**7. The neem opportunity**

**5. Bluetongue spread in Europe**

228 Insecticides Resistance

channel from North Africa [36, 37].

and Balearics.

corruption.

**6. Natural products help**

2004 Detection of strain BTV-4 in Sicily and France.

further north than before.

5772 infection sites were detected.

**Table 2.** Chronology of blue tongue virus (BTV) spread in Europe

1969 First isolation in Greece of strain BTV-9 and BTV-1

from South Africa, Nigeria, Sudan, US.

isolated in India. First outbreak in Bulgaria.

Bluetongue is a devastating disease of ruminants, mostly restricted to certain breeds of sheep, particularly fine wool and mutton breeds common in Europe [35] (Table 2). Until 1998, bluetongue has made only sporadic incursions in Europe, until six strains of the blue‐ tongue virus (BTV), from the Middle East, were transferred to Europe, through two main pathways. One spread northward involving Greece and Balkans. The second one interested the North Africa, and from Tunisia/Algeria landed to Sardinia, Sicily, Corsica, and Balearic islands. Clearly, these pathways are coincident with the traditional livestock trade routes, such ruminant street. The same routes were used in the last years by human migrants to reach the Italian peninsula, i.e., across the Adriatic Sea from Albania and across the Sicily

1998 Isolation in Tunisia of the strain BTV-2, endemic of sub-Saharan Africa, and belonging to strains

2000–2001 Isolation in Greece and Turkey of the European strain BTV-1, similar to viruses that have been

2003 A new strain BTV-4 type, different from that of Greece and Turkey, is isolated in Corsica, Sardinia

2005–2014 Distinct strains are still entering in Europe, affecting at least 12 countries and more than 800 km

2014 In Sardinia, the BT disease caused the deaths of 13,000 sheep and damages for 42 million of euro.

Since its arrival, BTV has caused the deaths of more than one million sheep, and the loss of trade in animals and animal products, with an estimated damage of US\$125 million in the US alone [38]. Sardinia was in particular affected, being the economy largely based on sheep, producing very appreciated like cheese (pecorino) and fine wool. The widespread use of a vaccine, although effective, caused a series of problems for its distribution and episodes of

Natural products are mainly derived from plants as the result of coevolution between organisms and environment. For this reason, they are used for centuries in popular and traditional medicines, as well as often as spices and insecticides. Unlike modern pharmacology

The tree *Azadirachta indica* A. Juss (sin. *Melia azadirachta*) is commonly known as neem or nimba, margosa or Indian neem, Indian lilac, the last one to distinguish from the similar species *Melia azedaracht* L*.*, named Melia o Persian lilac (Fig. 3). Several exceptional terms were used to describe the importance and the value of neem, i.e., "the marvellous tree, the tree of XXI century, the divine tree, India's tree of life, Nature's drugstore, Panacea for all diseases, a tree for solving global problems" [40–45]. In 1989, WHO/UNEP considered the neem tree as one of the most promising tree of the 21st century. In 1992, the US National Academy of Sciences published a report having the significant title "Neem—A Tree for Solving Global Problems" [45]. The medicinal use of neem is strongly eradicated into the Indian tradition. All its parts are largely used for many illnesses, and in Indian rural areas, the plant is called "the village pharmacy." Neem is considered a natural exemplar insecticide. collaboration with the animals present in the same habitat. They may be tailored for a positive or negative influence in physiologic activities and basic metabolism. These argumentations are in favor of the potential use of natural products as insecticides.

Natural products tend to target proteins more essential and general to an organism than other groups

of small-molecule targets, like those related to disease genes. They therefore work as a nonspecific

basic defense against predators or pathogens acting on more highly connected proteins, interrupting

essential protein activity of the environmental competitor or invader. However, natural products are

not only defense and toxic substances. On the contrary, the story of plant evolution and the

**Figure 3.** The neem tree (*Azadirachta indica* A. Juss)

<H1>**The neem opportunity**

Fig. 3. The neem tree (*Azadirachta indica* A. Juss) The tree *Azadirachta indica* A. Juss (sin. *Melia azadirachta*) is commonly known as neem or nimba, margosa or Indian neem, Indian lilac, the last one to distinguish from the similar species *Melia azedaracht* L*.*, named Melia o Persian lilac (Fig. 3). Several exceptional terms were used to The neem tree pertains to the Meliaceae (Mahogany family). It is a fast-growing evergreen tree, native of Indian subcontinent and distributed in the Tropical and Subtropical areas. Neem [46– 48], owing to its ability of growing so easily and surviving on dry, nutrient-lean soil, is now cultivated in tropical and subtropical countries, including South Asia, West Africa, central (i.e. Cuba) and South America, and Australia. Flowering occurs from January to May. Flowers are fragrant, beautiful, and abundant. Fruits ripening from June through August are green ellipsoidal drupes containing one seed. A single mature tree may produce annually 5–8 kg of seeds.

