the  facilities  stocked antivenin  sera,  thus  most   victims  rarely  seek  medical care  when  bitten  by snakes. A  retrospective  part  of this study  showed  that  in 140  surveyed  facilities, 593 snake- bite cases were recorded within six months  with bites re- ported  in  the  rainy  seasons  from  April  2018  to  June

2018  and  then  October   2018  to  December   2018  [8]. Thus, fatalities in rural  areas are due to lack of antidotes within the 24 h recommended  [6, 9, 10] and antisera  ad- ministration problems  [11, 12].

Snakes  are  taxonomically  carnivorous   vertebrates   of class  Reptilia, order  Squamata,  sub-order  Serpentes  and families: Colubridae, Boidae, Elapidae, Pythonidae, Viperi- dae  that  characteristically  kill their  prey  by  constriction

 

 

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rather than envenomation  [13, 14]. Most bites are due to circumstantial  stepping  on  the snakes by  unprotected or barefooted victims [6, 15], snake ecology [16] while others are initiated by malevolent and alcohol-intoxicated  victims [17–19]. Over 3500 species of snakes have been classified and about  600 (15–17%)  of these  are venomous [1, 20]. East Africa is home  to  about  200 species of snakes and

145 of these from  45 genera and 7 families are found  in Uganda [21]. Many are harmless or are a rarity though the puff adder  (Bitis arietans),  Gabon  viper (Bitis  gabonica), green or Jameson’s mamba  (Dendroaspis jamesoni), black mamba  (Dendroaspis polylepis), forest cobra (Naja  mela- noleuca),   and  black-necked   spitting  cobra   (Naja   naja nigricollis) are listed as venomous [10, 22].

Snake  venom  is  secreted  by  snake  oral  glands  and is  injected  subcutaneously  or  intravenously  through the  fangs into  the  victim on  the  hands,  feet, arms,  or legs [23]. Venoms  are  water-soluble,  acidic,  and  have a  specific  gravity  of  about   1.03  [24].  The  quantity, lethality,  and  composition   of  venoms  vary  with  the age   and   species   of   the   snake,   time   of   the   year, geographic    location    as    well   as   the    envenoming  snake’s  diet.  A snake  venom  is a complex  mixture  of toxic   proteins    such   as   cardiotoxins,    neurotoxins, metalloproteinases,  nucleotidases,   phospholipases  A2, serine      proteinases,                 acetylcholinesterase                                     nitrate, hyaluronidases,    phosphomonoesterase  and   phospho- diesterase  [25]  which  are  injected  to  immobilize  the victim   [10,   26].   The   toxins   cause   haemotoxicity- damage   to   blood   vessels   resulting   in   spontaneous systemic  and  muscle  paralysis,  myolysis, arrhythmias, cardiac,  and  renal  failure [6].

At  present,  serum   antivenom   immunotherapy  is  the mainstay  of treatment reported  for snake  envenomation [6, 10, 17, 26].  Antisera  are  either  derived  from  horse serum   after   injecting   it  with   sublethal   doses  of  the venom  (Antivenin  Polyvalent) or  sheep  serum  (Crotali- dae  Polyvalent  Immune   Fab)  [19].  Though   antivenom serum  is lifesaving, it is associated  with the development of immediate  or delayed hypersensitivity  (anaphylaxis  or serum  sickness)  and  does  not  prevent  local tissue  dam- age. The side effects are thought  to be due to the action of  non-immunoglobulin  proteins   present  in  high  con- centrations in antisera  [27]. Worse  still,  there  is a pau- city of snake  venom  antiserum in  rural  Africa that  even in the presence  of money, it may not be readily available for  purchase   [6,  17].  This  is  in  part  attributed  to  the decline   in   antivenom    production  in   Africa   due   to denationalization of the manufacturing industries  by Af- rican countries  [28], lack of ready market  and low profits from  the  business.   Thus,  several  attempts  have  been made  to  develop  snake  venom  antagonists  from  other sources   including   plants,  dogs,  rabbits,  camelids,  and avian eggs [12, 27, 29–33].

The   use  of  plants   in  addressing   medical  challenges have  been  witnessed   since  antiquity   and  is  regaining shape in  the  modern  era  due  to  their  safety, effective- ness,  cultural  preferences,  inexpensiveness,   abundance, and  availability.  In  Uganda,  more  than  230  species  of angiosperms belonging to about  168 genera and 69 fam- ilies are  being utilized  for treatment of erectile  dysfunc- tion,  malnutrition,  sickle  cell  anemia,  hernia,  venereal diseases  (syphilis,  HIV,  and  gonorrhoea),  post-partum hemorrhage,  snakebites,  cancer, menorrhagia, threatened abortion,  skin  diseases,   jaundice,   and  cough   [34–60]. This study compiled information on antivenin  plants  re- ported  in  different  districts   of  Uganda  and  presented some experimental  evidence supporting their use in anti- venom therapy.

 

Methodology

Description of the  study area

Uganda  is a landlocked  country  straddling  the  equator  in  Eastern  Africa  [61].  It  is  flanked  by  Lake  Victoria, Tanzania,  and  Rwanda  to  the  south,  Kenya to  the  East, South  Sudan  to  the  North  and  Democratic  Republic  of Congo  to  the  West  (Fig. 1).  The  climate  experienced  is equatorial  moderated by  relatively high  altitudes  with  a mean   annual   temperature  of  20.5  °C.   The   country’s population  is estimated  to be 35.92 million  with 5 main ethnic  families:  Nilotics  (Acholi,  Alur,  Padhola,  Lulya, and  Jonam),  Bantu  (Baganda,  Banyankole,  Batoro,  Bag- were,  Bakiga,  Bakiga,  Banyarwanda,  Bakonjo,  Banyoro, and    Bakiga),   Hamities    (mainly    constituted    by   the Bahima), the  Nilo-Hamities  (Teso, Karamojong,  Kakwa, Sebei, Labwor, and  Tepeth)  and  the  Sudanics  (Lugwara, Madi,  and  Lendu) [62].  Health  care  services  are  inad- equate  [63], and  access to  allopathic  drugs  is limited  in rural  areas  due  to  their  prohibitive  cost, poor  transport network,  chronic  poverty  and the  general  belief in effi- cacy of traditional  medicine than western medicine  [64].

