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Bee Venom: Overview of Main Compounds and Bioactivities for Therapeutic Interests

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Bee Venom: Overview of Main Compounds and Bioactivities for Therapeutic Interests molecules Review Bee Venom: Overview of Main Compounds and Bioactivities for Therapeutic Interests 1, 1,2, 3,4 5 Rim Wehbe y , Jacinthe Frangieh y, Mohamad Rima , Dany El Obeid , Jean-Marc Sabatier 6 and Ziad Fajloun 1,7,* 1 Laboratory of Applied Biotechnology (LBA3B), Azm Center for Research in Biotechnology and its Applications, EDST, Lebanese University, Tripoli 1300, Lebanon 2 Mitochondrial and Cardiovascular Pathophysiology—MITOVASC, Team 2, Cardiovascular Mechanotransduction, UMR CNRS 6015, INSERM U1083, Angers University, 49045 Angers, France 3 Department of Neuroscience, Institut de Biologie Paris Seine (IBPS), INSERM, CNRS, Sorbonne Université, F-75005 Paris, France 4 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS U7104, Université de Strasbourg, 67400 Illkirch, France 5 Faculty of Agriculture & Veterinary Sciences, Lebanese University, Dekwaneh, Beirut 2832, Lebanon 6 Institute of NeuroPhysiopathology, UMR 7051, Faculté de Médecine Secteur Nord, 51, Boulevard Pierre Dramard-CS80011, 13344-Marseille Cedex 15, France 7 Faculty of Sciences 3, Michel Slayman Tripoli Campus, Lebanese University, Ras Maska 1352, Lebanon * Correspondence: [email protected]; Tel.: +961-6-21-3255 These authors contributed equally to this work. y Received: 24 July 2019; Accepted: 16 August 2019; Published: 19 August 2019 Abstract: Apitherapy is an alternate therapy that relies on the usage of honeybee products, most importantly bee venom for the treatment of many human diseases. The venom can be introduced into the human body by manual injection or by direct bee stings. Bee venom contains several active molecules such as peptides and enzymes that have advantageous potential in treating inflammation and central nervous system diseases, such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. Moreover, bee venom has shown promising benefits against different types of cancer as well as anti-viral activity, even against the challenging human immunodeficiency virus (HIV). Many studies described biological activities of bee venom components and launched preclinical trials to improve the potential use of apitoxin and its constituents as the next generation of drugs. The aim of this review is to summarize the main compounds of bee venom, their primary biological properties, mechanisms of action, and their therapeutic values in alternative therapy strategies. Keywords: bee venom; apitoxin; apitherapy; Parkinson’s disease; Alzheimer’s disease; amyotrophic lateral sclerosis; cancer; HIV 1. Generalities about Honeybees Among honeybees, Apis mellifera (Figure1) is the main species used for crop pollination in the world [1]. The usage of all bee products, including bee venom and honey, dates back thousands of years as their medicinal properties were cited in religious books like the Bible and the Quran [2–4]. Apitherapy is a branch of alternative medicine that relies on the usage of honeybee products that consists of honey, pollen, propolis, royal jelly, and mainly bee venom (BV), which is also known as apitoxin [5,6]. Molecules 2019, 24, 2997; doi:10.3390/molecules24162997 www.mdpi.com/journal/molecules Molecules 2019, 24, 2997 2 of 13 MoleculesMolecules 2019 2019, 24, 24, x, x FOR FOR PEER PEER REVIEW REVIEW 2 2of of 12 12 FigureFigure 1. 1. ApisApis Apis mellifera mellifera (copyright(copyright (copyright Dany Dany Dany El El Obeid) Obeid). Obeid). BeeBee venomvenom venom therapytherapy therapy (BVT) (BVT) (BVT) is is theis the the medicinal medicinal medicinal application application application of BVof of BV fromBV from from honeybees honeybees honeybees into theinto into human the the human human body bodyforbody the for for treatment the the treatment treatment of some of of some some diseases, dise diseases, suchases, such assuch rheumatism as as rheumatism rheumatism arthritis arthritis arthritis [7]. [7]. This[7]. This This strategy strategy strategy has has has been been been used used used in inalternativein alternativealternative medicine medicinemedicine for more forfor thanmoremore 5000 thanthan years. 50005000 It years. consistsyears. ItIt of consistsconsists either indirect ofof eithereither application, indirectindirect by application,application, extracting BVbyby withextractingextracting an electric BV BV with with stimulus an an electric electric followed stimulus stimulus by its followed followed injection by by into its its theinjection injection body into or into directly the the body body via or beeor directly directly stings via [via8] bee (Figure bee stings stings2). [8]The[8] (Figure (Figure idea of 2). using2). The The BVidea idea in of of the using using medicinal BV BV in in the fieldthe medicinal medicinal was raised field field from was was the raised raised belief from from that the beekeepersthe belief belief that that hardly beekeepers beekeepers suffer hardlyfromhardly rheumatism suffer suffer from from or rheumatism rheumatism joints problems. or or joints joints problems. problems. FigureFigure 2. 