describe the importance and the value of neem, i.e., "the marvellous tree, the tree of XXI century, the divine tree, India's tree of life, Nature's drugstore, Panacea for all diseases, a tree for solving global problems" [40–45]. In 1989, WHO/UNEP considered the neem tree as one of the most promising tree of the 21st century. In 1992, the US National Academy of Sciences published a The main product of neem is the oil obtained by expressing the kernels containing the seeds (Figs. 4 and 5). Neem seed oil (NSO) is obtained by different extraction methods. Most of the NSO is produced in India by familiar little producers using very simple machines, but many other countries are now producing NSOs. Therefore, considering also the possible different geographical origin of the raw material, combined pre- and postharvesting factors can result in great differences in constituents present in marketed NSOs, as already reported [49].

report having the significant title "Neem—A Tree for Solving Global Problems" [45]. The medicinal use of neem is strongly eradicated into the Indian tradition. All its parts are largely used for many illnesses, and in Indian rural areas, the plant is called "the village pharmacy." Neem is considered a natural exemplar insecticide. The chemistry of neem is very complicated and still far to be completed, despite the great number of dedicated researches. More than 300 compounds have been characterized from the seeds. One-third of them are nortriterpenoids, which means triterpenoid lacking some carbon atoms. Partial loss of lateral chain is combined by a complicated rearranging of the remaining part, giving rise to different polyclicic molecular skeletons full of oxygenated functional groups, partially acylated.

Emerging Insect-Borne Diseases of Agricultural, Medical and Veterinary Importance http://dx.doi.org/10.5772/61467 231

for solving global problems" [40–45]. In 1989, WHO/UNEP considered the neem tree as one of the most promising tree of the 21st century. In 1992, the US National Academy of Sciences published a report having the significant title "Neem—A Tree for Solving Global Problems" [45]. The medicinal use of neem is strongly eradicated into the Indian tradition. All its parts are largely used for many illnesses, and in Indian rural areas, the plant is called "the village

favor of the potential use of natural products as insecticides.

Natural products tend to target proteins more essential and general to an organism than other groups

of small-molecule targets, like those related to disease genes. They therefore work as a nonspecific

basic defense against predators or pathogens acting on more highly connected proteins, interrupting

essential protein activity of the environmental competitor or invader. However, natural products are

not only defense and toxic substances. On the contrary, the story of plant evolution and the

experience evidence the progressive production of positive substances produced in favor of a

collaboration with the animals present in the same habitat. They may be tailored for a positive or

negative influence in physiologic activities and basic metabolism. These argumentations are in

The tree *Azadirachta indica* A. Juss (sin. *Melia azadirachta*) is commonly known as neem or

nimba, margosa or Indian neem, Indian lilac, the last one to distinguish from the similar species

pharmacy." Neem is considered a natural exemplar insecticide.

Fig. 3. The neem tree (*Azadirachta indica* A. Juss)

The neem tree pertains to the Meliaceae (Mahogany family). It is a fast-growing evergreen tree, native of Indian subcontinent and distributed in the Tropical and Subtropical areas. Neem [46– 48], owing to its ability of growing so easily and surviving on dry, nutrient-lean soil, is now cultivated in tropical and subtropical countries, including South Asia, West Africa, central (i.e. Cuba) and South America, and Australia. Flowering occurs from January to May. Flowers are fragrant, beautiful, and abundant. Fruits ripening from June through August are green ellipsoidal drupes containing one seed. A single mature tree may produce annually 5–8 kg of

The main product of neem is the oil obtained by expressing the kernels containing the seeds (Figs. 4 and 5). Neem seed oil (NSO) is obtained by different extraction methods. Most of the NSO is produced in India by familiar little producers using very simple machines, but many other countries are now producing NSOs. Therefore, considering also the possible different geographical origin of the raw material, combined pre- and postharvesting factors can result in great differences in constituents present in marketed NSOs, as already reported [49].

The chemistry of neem is very complicated and still far to be completed, despite the great number of dedicated researches. More than 300 compounds have been characterized from the seeds. One-third of them are nortriterpenoids, which means triterpenoid lacking some carbon atoms. Partial loss of lateral chain is combined by a complicated rearranging of the remaining part, giving rise to different polyclicic molecular skeletons full of oxygenated functional

considered a natural exemplar insecticide.