 

Literature search strategy

Relevant   original   articles,   books,   thesis,   dissertations, patents,  and  other  reports  written  in  English and  other local languages on ethnobotany and pharmacological  ev- idences  on  snakebites  in Uganda  were searched  in Sco- pus  [65],  Web  of  Science  [66],  PubMed   [67],  Science Direct  [68],  Google  Scholar  [69],  and  Scientific  Elec- tronic  Library  Online  (SciELO) [70] from  July 2019  to September   2019.   The   key  search   words   used   were “snakebite,”   “vegetal,”  “traditional    medicine,”   “ethno- botany,”   “alternative   medicine,”   “ethnopharmacology,” “antivenom,”   “antiophidian,”   “antitoxin,”   “snake   anti- dotes,” and “Uganda.” The botanical  names of the plants were  vetted  in  botanical databases:  the  Plant  List  [71], International  Plant  Names  Index  (IPNI) [72], NCBI tax- onomy  browser  [73], and  Tropicos  [74]. Where  a given

 

 

 

 

 

 

Fig. 1 Map of Uganda showing the location of the districts with reports of ethnobotanical surveys (marked X). Inset is the location of Uganda on the African continent

 

 

 

species was considered  as distinct  species in different re- ports,  the  nomenclature as per  the  botanical  databases took   precedence.   The   families,   local   names   (Lango, Acholi,  Ateso,  Luganda,  Lunyoro,  Rukiga, and  Lusoga), growth habit, part(s) used, conservation  status, preparation and administration mode, status of antivenin activity inves- tigation  of the  plants,  and  the  districts  where  the  plants were  surveyed  are  reported   (Table  1,  Additional  file 1). Pertaining  to  pharmacological   reports,  the  snake  venom studied, phytochemicals,  and positive results obtained using plants  identified  by this  study  (or  species from  the  same genus)  are reported.  In some  cases, some  activities of the plant  extracts  such  as  antioxidant and  radical  scavenging activities are reported as these are some of mechanisms  by which snake venoms are countered.

 

Results  and discussion

Only full-text articles in English, Lango, Acholi, Ateso, Lu- ganda, Lunyoro, Rukiga, and Lusoga were  considered.  A total of 15 articles (13 in English, 1 in Luganda, and 1 in Lusoga)  with  information  on  antivenin  plants  were  re- trieved, but  two of these  did  not  meet  inclusion  criteria

because one was not a full-text article while the other had only one  botanically  unidentified  antivenin  plant.  Thus, the following reports of interest specifically on the subject of antivenin plants in Uganda were retrieved (Table 1).

 

Traditional  concept of snakebites in Uganda

From  the electronic  survey of data, it is indubitable  that the  local communities in Uganda  have different  percep- tions  about  snakebites.  The  beliefs  appear  to  be  clan- related and include  snakes “can protect” (among  the Ba- ganda)  [18,  75]  or  “are  dangerous  and  connected  to witchcraft” in most communities [8]. By comparison,  the Luo of Kenya associate snakes with witchcraft  [76].

From   the  survey,  77  plant   species  from   65  genera belonging to 42 botanical  families claimed as antiophidic in  Uganda  were  retrieved  (Table  1,  Additional   file 1). The most  cited families were Fabaceae (31%), Euphorbi-  aceae  (14%),  Asteraceae   (12%),  Amaryllidaceae   (10%), and Solanaceae (10%) (Fig. 2). Most families encountered  in this  study  have  reported  antivenin  potential  in treat- ing or avoiding  snakebites  in other  countries  across  the globe.   For    example,    Apocynaceae,    Aristolochiaceae,

 

 

 

 

 

Table 1 Antivenin plants used in rural communities of Uganda

 

Plant family Latin botanical name References
Acanthaceae Asystasia  schimperi  T. Anders. [42]
Amaryllidaceae Allium cepa L. [41, 42, 49]
Amaryllidaceae Allium sativum L. [49]
Amaryllidaceae Crinum  kirkii [41]
Amaryllidaceae Scadoxus  multiflorus (Martyn) Raf. [10, 42]
Apocynaceae Carrisa edulis [50]
Apocynaceae Thevetia peruviana  (Pers.) Schumann [42]
Aristolochiaceae Aristolochia tomentosa Sims. [50]
Aristolochiaceae Aristolochia elegans Mast. [42]
Asclepiadaceae Cryptolepis sanguinolenta (Lindl.) Schltr [42]
Asparagaceae Sansevieria dawei Stapf [38]
Asparagaceae Sansevieria trifasciata var. trifasciata [10]
Asteraceae Bidens  pilosa  L. [42]
Asteraceae Crassocephalum mannii (Hook.f.) Milne-Redh. [35]
Asteraceae Echinops amplexicaulis  Oliv. [46]
Asteraceae Microglossa  pyrifolia (Lam.) O. Kuntze [42]
Asteraceae Vernonia cinerea (L) Less [41, 42]
Basellaceae Basella alba L. [39]
Boraginacea Trichodesma zeylanicum (L.) R.Br. [41]
Cleomaceae Cleome gynandra L. [35]
Capparidaceae Capparis tomentosa Lam. [42]
Caricaceae Carica papaya L. [41, 42, 50]
Celastraceae Maytensus  senegalensis  (Lam) Exell. [41]
Combretaceae Combretum collinum Fresen [41]
Combretaceae Combretum molle ex G.don. [41]
Commelinaceae Murdannia simplex Vahl. Branan [35]
Compositae Aspilia africana C.D Adams [46]
Convolvulaceae Hewittia sublobata L. Kuntze [49]
Convolvulaceae Ipomoea batatas (L.) Lam. [42]
Dracaenaceae Dracaena steudneri Engl. [49]
Ebenaceae Euclea divinorum Hiern [42]
Euphorbiaceae Acalypha bipartita Muell. Arg. [42, 47]
Euphorbiaceae Croton macrostachyus Hochst. ex. Delile [49]
Euphorbiaceae Euphorbia tirucalli L. [35]
Euphorbiaceae Jatropha curcas L. [42]
Euphorbiaceae Ricinus communis  L. [35, 42]
Euphorbiaceae Securinega  virosa (Willd) Baill. [41]
Fabaceae Acacia seyal Del. var. fistula (Schweinf.) Oliv. [42]
Fabaceae Acacia species [42]
Fabaceae Albizia coriaria (Welw. ex) Oliver [42]
Fabaceae Canavalia ensiformis  L. D.C [10]
Fabaceae Indigofera arrecta Host.  A. Rich. [42, 49]
Fabaceae Indigofera garckeana Vatk [42]
Fabaceae Indigofera capitata Forsk. [41]

