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Neem (Azadirachta indica)


Neem (Azadirachta indica) Image
Synonyms / Common Names / Related Terms
6-desacetyllnimbinene, Azadirachta indica, Azadirachta indica ADR, Azadirachta indica A. juss, azadirachtin, azadirachtin A, bead tree, beta-sitosterol, Bioneem™, dogonyaro, holy tree, immobile, Indian lilac, isomeldenin, limonoids, margosa, margosa oil, Meliaceae (family), Neemix™, neem flowers, neem-based pesticide, neem kernel powder (NP), neem leaf alcoholic extract (NLE), neem oil, neem seed kernel, neem seed oil, Nim, NIM-76, nimba, nimbandiol, nimbin, nimbinene, nimocinol, Persian lilac, Praneem polyherbal cream, Pride of China, quercetin, village of pharmacy.



Mechanism of Action

Pharmacology:

  • Constituents: Leaf extracts: Active constituents of neem leaf extract include isomeldenin, nimbin, nimbinene, 6-desacetyllnimbinene, nimbandiol, immobile, nimocinol, quercetin, and beta-sitosterol.7,8 Two additional tetracyclic triterpenoids zafaral [24,25,26,27-tetranorapotirucalla-(apoeupha)-6alpha-methoxy-7alpha-acetoxy-1,14-dien-3,16-dione-21-al] (1) and meliacinanhydride [24,25,26,27-tetranorapotirucalla-(apoeupha)-6alpha-hydroxy,11alpha-methoxy-7alpha,12alpha-diacetoxy,1,14,20(22)-trien-3-one] (2) have been isolated from the methanolic extract of neem leaves.7
  • Seed: Active constituents have not been determined with certainty.4 The neem seed extracts vary in each batch in terms of stability and activity. Two new tetranortriterpenoids, azadirachtin H [3] and azadirachtin I [4], have been isolated from neem seeds.9
  • Tree: Azadirachtin is a tetranortriterpenoid from the neem tree.10 Neem bark and leaves contain tannin and oil.
  • Antimalarial effects: Gedunin [1] has been reported as the antimalarial agent of Azadirachta indica.11 Researchers have found that azadirachtin and selected semi-synthetic derivatives block the development of the motile male malarial gamete in vitro.12
  • Antimicrobial effect: NIM-76, a spermicidal fraction obtained from neem oil, may directly inactivate a virus versus preventing viral replication, as it did not inhibit viral multiplication once the infection was present. NIM-76 stimulated cellular mediated immunity and lymphocyte proliferation, which may contribute to its antimicrobial effects.13
  • Contraceptive effects: The mechanism of action for the abortifacient effects of neem is not known but several actions may occur. Neem constituents may be absorbed and transferred to susceptible organs, such as the ovaries, or uptake of neem may occur by phagocytic cells. Abortion was preceded by a decrease in progesterone and chorionic gonadotrophin (CG) in monkeys, which could affect the maintenance of the endometrium and pregnancy.5 However, neem did not injure corpus luteum function in nonpregnant female baboons.6
  • More likely mechanisms for abortive effects involve the activation of macrophages by neem and subsequent secretion of cytokines that may alter immune and non-immune cells. In rats, CD4 and CD8 cells (particularly CD8 cells) increased in the spleen 96 hours after treatment onset and tumor necrosis factor alpha and gamma-interferon increased in serum, mesenteric lymph nodes, and fetoplacental tissue.5 These cell-mediated immunomodulatory effects were confirmed in another animal study.4 Elevations in gamma-interferon and tumor necrosis factor alpha (TNF-alpha) were observed in rats treated with neem while these cytokines were not elevated in control animals. Elevations in these cytokines may be responsible for the adverse effects noted during implantation. Neem treatment also increased CD8+ cells, which are known to secrete gamma-interferon, TNF-alpha, and interleukin-2.
  • The postcoital contraceptive effect of neem may not be due to hormonal effects. Neem did not exhibit estrogenic or progestational activity nor did it display hormonal antagonistic effects. Neem may have induced uterine damage, including endometrial disruption and toxic lesions. Other possible mechanisms include a spermicidal or ovicidal effect or a direct effect of neem on the zygote, causing blastocidal activity. Endometrial damage may also prevent proper implantation.1 These results were confirmed in another study that also concluded the effects of neem on uterine and ovarian tissue are not due to hormonal effects. Subcutaneously administered neem oil caused histological and biochemical uterine changes in cyclic and ovariectomized rats that were not consistent with changes expected to occur as a result of hormonal effects. Observed effects included luminal epithelial damage to the uterus and surrounding glands in cyclic rats. Glycogen and protein depletion occurred in the ovary and uterus while acid phosphatase increased in both cyclic and ovariectomized rats. No synergistic or antagonistic activity was evidence when neem was given with estradiol dipropionate or progesterone. The toxic effects of neem oil versus hormonal effects may be responsible for these changes.3
  • Pesticidal effects: Azadiractin is a tetranortriterpinoid constituent of neem that interrupts metamorphosis in insects, causing pesticidal effects.2
  • Toxic effects: In rat liver mitochondria in vitro, neem oil was a strong mitochondrial toxin, causing overall mitochondrial dysfunction and energy crisis. It caused uncoupling of mitochondrial oxidative phosphorylation, resulting in decreased ATP production, inhibition of the electron-transport chain, and decreases in concentrations of intramitochondrial acetyl CoA and free CoA-SH. The toxic effects on mitochondrial respiration may be due to alteration of fatty acid metabolism by neem oil. Reye-like syndrome symptoms noted in infants who had consumed neem oil may occur because of its mitochondrial toxic effects. Neem oil consists mainly of long-chain saturated and unsaturated fatty acids (stearic, oleic, palmitic, linoleic) and some medium chain fatty acids. It also contains terpenoids, nimbin and nimbiol.14 Neem oil induced mitochondrial permeability transition in rat liver mitochondria, causing mitochondrial swelling, depolarization, and uncoupling of oxidative phosphorylation.15