<H1>**The neem opportunity**

**Figure 3.** The neem tree (*Azadirachta indica* A. Juss)

seeds.

230 Insecticides Resistance

groups, partially acylated.

Fig. 4. The kernels, containing the seeds, that are used as raw material for the production of the oil, **Figure 4.** The kernels, containing the seeds, that are used as raw material for the production of the oil, mainly pro‐ duced in India by little and simple producers (figure on the right).

mainly produced in India by little and simple producers (figure on the right).

*Melia azedaracht* L*.*, named Melia o Persian lilac (Fig. 3). Several exceptional terms were used to **Figure 5.** The process of neem oil production and neem cake (modified from Benelli et al., 2015).

cake deooiled Neem cake Est razione con esano

**4,5% Neem oil**

 

describe the importance and the value of neem, i.e., "the marvellous tree, the tree of XXI century, the divine tree, India's tree of life, Nature's drugstore, Panacea for all diseases, a tree for solving global problems" [40–45]. In 1989, WHO/UNEP considered the neem tree as one of the most promising tree of the 21st century. In 1992, the US National Academy of Sciences published a report having the significant title "Neem—A Tree for Solving Global Problems" [45]. The medicinal use of neem is strongly eradicated into the Indian tradition. All its parts are largely used for many illnesses, and in Indian rural areas, the plant is called "the village pharmacy." Neem is Among major nor-triterpenes are limonoids, azadirachtin A and B, nimbin, nimbidin, salannin, and nimbolides (Fig. 6) [50]. Unlike chemical insecticides, neem compounds work on the insect's hormonal system, not on the digestive or nervous system, and therefore do not lead to development of resistance in future generations. The limonoids present in neem make it a harmless and effective insecticides, pesticide, nematicide, fungicide, etc. The most significant limonoids found in neem with proven ability to block insect growth are azadirachtin, salanin, meliantriol, and nimbin. Azadirachtin is currently considered as neem main agent for con‐ trolling insects. It appears to cause 90% of the effect on most pests. It does not kill insects – at least not immediately – instead both repels and disrupts their growth and reproduction. Research over the past years has shown that it is the most potent growth regulator and feeding deterrent ever assayed. It can repel or reduce the feeding of many species of pest insects as well as some nematodes. In fact, it is so potent a deterrent that a mere trace of its presence prevents some insects from even touching plants. The main product of neem is the oil obtained by expressing the kernels containing the seeds (Figs. 4 and 5). Neem seed oil (NSO) is obtained by different extraction methods. Most of the NSO is produced in India by familiar little producers using very simple machines, but many other countries are now producing NSOs. Therefore, considering also the possible different geographical origin of the raw material, combined pre- and postharvesting factors can result in great differences in constituents present in marketed NSOs, as already reported [49].

Fig. 5. The process of neem oil production and neem cake (modified from Benelli et al., 2015).

**Figure 6.** The main limonoids of neem.

cake deoiled, with a residue up to 1.5% [62].

Figure 6. The main limonoids of neem. Many formulations deriving from neem seeds show antifeedancy, fecundity suppression, ovicidal and larvicidal activity, insect growth regulation, and/or repellence against insect pests, even at low dosages [51–56], including ticks, house dust mites, cockroaches, raptor bugs, cat fleas, bed bugs, *Sarcoptes scabiei* mites infesting dogs, poultry mites, and beetle larvae parasitizing the plumage of poultry. The insecticidal properties, environmental safety, and public acceptability of neem and its products have been certified by the US EPA [57] and have led to its adoption into some control programs against Diptera pests [58]. Noticeably, emulsified formulations of *A. indica* oil showed an excellent larvicidal potential against different mosquito genera, including *Aedes*, *Anopheles*, and *Culex*, also under field conditions. Many formulations deriving from neem seeds show antifeedancy, fecundity suppression, ovicidal and larvicidal activity, insect growth regulation, and/or repellence against insect pests, even at low dosages [51–56], including ticks, house dust mites, cockroaches, raptor bugs, cat fleas, bed bugs, *Sarcoptes scabiei* mites infesting dogs, poultry mites, and beetle larvae parasit‐ izing the plumage of poultry. The insecticidal properties, environmental safety, and public acceptability of neem and its products have been certified by the US EPA [57] and have led to its adoption into some control programs against Diptera pests [58]. Noticeably, emulsified formulations of *A. indica* oil showed an excellent larvicidal potential against different mosquito genera, including *Aedes*, *Anopheles*, and *Culex*, also under field conditions.