 

 

 

 

 

Table 1 Antivenin plants used in rural communities of Uganda (Continued)

 

Plant family Latin botanical name References
Fabaceae Pseudarthria hookeri Wight and Arn. [42, 48]
Fabaceae Senna occidentalis (L.) Link [42]
Fabaceae Senna septemtrionalis (Viv.)  I. et B. [39]
Fabaceae Senna siamea (Lam.) Irwin and Barneby [42]
Fabaceae Senna singueana (Del.) Lock [42]
Lamiaceae Hoslundia opposita Vahl [42]
Lamiaceae Plectranthus barbatus [37, 50]
Leguminosae Cassia occidentalis L. [35]
Liliaceae Anthericum cameroneii Bak [41]
Loganiaceae Strychnos innocua Del. [41]
Malvaceae Urena lobata L. [42]
Melastomataceae Tristemma mauritianum J.F. Gmel. [41]
Meliaceae Ekebergia capensis Sparrm [44]
Meliaceae Trichilia ematica Vahl [38, 46]
Menispermaceae Cissampelos muchronata A.Rich. [41, 49]
Moraceae Ficus natalensis  Hochst. [42]
Myricaceae Morella kandtiana (Engl.) Verdic and Polhill [49]
Papillionaceae Ormocarpum trachycarpum [50]
Passifloraceae Adenia cissampeloides  (Hook.) Harms [42]
Poaceae Imperata cylindrica  (L.) P. Beauv [42, 49]
Poaceae Sporobolus  pyramidalis  P. Beauv. [42]
Polygalaceae Securidaca longipedunculata Fres. [41, 42, 50]
Rosaceae Rubus rigidus Sm [49]
Rubiaceae Gardenia ternifolia Schumach. and Thonn. [42]
Rutaceae Citrus  sinensis  (L.) Osb. [42]
Rutaceae Fagaropsis angolensis  (Engl.) Dale [59]
Simaroubaceae Harrisonia  abyssinica  Oliv. [41, 42, 50]
Solanaceae Datura stramonium L. [41]
Solanaceae Nicotiana tabacum L. [42, 49, 59]
Solanaceae Solanum aculeatissimum Jacq [41, 46]
Solanaceae Solanum incanum L. [41, 42]
Umbifellifereae Steganotaenia araelicea Hoscht [41]
Verbenaceae Lantana camara L. [50]

 

 

Asteraceae,   Convolvulaceae,   Fabaceae,   and   Myricaceae were cited in Kenya [17] and Tanzania  [77], Meliaceae in Ghana [78], Fabaceae in Rwanda [79], Asparagaceae, Legu- minosae, and Menispermaceae in Sudan [80], Acanthaceae, Apocynaceae,  Asteraceae,  Capparaceae,   Cariaceae,  Com- bretaceae,  Convulaceae,  Ebenaceae,  Eurphorbiaceae,  Faba- ceae, Malvaceae,  Meliaceae,  and  Poaceae  in Ethiopia  [81] and Pakistan  [82], Fabaceae, Aristolochiaceae,  and Lamia- ceae  in  Djibouti  [83]  and  Nigeria  [84],  Melastomataceae and   Menispermaceae in Cameroon [85]. Acanthaceae, Apocynaceae, Asteraceae,  Euphorbiaceae,  Fabaceae,  Mora- ceae, Rubiaceae, and Rutaceae were cited in India [86, 87],

Bangladesh [88, 89], and Central America [90]. Fabaceae is always dominant  in ethnobotanical reports  because  of the abundance  of plant species from this family [88, 91–93].

The  families reported  were from  different  districts  of

Uganda (Fig. 3) representing different ethnic groups with diverse  cultural  beliefs and  practices.  About  40% of the plant  species  were  reported  in  Kaliro  (inhabited  by the Basoga)  followed  by  21% from  Lira  (occupied   by  the Lango) and 11% from Mukono-Buikwe  frontier  occupied by the  Baganda.  In  a similar  cross-cultural comparison of antiophidic  floras  in  the  Republic  of Kenya, Owuor and   Kisangu   [17]   reported   that   two   culturally   and

 

 

 

 

 

 

14

 

12

 

10

 

8

 

6

 

4

 

2

 

0

 

 

 

Family

Fig. 2 Major families from which vegetal antivenins are obtained in Uganda

 

 

