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Prophylaxis against malaria with Azadirachta extracts and NeemAzal*

December 17, 2017 - 09:51 -- Pierre Lutgen

Azardirachta indica, Neem, is considered as the miracle tree against many diseases in many countries. One of the specific molecules of this plant is the limonoid azadirachtin, with a concentration of 0.1g/100 g in the leaves and 0.9 g/100 in the kernels.

Its effect against Plasmodium parasites is controversial, as in vivo and in vitro studies often give contradictory results. It appears also that the efficacy is much higher in the sexual (gametocyte) phase than in the asexual (trophozoite) phase. There are no negative health effects known for this plant and its constituents at the concentrations where they are usually used.

Swiss albino mice were intraperitoneally infected with Plasmodium berghei ANKA, a rodent malaria parasite. Ethanolic extracts of Neem at 300, 500 and 1000 mg/kg were administered intraperitoneally daily for five days from the day parasitaemia reached 5% of parasite inoculation. Intraperitoneal chloroquine and artemether were used as standard drug treatment controls. All Neem treatment groups displayed parasitaemia that gradually increased during treatment, and showed signs of terminal illness (i.e. hypothermia, ptosis and convulsions) within 2–4 days post-treatment. In contrast, the chloroquine and artemether groups showed no cerebral malaria symptoms and no deaths. Neem extract failed to prevent the reduction in body temperature, ptosis, convulsions and increased parasitaemia. Caution in the use of Neem extracts is thus recommended.

             Mohammed Farahna, Selma Bedri, Anti-plasmodial effects of Azadirachta indica in experimental cerebral malaria. North American Journal of Medical Sciences 2010 November, Volume 2. No. 11.

Many studies are based on the use of the commercial product NeemAzal*. NeemAzal* is a methanolic standardized extract from Azadirachta indica kernels containing about 55% limonoids. According to the manufacturer these include 33% azadirachtin A, 16% other azadirachtins (B to K), 4% salannin and 2% nimbin. NeemAzal* also contains 5% fatty acids and other seed kernel components. The price of this commercial product is 60 euro/L. It is approved in many countries and toxicology studies have shown that it has no teratogenic, mutagenetic or carcinogenetic effects.

             SJ Boeke; M Boersma, Safety evaluation of neem (Azadirachta indica) derived pesticides J Ethnopharmacology 2004, 94, 25-41

The antiplasmodial effects of NeemAzal* against the early vector stages of Plasmodium falciparum, were studied using field isolates. In an ex vivo assay gametocytaemic blood was supplemented with the plant extracts and offered to Anopheles coluzzii females by membrane feeding. Transmission blocking activity was evaluated by assessing oocyst prevalence and density on the mosquito midguts. Up to a concentration of 70 ppm the commercial extract NeemAzal completely blocked transmission and at 60 ppm mosquitoes of 4 out of 5 replicate groups remained uninfected.

             Yerbanga RS, Lucantoni L, Ouédraogo RK, Da DF, Yao FA,Transmission blocking activity of Azadirachta indica and Guiera senegalensis extracts on the sporogonic development of Plasmodium falciparum field isolates in Anopheles coluzzii mosquitoes. Parasit Vectors. 2014 Apr 15;7:185. doi: 10.1186/1756-3305-7-185.

This in vivo result is thus in contradiction with in vitro results on the asexual stage. The antimalarial activities of an extract from the leaves were compared with those of chloroquine, in in-vitro assays (thus not in vivo) against Plasmodium falciparum and were much more efficient against the asexual stages. But the extract also lysed 50% and 100% of developing and mature gametocytes, at 10(-3) microg/ml.

             Udeinya IJ, Brown N, Shu EN, Udeinya F, Quakeyie . Fractions of an antimalarial neem-leaf extract have activities superior to chloroquine, and are gametocytocidal. Ann Trop Med Parasitol. 2006 Jan;100(1):17-22.

