Plant Natural Products for the Control of Aedes Aegypti: the Main Vector of Important Arboviruses
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molecules Review Plant Natural Products for the Control of Aedes aegypti: The Main Vector of Important Arboviruses Maíra Rosato Silveiral Silvério 1 , Laila Salmen Espindola 2 , Norberto Peporine Lopes 1,* and Paulo Cézar Vieira 1,* 1 NPPNS, Departamento de Ciências BioMoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto 14040-903, São Paulo, Brazil; [email protected] 2 Laboratório de Farmacognosia, Universidade de Brasília, Brasília 70910-900, Brazil; [email protected] * Correspondence: [email protected] (N.P.L.); [email protected] (P.C.V.); Tel.: +55-16-3315-4707 (N.P.L.); +55-16-3315-4248 (P.C.V.) Academic Editor: Roberto Fabiani Received: 29 June 2020; Accepted: 28 July 2020; Published: 31 July 2020 Abstract: The mosquito species Aedes aegypti is one of the main vectors of arboviruses, including dengue, Zika and chikungunya. Considering the deficiency or absence of vaccines to prevent these diseases, vector control remains an important strategy. The use of plant natural product-based insecticides constitutes an alternative to chemical insecticides as they are degraded more easily and are less harmful to the environment, not to mention their lower toxicity to non-target insects. This review details plant species and their secondary metabolites that have demonstrated insecticidal properties (ovicidal, larvicidal, pupicidal, adulticidal, repellent and ovipositional effects) against the mosquito, together with their mechanisms of action. In particular, essential oils and some of their chemical constituents such as terpenoids and phenylpropanoids offer distinct advantages. Thiophenes, amides and alkaloids also possess high larvicidal and adulticidal activities, adding to the wealth of plant natural products with potential in vector control applications. Keywords: Aedes aegypti; dengue; natural products; botanical species; essential oils; terpenes; phenylpropanoids; thiophenes; alkaloids; mechanisms of action 1. Introduction The mosquito Aedes aegypti (Diptera: Culicidae) originated in Egypt and it is widely distributed in tropical and subtropical regions, including North America and Europe [1,2]. Ae. aegypti presents complete metamorphosis from immature egg, larva and pupa stages to the adult mosquito itself (Figure1). The life cycle varies according to environmental temperature, food availability and quantity of larvae in the same breeding site. Under favorable conditions, after egg hatching, the mosquito transforms into the adult stage within 10 days, even though the eggs can be viable up to 450 days in the absence of water [3]. The female mosquito requires hematophagy for egg maturation. Viral transmission to humans occurs during this process if the mosquito is infected. The lifetime of a female mosquito is approximately 45 days [1]. Ae. aegypti population control is considered the principal measure to combat arboviral diseases as this species is the primary vector of dengue, Zika, chikungunya and urban yellow fever [4,5]. In 2012, dengue was considered the mosquito-borne disease of major importance in the world [5]. According to the World Health Organization, 390 million people are infected annually with the dengue virus, 96 million of which have clinical manifestations [6]. There are various symptoms, the first is usually high fever (39–40 ◦C) with headache, prostration, arthralgia, anorexia, asthenia, nausea, among others. Some clinical aspects often depend on patient age. There is no specific treatment for dengue and the more complicated cases of the disease can cause hemorrhage, shock and even death [7]. Molecules 2020, 25, 3484; doi:10.3390/molecules25153484 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 45 nausea, among others. Some clinical aspects often depend on patient age. There is no specific treatment for dengue and the more complicated cases of the disease can cause hemorrhage, shock andMolecules even2020 death, 25, 3484[7]. 2 of 42 Figure 1. Aedes aegypti life cycle and the main arboviruses transmited by the female mosquito. Figure 1. Aedes aegypti life cycle and the main arboviruses transmited by the female mosquito. Ae. aegypti is considered the main Zika virus vector (Figure1), but infection can also occur by sexualAe. transmissionaegypti is considered or blood transfusionthe main Zika [8]. virus Symptoms vector are (Figure non-specific 1), but andinfection self-limited, can also being occur easily by sexualconfused transmission with other or arboviral blood transf diseases.usion [8]. Some Symptoms important are complicationsnon-specific and exist, self-limited, such as microcephaly being easily confusedin fetuses with and other Guillan arboviral Barré diseases.syndrome. Some