 

floristically  distinct   African  groups   (Kamba  and  Luo) had  similar  knowledge  of  snakebites  but  the  antivenin plants  utilized by the two ethnic  groups were independ- ently  derived.  The  abundance   of  antivenin  plants  from Kaliro,  Lira, and  Mukono/Buikwe  could  be  due  to  the presence   of   forest   reserves   in  these   districts.   Kaliro, Namalemba,   and  Namukooge  local  forest  reserves  are found in Kaliro [94]. The district  is also rich in water re- sources  such  as Lake Nakuwa,  River  Mpologoma,  Nai- gombwa, and  Lumbuye  wetlands  which  provide  rainfall for the  growth  of plants.  Lira  District  has Lake Kwania, Okole, Moroto  and Olweny wetland  systems which sup- port  the growth of plants [95]. The district  gazetted over

1000  hectares  of  land  for  forest  conservation   and  this serves as a good source of plants for traditional medicine [96]. The Mukono-Buikwe  frontier  has Mabira  forest re- serve which has been protected since 1932 and contains a number  of endangered  plant  species  in  Uganda  [97]. The  rainforest  is a  rain  catchment for  areas  supplying River Nile and  Ssezibwa River and  has rainfall through-  out the year thus plants flourish in this area [98].

 

Growth  habit,  parts  used,  preparation, and administration of antivenin preparations

Antivenin   plants   used  in  Uganda  are  majorly  shrubs

(41%), trees  (33%) and herbs  (18%) and  the  commonly

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fig. 3 Distribution of antivenin plant species in Ugandan districts as per ethnobotanical reports

 

 

 

 

 

 

used   plant   parts   are   roots   (54%)  and   leaves   (23%) followed by whole plant  (4%), bark (4%), and tuber  (4%) (Figs. 4 and  5). The  regular  use  of roots  and  leaves in antivenin  preparations is a characteristic feature of trad- itional antivenin  therapy [17, 81, 86, 99, 100], no wonder some  of  these  plants  are  named  “snakeroot”  in  some rural    communities    [101].   Comparatively,    embryonal plant  parts such as fruits, seeds, buds, bulbs, and flowers which  have  reputation  for  accumulating   certain   com- pounds are less frequently used, concordant with reports from  other  countries  [17, 81]. Majority  of the  plants  re- ported grow in the  wild (82%), 14% are cultivated  while

4% are semi-wild (occurs  in the wild but can also be cul- tivated).  The  commonest mode  of preparation is  as de- coctions   and  infusion.  The  plants   are  collected   from fallow  land,   cultivated   fields  or   home  gardens   when needed. Traditional medicine  practitioners either  collect herbal  plants personally or hire collectors.  All traditional medical practitioners cultivate some medicinal  plants es- pecially   fast   growing   ones   around   their   homes   and shrines  in  order  to  have  them  within  easy access  when needed.  The  antidotes  are  administered orally (67%) or applied at the point of snakebite  (17%).

In  this  survey, it was noted  that  few plant  species  are used against  snakebites  simultaneously  in  different  dis- tricts. This could probably  be attributed to the abundant distribution of the  analog active  substances  among  spe- cies  especially  those  of  family  Fabaceae.  Some  of  the plants listed are also used for wading off or discouraging  snakes  from  reaching  human   and  livestock  abodes.  In most  instances,  the  plants  possess  a  strong  smell  that causes  discomfort   and  disorientation  to  snakes  when they  slither   over  them.  In  exceptional   cases   as  with

tobacco, the plant (dried whole plant or leaves) are burnt to   produce   unpleasant  odor   that   discourages   snakes (Table  2). The  Lango of Northern  Uganda  burn  bicycle, motorcycle, and vehicle tyres to discourage  snakes.

 

Other  ethnomedicinal uses  and  toxicity of the reported antivenin plants

Almost  all  the  plants  recapitulated   in  this  review  are

employed  for the treatment  of various  ailments.  For  ex- ample, Bidens pilosa L. has been reported  to be useful in the treatment of more than 40 disorders including inflam- mation,  immunological  disorders,  digestive disorders,  in- fectious    diseases,   cancer,    metabolic    syndrome,    and wounds among others [103–106]. Albizia coriaria  (Welw. ex) Oliver  is used  in the  management   of syphilis, post- partum  haemorrhage,  sore  throats,  menorrhagia,  threat- ened  abortion,  skin  diseases, jaundice,  cough,  sore  eyes, and as a general tonic [35]. Such plants tend to be used in different communities for treating snakebites and can be a justification of their pharmacological efficacy [107].

On  the other  hand,  some of the antivenin  plants cited exhibit  marked  toxicity.  A striking  example  is  Jatropha carcus L. leaf and latex which contain  a purgative oil (ir- ritant  curcanoleic  acid and  croton  oil), curcin  (toxalbu- min),   and  diterpene   of   tigliane  skeleton   classified  as phorbol   esters   [108].   Curcin   has   protein   translation inhibitory (N-glycosidase) activity whereas phorbol  esters are  amphiphillic molecules that can bind phospholipid membrane  receptors   [109].  This   observation   explains why some  antivenin  preparations in Uganda  are applied topically  or   ingested   in  small   amounts.   Fortuitously, topical application  is a better  approach  for  reducing  the local action of venoms at the bitten site.

 

 

 

35

 

 

30

 

 

25

 

 

20

 

 

15

 

 

10

 

 

5

 

 

 

0

Shrub

Tree

Herb

Climber

Liana

Grass

 

Growth habit

Fig. 4 Growth habit of the antivenin plants used in rural communities of Uganda

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fig. 5 Parts of antivenin plants used in rural communities of Uganda

 

 

 

Knowledge dynamics of antivenin plants in Uganda Knowledge  of traditional  medicine  and  medicinal  plants are usually acquired  and passed on orally from the elders to  the  young  [34]. This  is comparable   to  reports  from other  African  countries   [17,  78].  Knowledge  is  gained through  trainings,  divine call, and in some instances,  the plant to be used can be asked for from the dead [42, 59]. Because  of   civilization,   efforts  to  pass  on   traditional  medical  knowledge  to  children   is  impeded   by  lack  of interest  and   the   fact  that  most   children   spend   their youthful  years  in  school  [17,  34,  60].  Most  Ugandans know  that  their  current social  conditions  such  as pov- erty, sleeping in mud  houses  and activities such as culti- vation,   hunting,    and    herding    cattle    increase    their chances  of getting  bitten  by a snake.  Snakebites  are  al- ways  taken   as  exigencies  with  economic   implications  due to the expenses involved in transporting the victims for   treatment,  the   care   needed,   enforced   borrowing,

amputation  of necrosed  legs, and arms  as well as loss of time [8].