2. ApplicationApplication Application of ofof bee beebee venom venomvenom by byby direct directdirect bee bee stings stings into into the the body. body. BV is produced by female worker bees and is known to contain many active components including: BVBV isis producedproduced byby femalefemale workerworker beesbees andand isis knownknown toto containcontain manymany activeactive componentscomponents (i) peptides like melittin, apamin, mast cell degranulating (MCD) peptide, and adolapin, (ii) enzymes, including:including: (i) (i) peptides peptides like like melittin, melittin, apamin, apamin, mast mast cell cell degranulating degranulating (MCD) (MCD) peptide, peptide, and and adolapin, adolapin, such as phospholipase A2 (PLA2) and hyaluronidase, and (iii) amino acids and volatile compounds. (ii)(ii) enzymes, enzymes, such such as as phospholipase phospholipase A2 A2 (PLA2) (PLA2) and and hyaluronidase, hyaluronidase, and and (iii) (iii) amino amino acids acids and and volatile volatile Several studies assessed the therapeutic potential of these components in treating human inflammatory compounds.compounds. SeveralSeveral studiesstudies assessedassessed thethe therapeutitherapeuticc potentialpotential ofof thesethese componentscomponents inin treatingtreating diseases as well as central nervous system diseases, such as Parkinson’s disease (PD), Alzheimer’s humanhuman inflammatory inflammatory diseases diseases as as we wellll as as central central nervous nervous system system diseases, diseases, such such as as Parkinson’s Parkinson’s disease disease disease (AD), and amyotrophic lateral sclerosis (ALS), as well as many other conditions [9,10]. (PD),(PD), Alzheimer’sAlzheimer’s diseasedisease (AD),(AD), andand amyotrophicamyotrophic laterallateral sclerosissclerosis (ALS),(ALS), asas wellwell asas manymany otherother Interestingly, bee venom, in similarity to other animal venoms, has also shown beneficial anti-cancer conditionsconditions [9,10]. [9,10]. Interestingly, Interestingly, bee bee venom, venom, in in si similaritymilarity to to other other animal animal venoms, venoms, has has also also shown shown and anti-viral potential against ovarian and prostate cancer, as well as HIV [11–14]. beneficialbeneficial anti-cancer anti-cancer and and anti-viral anti-viral potential potential agains against tovarian ovarian and and prostate prostate cancer, cancer, as as well well as as HIV HIV [11– [11– Bee venom is characterized by inducing allergic reactions following the sting. These reactions 14].14]. can take place in the skin, the respiratory track, the cardiovascular system, and the gastrointestinal BeeBee venom venom is is characterized characterized by by inducing inducing allergic allergic reactions reactions following following the the sting. sting. These These reactions reactions system. Subsequently, severe anaphylactic shock could lead to cerebral or myocardial ischemia [15,16]. cancan take take place place in in the the skin, skin, the the respiratory respiratory track, track, the the cardiovascular cardiovascular system, system, and and the the gastrointestinal gastrointestinal These allergic responses are due to the presence, within the venom, of multiple protein allergens, most system.system. Subsequently,Subsequently, severesevere anaphylacticanaphylactic shockshock cocoulduld leadlead toto cerebralcerebral oror myocardialmyocardial ischemiaischemia of which possess an enzymatic activity [9]. The major BV allergens and specific Immunoglobulin E [15,16].[15,16]. TheseThese allergicallergic responsesresponses areare duedue toto thethe presence,presence, withinwithin thethe venom,venom, ofof multiplemultiple proteinprotein (IgE) inducers are PLA2, melittin, and hyaluronidase. Apart from IgE-mediated mechanisms, studies allergens,allergens, mostmost ofof whichwhich possesspossess anan enzymaticenzymatic acactivitytivity [9].[9]. TheThe majormajor BVBV allergensallergens andand specificspecific suggest that allergens can also involve IgE-independent reactions, such as a bradykinin (BK) mediator, ImmunoglobulinImmunoglobulin E E (IgE) (IgE) inducers inducers are are PLA2, PLA2, melitti melittin,n, and and hyaluronidase. hyaluronidase. Apart Apart from from IgE-mediated IgE-mediated leading to various anaphylactic symptoms [17,18]. The production of this non-immune mediator can mechanisms,mechanisms, studies studies suggest suggest that that allergens allergens can can al alsoso involve involve IgE-independent IgE-independent reactions, reactions,
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