The import virusant has complications been reported exist, in such countries as microcephaly in Americas, in fetusesEurope, and Asia Guillan and the Barré Pacific syndrome. region [8 The]. Like virus dengue has be anden reported Zika, chikungunya in countries has in no Americas, specific treatment. Europe, AsiaThe diseaseand the emergedPacific region in the [8]. Americas Like dengue in 2013, and with Zika, about chikungunya 1.7 million has cases no identified specific treatment. and 252 deaths The diseasereported emerged by August in the 2015 Americas [9]. in 2013, with about 1.7 million cases identified and 252 deaths reportedIn 2013, by August dengue 2015 generated [9]. a global cost of US $8.9 billion, with around 58.4 million symptomatic casesIn (13.5 2013, million dengue fatalities) generated in a the global 141 countriescost of US and$8.9 territories.billion, with The around per capita 58.4 million costs of symptomatic dengue were cases$70.1 (13.5 for hospital million treatment,fatalities) in $51.1 the 141 for outpatientcountries and treatment territories. and The $12.9 per for capita cases costs that didof dengue not reach were the $70.1health for system. hospital According treatment, to $51.1 this study, for outpatient Brazil had treatment an incidence and of$12.9 751 tofor 1,000 cases cases that perdid 100,000not reach people. the healthThe expenses system. wereAccording proportional to this to study, the incidence Brazil had and an ranged incidence from $2.5of 751 to $5to for1,000 each cases treated per case100,000 [10]. people.A The more expenses recent study were showed proportional that in to 2016 the inci thedence Brazilian and government ranged from spent $2.5 aroundto $5 for R each $805 treated million case(ca. [10]. 160 million US$) to treat diseases caused by the Ae. aegypti mosquito, including direct medical expensesA more and recent indirect study costs. showed In addition,that in 2016 about the Brazilian R $1.5 billion government were destined spent around to combat R $805 the million vector, (ca.totaling 160 million R $2.3 billion,US$) to thattreat was diseases 2% of caused the health by the budget Ae. aegypti for that mosquito, year. More including than 2 milliondirect medical cases of expensesAe. aegypti andrelated indirect diseases costs. were In addition, verified. Theseabout numbersR $1.5 billion were underestimatedwere destined to as theycombat did the not vector, include totalingcomplications R $2.3 billion, such as that microcephaly was 2% of andthe health Guillain-Barr budget éforsyndrome that year. [11 More]. than 2 million cases of Ae. aegyptiA related study estimateddiseases were that verified. about 60% These of thenumbers world were population underestimated will be at as risk they of did dengue not include in 2080, complicationswhich represents such over as microcephaly 6.1 (4.7–6.9) and billion Guillain-Barré people [12]. syndrome Considering [11]. that vector control is the main toolA for study controlling estimated these that expensive about 60% arboviruses, of the world investment population in techniques will be at torisk combat of dengue the Ae. in aegypti2080, whichmosquito represents is growing over [6.13]. (4.7–6.9) Investments billion are people particularly [12]. Considering focused on that techniques vector control with minimal is the main negative tool forimpacts controlling on non-target these expensive animals and arboviruses, the environment investment [4,13 ].in techniques to combat the Ae. aegypti mosquito is growing [3]. Investments are particularly focused on techniques with minimal negative impacts2. Mosquito on non-target Control animals and the environment [4,13]. There are several techniques already used to combat mosquitoes, which act both in the immature 2.phases Mosquito (egg, Control larva and pupa) and in the adult [13]. Highly toxic synthetic insecticides such as organophosphates,There are several pyrethroids techniques andalready carbamates used to comb haveat been mosquitoes, historically which used act to both combat in the the immature mosquito, phasesacting mainly(egg, larva on insect and larvaepupa) [ 4and]. More in the recently, adult insecticides [13]. Highly with toxic less toxicitysynthetic which insecticides are less persistentsuch as organophosphates,in the environment pyrethroids have been developed,and carbamates including have been neonicotinoids historically and used oxadiazines to combat [the14]. mosquito, However, these products are still widely used and harmful to living organisms and the environment, and the use of foogers and aerial applications of sintetic insecticides against adults, such as pyrethroids Molecules 2020, 25, 3484 3 of 42 products, contributes to insect resistance problems [4]. Therefore, efforts must be made to ensure newly developed alternative