 

Treatment of snakebites

Treatment of snakebites  in Uganda involves various pro- cedures  that  vary from culture  to culture  and religion to religion,  for  example,  Pentecostal   Assemblies  of  God (PAG) believe prayers  can treat  snakebites.  Use of tour- niquets  to tie the injured  part above the affected area to prevent  the  venom  from  spreading  to  heart,  the  lungs, kidney,  and  other  delicate  parts  of  the  body  has  been prescribed  as a  supportive  first aid in Northern Uganda [6]. This is usually done at five-minute  intervals to avoid the weakening of the local tissues.

Among   the   Baganda  (Central   Uganda),   the   use   of black  stones  (carbonized  absorptive  animal  bone)  and Haemanthus multiflorus bulb have been reported (Fig. 6) [10]. A black stone  is placed  on  incisions  made  around

 

 

Table 2 Plants used in Ugandan rural communities for repelling of snakes

 

Family                 Botanical name

Growth habit

Part used       Mode of use to prevent snakes                                                                        References

 

Amaryllidaceae  Allium cepa L     Herb         Bulb                Decoction made and sprinkled around the house. Snakes are discouraged by the sharp onion smell.

[10]

 

 

Amaryllidaceae  Allium sativum L.

 

Asteraceae              Tagetes minuta

Herb       Bulb              Decoction made and sprinkled around the house. Snakes do not are discouraged by the sharp onion smell.

 

Herb       Leaves          Plants have bitter tastes and strong smells that cause discomfort and disorientation to snakes when they slither over them.

[10]

 

[10]

 

 

Euphorbiaceae   Ricinus communis

Herb       Leaves/

whole plant

Plant have strong smell that cause discomfort and disorientation to snakes when they slither over them.

[10]

 

 

Poaceae           Cymbopogon citrus

Grass      Leaves          Decoction made and sprinkled around the house. Snakes do not like the citrus smell from the leaves

[10]

 

 

Solanaceae       Nicotiana tabacum L.

Shrub     Leaves          Planted around the house, leaves burnt                                                        [10, 102]

 

 

 

 

 

 

Fig. 6. Treatment of snake bites in Uganda. a 500 Uganda shillings copper coin. Side displayed is usually placed on the bite. b Haemanthus multiflorus bulb. c black stone

 

 

 

the  bitten  area until  it sticks. It is administered to  reas- sured  victims  and left for 20-30 minutes  for it  to “suck out” the poison.  The  stone is reported  to be 30% effect- ive and can be reused if boiled in hot water after use and can be used alongside other medical treatments [10]. For Haemanthus multiflorus,  the  bulb  is chewed  by the  vic- tim or it is crushed and put on the bite.

In  Northern  Uganda,  the  use  of 500 Uganda  shilling copper  coins  and  black  stones  have  been  reported  [6]. The  copper  coins  are  placed  on  the  bite until  it  gets stuck  and  it is left to fall off on  its  own. In some com- munities  like Lango of Northern Uganda, antivenin  ther- apy involves oral administration of egg yolk and albumin similar to the therapy  reported  among the Luo of Kenya [17]. Overall, traditional  antivenin  therapy  in Uganda in- volves administration  of  plant  preparations to  the  vic- tims [35].

 

Antivenin  activity of plants and  pharmacological evidence Pharmacological  studies  have revealed  that  some  plants used in  traditional  medicine  are  able  to  antagonize  the activity  of  various   crude   venoms  and  purified   toxins [110–112].  Antigen-antibody  interaction is the proposed mechanism   through   which  the   activity  of  venoms   is countered    by    antivenins.    Reported    mechanisms    of venom  inactivation  include  precipitation or  inactivation of  the toxic  venom  proteins  [113], inactivation,  or  en- zyme  inhibition  [114],  chelation  [115],  adjuvant  action [116], antioxidant  activity or a synergistic  interaction of these  mechanisms.  Enzyme  inhibition  and  protein  pre- cipitation   are  by  far  the  most  conventionally   accepted mechanisms  [117]. To start with, plant  metabolites  such as flavonoids, polyphenols, saponins,  tannins,  terpenoids, xanthenes, quinonoids,  steroids, and alkaloids have been reported   to  snuggly  bind   to  toxic   proteins   of  snake venoms,  thereby  offsetting  their  deleterious  effects.  An- other  explained  scientific  possibility  is  the  competitive blocking of the target receptors  [118]. For example, atro- pine  (an  alkaloid  reported   in  family  Solanaceae)  is re- ported to  inhibit  the  activity of  green  and  dark  mamba

(Drendroaspis  angusticeps  and D. polylepsis) venoms  by blocking cholinergic  nerve terminals  usually  attacked  by the venoms. Aristolochic acid I (8-methoxy-6-nitro-phe- nanthro(3,4-d)1,3-dioxole  5-carboxylic  acid), an  alkaloid present  in Aristolochia species acts in the same way.