A study was undertaken to assess the impact of the standardized neem extract NeemAzal® on the fitness of the malaria vector Anopheles stephensi following repeated exposure to the product through consecutive blood meals on treated mice. Batches of An. stephensi mosquitoes were offered 5 consecutive blood meals on mice treated with NeemAzal® at an azadirachtin A concentration of 60, 105 or 150 mg/kg. A dose and frequency dependent impact of NeemAzal® treatment on the mosquito feeding capacity, oviposition and egg hatchability was demonstrated. In the 150 mg/kg treatment group, the mosquito feeding capacity was reduced by 50% already at the second blood meal and by 50 to 80% in all treatment groups at the fifth blood meal. Consequently, a 50 – 65% reduction in the number of eggs laid per female mosquito was observed after the fifth blood meal in all treatment groups. Similarly, after the fifth treated blood meal exposure, hatchability was found to be reduced by 62% and 70% in the 105 and 150 mg/kg group respectively.

            Edson G Dembo, Solomon M Abay, Nisha Dahiya, Impact of repeated NeemAzal®-treated blood meals on the fitness of Anopheles stephensi mosquitoes. Parasit Vectors. 2015; 8: 94. PMCID: PMC4330930

Prophylactic activities of methanol, ethanol and aqueous extracts of neem leaves against plasmodium development in mice were investigated. Various extracts of the plants were prepared with soxhlet apparatus. The drugs were administered to all the mice by forceful feeding using anoral canular for 7 consecutive days. All the animals were left for eight days after treatment, and then infected with P. berghei and left for three days after which thick blood smear was prepared from their tail veins. The prophylactic effect of the water extract was the highest at 76.21 vs 25.47 for the methanol extract and 23,32 for the ethanol extract.

             Mgbemena, I. C, Opara, F.N, Prophylatic Potential of Lemon Grass and Neem as Antimalarial Agents. Journal of American Science 2010;6(8)

Previously it had already been found that the aqueous Neem extract had a stronger antipyretic effect than extracts obtained with organic solvents.

             Obaseki, and Jegede - Antipyretic effect of Azadirachta indica in bacteriaendotoxin. Proceedings of the 2nd O.A.U symposium on African Medicinal Plants. Cairo.1986

Another study demonstrated the transmission blocking activity of NeemAzal*. Anopheles stephensi females were offered a blood-meal on P. berghei infected, gametocytaemic mice, treated intraperitoneally with NeemAzal*, one hour before feeding. The transmission-blocking activity of the product was evaluated by assessing oocyst prevalence, oocyst density and capacity to infect healthy mice. NeemAzal* completely blocked P. berghei development in the vector, at an azadirachtin dose of 50 mg/kg mouse body weight. The totally 138 examined, treated mosquitoes did not reveal any oocyst and none of the healthy mice exposed to their bites developed parasitaemia. The examination of midgut content smears revealed a reduced number of zygotes and post-zygotic forms. But the blocking effect is only effective in the early sporogonic stages in the mosquito. The exposure of early P. berghei oocysts in the mosquito to NeemAzal* through a second treated blood meal on day 7 after mosquito infection did not affect the oocysts’ subsequent development.

              Leonardo Lucantoni, Rakiswendé S. Transmission blocking activity of a standardized neem (Azadirachta indica) seed extract on the rodent malaria parasite Plasmodium berghei in its vector Anopheles stephensi. Malaria Journal.

The same selective transmission blocking effect during the early sporogonic development was demonstrated in another study.

              Tapanelli S, Chianese G, Lucantoni L, Yerbanga RS. Transmission blocking effects of neem (Azadirachta indica) seed kernel limonoids on Plasmodium berghei early sporogonic development. Fitoterapia. 2016 Oct;114:122-126. doi: 10.1016/j.fitote.2016.09.008..

All these studies confirm the activity of this limonoid-rich medicinal plant on the sporogonic development of P. falciparum isolates in mosquitoes. The results strongly suggest azadirachtin and nimbin to be important compounds, but the results also provide evidence for the presence of other molecules with transmission blocking activity. These compounds hold promise for the design of new, effective, multi-stage combination medicines. Herbal medicines designed as preventive-transmission blocking formulations, if used by entire communities, may reduce incidence of malaria cases and decrease the intensity of transmission. 

Our association IFBV-BELHERB has initiated last year clinical trials with Artemisia and Neem prophylaxis. The first results are encouraging. But until the impact on the asexual phase is cleared, we recommend not to administer Neem during a severe malaria disability. We also recommend to use Neem in powder form. Azadirachtin is not stable in hot water.