Action mechanisms include repellence, feeding and oviposition deterrence, but hormonal effects are the key of the inversion of control strategy, changing the target from the adult everywhere dispersed to the locally maintained larvae, through growth inhibition, mating disruption, chemo-sterilization, etc. In fact, hormones are necessary for to complete the process of metamorphosis as the insects pass from larva to pupa to adult. In any case, if the larva manages to enter the pupal stage, the adult emerging from the pupa is 100% malformed, absolutely sterile without any capacity for reproduction. The insect populations decline drastically as they become unable to reproduce. However, also antifeedant and deterrent activities are important to defend crops. The ideal plant-derived product, including insecticide, should be eco-friendly, sustainable, low cost, and target specific, leaving unaffected the beneficial ones. Neem products do not leave any residue on the field, being biodegradable by the action of sunlight. Azadirachtin in open space after dissipation has a half-time of about 20 h. The degradation slowly occurs also when neem products are stored under appropriate conditions [59–60]. Neem, at usual concentrations, is harmless to nontarget and beneficial organisms like pollinators, honeybees, mammals, and other vertebrates [61]. The absence of toxicity is largely evidenced by the millenary use in Indian traditional medicine, as well as by the EPA report and the large use during the last 30 years, including products for pet care. Action mechanisms include repellence, feeding and oviposition deterrence, but hormonal effects are the key of the inversion of control strategy, changing the target from the adult everywhere dispersed to the locally maintained larvae, through growth inhibition, mating disruption, chemo-sterilization, etc. In fact, hormones are necessary for to complete the process of metamorphosis as the insects pass from larva to pupa to adult. In any case, if the larva manages to enter the pupal stage, the adult emerging from the pupa is 100% malformed, absolutely sterile without any capacity for reproduction. The insect populations decline drastically as they become unable to reproduce. However, also antifeedant and deterrent activities are important to defend crops. The ideal plant-derived product, including insecticide, should be eco-friendly, sustainable, low cost, and target specific, leaving unaffected the beneficial ones. Neem products do not leave any residue on the field, being biodegradable by the action of sunlight. Azadirachtin in open space after dissipation has a half-time of about 20 h. The degradation slowly occurs also when neem products are stored under appropriate

Neem cake is the residue that is left over when the kernel is crushed from neem kernels containing seeds and the remaining is pressed to obtain the oil (Fig. 5). In fact, although the overall marketed name is seed neem oil, not only the seeds are utilized. Neem cake looks more like flour than cake, with differences in color and size of particles. Two products are therefore in the market: neem oil cake obtained by cold pressure, with 6% of the oil still residue, and neem

Actually, it is not approved as pesticide, and mainly it is highly appreciated as organic fertilized. Neem cake acts as a

India alone has an annual potential of 80,000 tons of oil and 330,000 tons of neem cake from 14 million plants that grow naturally. To this potentiality, the high number of cultivations actually occurring in many parts of the world must be

natural fertilizer with pesticide properties, protecting crops from nematodes, soil grubs, and white ants.

conditions [59–60]. Neem, at usual concentrations, is harmless to nontarget and beneficial organisms like pollinators, honeybees, mammals, and other vertebrates [61]. The absence of toxicity is largely evidenced by the millenary use in Indian traditional medicine, as well as by the EPA report and the large use during the last 30 years, including products for pet care.

Neem cake is the residue that is left over when the kernel is crushed from neem kernels containing seeds and the remaining is pressed to obtain the oil (Fig. 5). In fact, although the overall marketed name is seed neem oil, not only the seeds are utilized. Neem cake looks more like flour than cake, with differences in color and size of particles. Two products are therefore in the market: neem oil cake obtained by cold pressure, with 6% of the oil still residue, and neem cake deoiled, with a residue up to 1.5% [62].

Actually, it is not approved as pesticide, and mainly it is highly appreciated as organic fertilized. Neem cake acts as a natural fertilizer with pesticide properties, protecting crops from nematodes, soil grubs, and white ants.

India alone has an annual potential of 80,000 tons of oil and 330,000 tons of neem cake from 14 million plants that grow naturally. To this potentiality, the high number of cultivations actually occurring in many parts of the world must be added. This situation evidences the neem's high sustainability and possibility to have an increasing production of low cost products to be utilized in many fields, not only insecticides, from medicine to the cosmetic one. The importance of the neem future is strictly related to this wild range of utilizations, which are strictly linked to the new market of plant natural products.