Another  mechanism  of snake  venom  inactivation  in- volves inhibition of the active enzymes such as phospho- lipase   A2,   metalloproteases,  and    hyaluronidases    by polyphenolic  compounds such  as  tannins.   In  this  sce- nario,  the  metabolites  interact  with the  venom  enzymes by non-specific  binding proteins  [119] through hydrogen bonding  with  hydroxyl  groups  in the  protein  molecules generating  chemically  stable  complexes  [120].  For  ex- ample,  in a study  experimented with  aristolochic  acid I and  PLA2   isolated  from  Viper russelli venom, molecular interactions between  the  two  were  reported  to  be  be- tween their hydroxyl groups which formed  two hydrogen bonds  with  Granulocyte   Marker  Monoclonal Antibody (His48)  and  myotoxins  I  (Asp49)  of  the  venom  [121]. Aristolochic  acid  I is  also an  inhibitor  of hyaluronidase  of Naja  naja  venom [122]. Other  examples  of these are outlined  in  Table  3. Chelation  on  the  other  hand  is re- ported  to be  effective for  antivenin  plant  extracts  with molecules  (compounds)  capable  of  binding  to  divalent metal  ions  necessary  for some  enzymatic  activities.  For the cause that chemical coordination  of metal ions is in- dispensable  for normal  hydrolytic activities of phospholi- pases    and    metalloproteases,    secondary    metabolites capable  of disrupting  the enzyme-metal ion bondage  in- hibits   enzymatic   progression    [166].   In   antioxidation  mechanism,   plant  metabolites   (flavonoids,   terpenoids, tannins,  polyphenols,   vitamins  A,  C,  E,  and  minerals such   as  selenium)   prevent,   stop   or   reduce   oxidative damage  due  to  phospholipase  A2    activity  by  selectively binding  to  the  active  sites  or  modifying  the  conserved residues  that  are  inevitable  for  phospholipase  A2    cata- lytic action [119].

The   efficacy  of  plant   extracts   in  antivenom   action tends  to be related  to the solvent used for the extraction of the bioactive compounds. A study [152] reported  that

 

 

 

 

 

Table 3 Antivenin activities of some plants used for snakebite treatment in Uganda as per global reports

 

Plant               Part used    Solvent used

Antivenin activity (comments)                               Active chemical constituents                               Authors

 

Allium cepa L.     Bulb            Methanol    Cardioprotective activity (14.8 ± 1.65 units/l; p >

0.5) on creatine kinase isoenzyme levels to neutralize snake venoms. Concentrations (< 160

μg/ml) stabilized human red blood corpuscles membrane (antihemolytic) against N. naja karachiensis venom, though elevated

concentrations were cytotoxic. Provided 50%

protection from N. naja karachiensis phospholipase A (PLA2) in terms of an increase in pH of an egg yolk suspension. Neutralized the anticoagulant effect induced by weak PLA2 enzymes in N. naja karachiensis venom (76% inhibition, coagulation time of 106 ± 0.57 s). Quercetin is a potent inhibitor of lipoxygenase

Quercitin, sulfurous volatile oils, oleanolic acid, protocatechuric acid

[123–

127]

 

 

Allium sativum L.

Bulb         Methanol     Hepatoprotective activity (p > 0.5, 49 ± 5.01 and

82.5 ± 18.55 units/l of aspartate aminotransferase and alanine aminotransferase against 52.5 ± 3.51 and 69.5 ± 18.55 units/l for standard antiserum) assessed in rabbits. Provided 50% protection from

  1. naja karachiensis PLA2in terms of an increase in pH of an egg yolk suspension. Provided 50% protection from N. naja karachiensis PLA2  in terms of an increase in pH of an egg yolk suspension. Neutralized the anticoagulant effect

induced by weak phospholipase A enzymes in N. naja karachiensis venom (40% inhibition, coagulation time of 115 ± 1.52 s).

Quercetin, scordinines A, B allicin, thiosulfinates,

2 mercapto-L-cysteines, anthocyanins, alliinase, polysaccharides, sativin I, sativin II, glycosides of kaempferol

[123,

125,

126]

 

Asystasia spp (A. gangetica L)

Leaves     Methanol     1000 mg/kg provided 80% protection against N. melanoleuca venom (PLA2)

Flavonoids, saponins and tannins                        [128]

 

Aristolochia spp (A. indica,  A. odoratissima)

Leaves          Methanol, Ethanol, Water, pentane

PLA2    and hyaluronidase enzymes from N. naja and V. russelli  venoms inhibited. Strong gelatinolytic, collagenase, peroxidase, and nuclease activities, L-amino acid oxidase and protease inhibitory potencies. Protected mice against lethal effects of Bothrops atrox venom at higher doses of 8 and 16 mg/kg

Aristolochic acid I, lignan (-)-cubebin                           [129–

131]

 

 

Basella alba L.    Fruit             Methanol    Radical scavenging activity against 1,1-diphenyl 2- picrylhydroxyl (DHPP) experimented in mice.

Flavonoids, phenolics, betacyanins, Lupeol, β

sitosterol

[132–

134]

 

 

Capparis tomentosa Lam.

 

 

 

Carica papaya L.

Root         Water, petroleum ether

 

 

 

Leaves     Water, ethanol

The antioxidant activity by DPPH was 35.50 ±

0.02%, by phosphomolybdate assay was 41.22 ±

0.17 mg/kg ascorbic acid equivalent, and the reducing power increased with increase in

concentration up to a maximum at 800 μg/ml in alloxanized male mice (aqueous extracts).

 

Hepatoprotective against carbon tetrachloride induced hepatotoxicity in mice.

N-benzoylphenylalanylaninol acetate, 24- ethylcholestan-5-en-3-ol, L-stachydrine, 3- hydroxy-3-methyl-4-methoxyoxindole

 

 

 

Saponins, cardiac glycosides, alkaloids, phenolic acids, chlorogenic acid, flavonoids and coumarin compounds

[135,

136]

 

 

 

 

[137–

140]

 

 

Carissa spp (C. spinarum L.)