Pharmacodynamics/Kinetics:

  • Insufficient available evidence.

References

  1. Prakash, A., Tewari, R., and Mathur, R. Non-hormonal post-coital contraceptive action of Neem oil in rats. J Ethnopharmacol 1988;23(1):53-59.
  2. Raizada, R. B., Srivastava, M. K., Kaushal, R. A., and Singh, R. P. Azadirachtin, a neem biopesticide: subchronic toxicity assessment in rats. Food Chem Toxicol 2001;39(5):477-483. 11313114
  3. Tewari, R. K., Pathak, S., and Prakash, A. O. Biochemical and histological studies of reproductive organs in cyclic and ovariectomized rats supporting a non-hormonal action for neem oil. J Ethnopharmacol 1989;25(3):281-293. 2747262
  4. Mukherjee, S., Garg, S., and Talwar, G. P. Early post implantation contraceptive effects of a purified fraction of neem (Azadirachta indica) seeds, given orally in rats: possible mechanisms involved. J Ethnopharmacol 11-30-1999;67(3):287-296. 10617063
  5. Talwar, G. P., Shah, S., Mukherjee, S., and Chabra, R. Induced termination of pregnancy by purified extracts of Azadirachta Indica (Neem): mechanisms involved. Am J Reprod Immunol 1997;37(6):485-491. 9228306
  6. Mukherjee, S., Lohiya, N. K., Pal, R., Sharma, M. G., and Talwar, G. P. Purified neem (Azadirachta indica) seed extracts (Praneem) abrogate pregnancy in primates. Contraception 1996;53(6):375-378. 8773426
  7. Siddiqui, B. S., Afshan, F., Gulzar, T., and Hanif, M. Tetracyclic triterpenoids from the leaves of Azadirachta indica. Phytochemistry 2004;65(16):2363-2367. 15381008
  8. Tiwary, B. S. Neem leaf poisoning. Assoc Physicians India 1985;33(12):817. 3837008
  9. Govindachari, T., Sandhya, G., and Ganesh Raj, S. Simple method for the isolation of azadirachtin by preparative high-performance liquid chromatography. J Chromatogr 1992;513:389-391.
  10. de Azambuja, P. and Garcia, E. S. Effects of azadirachtin on Rhodnius prolixus: immunity and Trypanosoma interaction. Mem Inst Oswaldo Cruz 1992;87 Suppl 5:69-72. 1342719
  11. Khalid, S. A., Duddeck, H., and Gonzalez-Sierra, M. Isolation and characterization of an antimalarial agent of the neem tree Azadirachta indica. J Nat Prod 1989;52(5):922-926. 2607354
  12. Jones, I. W., Denholm, A. A., Ley, S. V., Lovell, H., Wood, A., and Sinden, R. E. Sexual development of malaria parasites is inhibited in vitro by the neem extract azadirachtin, and its semi-synthetic analogues. FEMS Microbiol Lett 7-15-1994;120(3):267-273. 7980823
  13. SaiRam, M., Ilavazhagan, G., Sharma, S. K., Dhanraj, S. A., Suresh, B., Parida, M. M., Jana, A. M., Devendra, K., and Selvamurthy, W. Anti-microbial activity of a new vaginal contraceptive NIM-76 from neem oil (Azadirachta indica). J Ethnopharmacol 2000;71(3):377-382. 10940573
  14. Koga, Y., Yoshida, I., Kimura, A., Yoshino, M., Yamashita, F., and Sinniah, D. Inhibition of mitochondrial functions by margosa oil: possible implications in the pathogenesis of Reye's syndrome. Pediatr Res 1987;22(2):184-187. 3658544
  15. Trost, L. C. and Lemasters, J. J. The mitochondrial permeability transition: a new pathophysiological mechanism for Reye's syndrome and toxic liver injury. J Pharmacol Exp Ther 1996;278(3):1000-1005. 8819478




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