Leaves     Methanol     Acetylcholinesterase, PLA2, hyaluronidase, phosphomonoesterase, phosphodiesterase,5- nucleotidase enzymes from Bungarus caeruleus and V. russelli  venoms inhibited by 100 μg/ml of the extract.

Steroids, flavonoids, tannins, saponins, alkaloids, ursolic acid

[141,

142]

 

 

Cassia occidentalis L.

Leaves, roots

Ethanol       Stimulated angiogenesis, inhibited epidermal hyperplasia, and minimized local effects caused by Bootrops moojeni venom.

Anthraquinones                                              [143,

144]

 

Citrus spp. (C. limon L. Burm. F)

Root, ripe fruits

Methanol    Neutralized the anticoagulant effect induced by weak PLA2  enzymes in N. naja karachiensis venom (64% inhibition, coagulation time of 109

± 1.00 s). In vitro inhibitory ability against the lethal effect of Lachesis muta venom with effective dose 50% of 710 μg extract per mouse

d-x-pinene camphene, d-limonene, linalool, ichangin 4-β-glucopyranoside, nomilinic acid,

4-β-glucopyranoside

[126,

145,

146]

 

 

 

 

 

Table 3 Antivenin activities of some plants used for snakebite treatment in Uganda as per global reports (Continued)

 

Plant               Part used    Solvent used

Antivenin activity (comments)                               Active chemical constituents                               Authors

 

Cleome spp

(C. viscosa)

Bulb           Methanol, ethyl acetate

Significant anti-inflammatory activity against cara- geenin-, histamine-, dextran-induced rat paw edema compared to Diclofenac sodium (20 mg/ kg) standard

Flavonoid glycosides, querection 3-0-(2″-acetyl)- glucoside, phenolics

[147,

148]

 

Crinum spp

(C. jagus)

Bulb         Methanol     Extract of 1000 mg/kg protected 50% of mice; injection of a pre-incubated mixture of the same extract dose and venom gave 100% protection against E. ocellatus venom (10 mg/kg). Adminis- tration of extract at 250 mg/kg, 30 min before the injection of E. ocellatus venom (10 mg/kg) prolonged (p < 0.05) death time of poisoned

mice. Extract of 500 mg/kg provided 50% protec- tion against Betans venom (9.5 mg/kg) while pre- incubation of a mixture of the same dose of venom and extract prior to injection provided

33.3% protection. Plasma creatine kinase concen-

trations in poisoned mice reduced with injection

1000 mg/kg of extract pre-incubated with 5 mg/

kg of E. ocellatus or 7 mg/kg B. arietans venoms. The extract blocked hemorrhagic activity of a

standard hemorrhagic dose (2.8 mg/ml) of E. ocel-  latus venom at 1.7, 3.3, and 6.7 mg/ml.

Phenolic compounds, tannins, alkaloids, cardiac glycosides

[148,

149]

 

Indigofera

spp.

(I. capitata Kotschy, I. conferta

Gillett)

Leaves          Methanol, ethanol, water

Extracts reduced bleeding and clotting times of N. nigricollis  envenomed rats. Ethanol and aqueous extracts of I. capitata were more effective at dose of 300 mg/kg with lowest clotting time of 174 ± 3.67 s and 1000 mg/kg with lowest bleeding time of 228 ± 3.00  s. I. conferta at a dose of 1000 mg/kg had the lowest

clotting time of 173 ± 5.61 s (ethanol extract) and

234 ± 7.64 s for aqueous extract). Edema forming activity was inhibited by ethanol and aqueous

extracts, effective at higher doses of 300 mg/kg (ethanol extract) and 1000 mg/kg (aqueous extract) with the lowest edema forming activity

of 108.80 ± 1.90 and 102.00 ± 1.90 (%mm)

respectively by I. capitata and at dose of 250 mg/ kg, 500 mg/kg, and 1000 mg/kg of aqueous extract with the lowest edema forming activities

of 100.8 ± 1.89, 100.20 ± 1.90 and 100.60 ± 1.90

(%mm) by I. conferta

Flavonoids, phenolic compounds, steroids, triterpenes, anthraquinone, alkaloids

[150]

 

(I. pulchra

Willd.)

Methanol                     Extract inhibited anticoagulant, hemolytic and

PLA2    activities of N. nigricollis  venom

Tannins, flavonoids, saponins, and steroids                  [148,

151]

 

Jatropa carcus L.

Leaf latex   Methanol    Inhibits hemolytic activity of PLA2  from N. naja

venom

Terpenoids, alkaloids, phenolics, flavonoids, saponins

[152]

 

Vernonia cinerea (L) Less.

 

Sansevieria

spp

(S. liberica

ger. and labr)

Whole plant

 

 

Rhizome, root

Methanol    Antioxidant activity by DPPH free radical scavenging assay. Ethyl acetate fraction exhibited

63.3% DPPH radical scavenging activity at 100

μg/ml.

 

Methanol    LD50  of 353.5 ug/kg. The extract, n-hexane, ethyl acetate, and butanol fractions significantly pro- tected mice from N. naja nigricollis venom- induced mortality

Phenolics, flavonoids                                           [153]

 

 

 

Terpenoids, flavonoids, saponins                               [154]

 

Albizia spp (A. lebbeck L. (Benth) bark)

Root/bark  Water         1000 mg/kg, N. kauothia venom, provided 50% protection from N. naja karachiensis PLA2  in terms of an increase in pH of an egg yolk suspension

Carbohydrates, proteins, alkaloids, flavonoids, tannins, echinocystic acid, amino acids

[109,

123,

125,

154]

 

 

Euphorbia species (E. hirta)

Whole plant

Methanol    LD50  not specified, against N. naja) venom                Quercetin-3-O-alpha-rhamnoside, terpenoids, alkaloids, steroids, tannins, flavonoids, phenolic compounds

[155,

156]

 

Bidens pilosa

L.

Leaves, whole

water, hexane

Effective against Dendroaspis jamesoni and Echis ocellatus  venom

Linalool, Cadinene,            -Caryophyllene,          – Cubebene, Cedrene, Humulene, Selina-3,7(11)-

[157,

158]

 

 

 

 

 

Table 3 Antivenin activities of some plants used for snakebite treatment in Uganda as per global reports (Continued)

 

Plant               Part used    Solvent used

Antivenin activity (comments)                               Active chemical constituents                               Authors

 

part                                                                                                        diene, Thujopsene, (−)-Globulol, Elixene, 2- Hexen-1-ol, 2-Hexenal

 

 

Hoslundia opposita Vahl

Root, leaves

Methanol, Water

DPPH radical scavenging activity of 32.3 ± 1.9 μg/ ml compared to standard L-ascorbic acid with the activity of 21.1 ± 1.1 μg/ml.

-Cadinol  Ethyl linolenate, Palmitic acid                      [158,

159]

 

 

Maytensus senegalensis

Root           Methanol, chloroform

Anti-inflammatory activity inhibited ear edema induced by croton oil in mice

Maytenoic acid, lupenone, β−amyrin              [160]

 

 

Securinega virosa

Leaves     Hexane, ethyl acetate, methanol

N-hexane extract provided protection against lethal dose of Naja nigricollis venom (significant at 20 mg/kg, p < 0.05)

Alkaloids, phenols, saponins and triterpenes/

steroids

[161,

162]

 

 

Solanum incanum L.

Root         Water          Inhibited the response to acetylcholine in a concentration-dependent manner like atropine. The extract inhibited charcoal travel in mice intestine by

36.28, 51.45, 52.93, and 38.53% in doses of 50, 100,

200, and 400 mg/kg body weight respectively

Quercetin, Isoquercitrin, Kaempferol, β- Sitosterol, Luteolin 7-O-b-D-glucopyranoside, sodium, potassium, chromium, vitamins B and C

[162–

165]

 

 

 

methanolic  extracts  of Jatropa  curcas  L. were  more  ef- fective  than  the  aqueous   and  chloroform  fractions  in inhibiting phospholipase A2   activity. The  authors  attrib- uted  this  to the  possible  presence  of  divalent  ions  (Cal- cium   (II),  Strontium  (II),  and   Barium   (II)  ions)   or quercetin-like  compounds  which  are  reported  to  aug- ment  the activity of phospholipase A2   through induction of conformational  changes  in its substrate-binding sites [167,  168].  Table  3  summarizes   some  of  the  solvents employed by studies done on antivenom  activity of some plants  reported  in  this  survey.  It  is  worth  noting  that methanol  appears  to  be  the  solvent  of choice  probably because  of  its  ability  to  dissolve  both  polar  and  non- polar compounds [169, 170].

Testing   for  the  efficacy  of  plants   as  antivenins  has been perfected  using mice as the test specimens. Experi- mentally, the  extracts  are  tested  against  the  lethal  dose of the  venom  that  causes  death  of 50%  of  the  subjects (LD50). Tests  are done  either  in vivo  or in vitro on spe- cific toxic activities of venoms.  So  far, the inhibitory  ac- tivity    of    most    extracts    has    been    tested    against phospholipase A2, one of the toxic constituents  of snake venoms  [111].

 

Conclusions and recommendations

Uganda  has over 125 districts  hence less than  1% of the country  have been surveyed for antivenin  plants. The in- ventory   of  plants   utilized   by  Ugandan   communities present  considerable  potential  for the treatment of snake envenomation. The  present  review  therefore  opens  the lead for isolation  and  elucidation of the  chemical  struc- tures  of  the  antivenom   compounds  from  the  claimed plants that could be harnessed  in combined  therapy with commercial  antiserum.  There  is a need for concerted ef- forts  by  scholars,  traditional   healers,  local  authorities, and  the  state  to  address  the  ongoing  African  snakebite

 

crisis and meet World  Health  Organizations’ great inter- est in documenting the various medicinal  plants utilized by different tribes worldwide.

 

Supplementary information

Supplementary information accompanies this paper at https://doi.org/10.

1186/s41182-019-0187-0.

 

Additional file 1. Family, local name, botanical name, growth habit, conservation status, part used, method of preparation and route of administration of antivenin plants used in different districts of Uganda.

 

 

Abbreviations

DPPH: 1,1- diphenyl 2-picrylhydroxyl;  DPPH-1,1: Diphenyl 2-picrylhydroxyl; LD50: Median lethal dose; N. naja: Naja naja; PLA2: Phospholipase A;

spp: Species; V. russelli: Viper russelli

 

Acknowledgements

TO,  KMK, and OB are grateful to the World Bank and the Inter-University Council of East Africa (IUCEA) for the scholarship awarded to them through the Africa Centre of Excellence II in Phytochemicals,  Textiles and Renewable Energy  (ACE II PTRE)  at Moi University, Kenya, that prompted this ethnomedi- cal communication. The authors commend preceding authors for their fruit- ful quest for knowledge on medicinal plants utilized by rural communities of Uganda.

 

Authors’ contributions

TO,  SK, and OB designed the study. AO, TO, SS, and KMK performed the literature search. TO, AO, TO, KMK, and OB analyzed the collected data. TO, SK, TO, SS, and OB verified the plant names in botanical databases, Lusoga, Lango, Luganda, and Acholi, respectively. TO, SK, AO, TO, and OB wrote the first draft of the manuscript. All authors revised and approved the final manuscript.

 

Funding

This research received no external funding.

 

Availability of data  and materials

This is a review article and no raw experimental data was collected. All data generated or analyzed during this study are included in this published article.

 

Ethics approval and consent to participate

Not applicable

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