Toosendanin

Biological effects of toosendanin, a triterpenoid extracted from Chinese traditional medicine.[Pubmed: 17363132 ]

Prog Neurobiol. 2007 May;82(1):1-10.

Toosendanin (TSN) is a triterpenoid extracted from Melia toosendan Sieb et Zucc, which was used as a digestive tract-parasiticide and agricultural insecticide in ancient China. TSN was demonstrated to be a selective presynaptic blocker and an effective antibotulismic agent.
METHODS AND RESULTS:
By interfering with neurotransmitter release through an initial facilitation followed by a subsequent depression, TSN eventually blocks synaptic transmission at both the neuro-muscular junction and central synapses. Despite sharing some similar actions with botulinum neurotoxin (BoNT), TSN has a marked antibotulismic effect in vivo and in vitro. Studies suggest that the antibotulismic effect of TSN is achieved by preventing BoNT from approaching its enzymatic substrate, the SNARE protein. It is also found that TSN can induce differentiation and apoptosis in several cell lines, and suppress proliferation of various human cancer cells. TSN inhibits various K(+)-channels, selectively facilitates Ca(2+)-influx via L-type Ca(2+) channels and increases intracellular Ca(2+) concentration ([Ca(2+)](i)).
CONCLUSIONS:
The TSN-induced [Ca(2+)](i) increase and overload could be responsible for the TSN-induced biphasic effect on transmitter release, cell differentiation, apoptosis as well as the cytoxicity of TSN.

Effects of the botanical insecticide, toosendanin, on blood digestion and egg production by female Aedes aegypti (Diptera: Culicidae): topical application and ingestion.[Pubmed: 23427659]

J Med Entomol. 2013 Jan;50(1):112-21.

Botanical insecticides offer novel chemistries and actions that may provide effective mosquito control.
METHODS AND RESULTS:
Toosendanin (TSN, 95% purity) is one such insecticide used to control crop pests in China, and in this study, it was evaluated for lethal and sublethal effects on larvae and females of the yellowfever mosquito, Aedes aegypti (L.). Toosendanin was very toxic to first instar larvae after a 24 h exposure (LC50 = 60.8 microg/ml) and to adult females up to 96 h after topical treatment (LD50 = 4.3 microg/female) or ingestion in a sugar bait (LC50 = 1.02 microg/microl). Treatment of first instars for 24 h with a range of sublethal doses (6.3-25 microg/ml) delayed development to pupae by 1 to 2 d. Egg production and larval hatching from eggs were dose dependently reduced (>45%) by Toosendanin doses (1.25-10.0 microg) topically applied to females 24 h before or 1 h after a bloodmeal. Ingestion of Toosendanin (0.031-0.25 microg/microl of sugar bait) by females 24 h before a bloodmeal also greatly reduced egg production and larval hatch; no eggs were oviposited by females ingesting the highest dose. Further studies revealed that topical or ingested Toosendanin dose-dependently disrupted yolk deposition in oocytes, blood ingestion and digestion, and ovary ecdysteroid production in blood-fed females.
CONCLUSIONS:
Overall, our results indicate that Toosendanin is an effective insecticide for Ae. aegypti larvae and adults, because of its overt toxicity at high doses and disruption of development and reproduction at sublethal doses.

Antifeedant and growth inhibitory effects of the limonoid toosendanin and Melia toosendan extracts on the variegated cutworm, Peridromasaucia (Lep., Noctuidae)[Reference: WebLink]

J. Appl. Entomol., 1995, 119(1-5):367-70.

Antifeedant and growth inhibitory effects of Toosendanin, a limonoid allelochemical from the bark of the trees Melia toosendan and M. azedarach, were determined for the variegated cutworm, Peridroma saucia, using different bioassays.
METHODS AND RESULTS:
Toosendanin significantly deterred feeding of 2nd and 4th instar larvae in diet choice and leaf disc choice bioassays, respectively. Refined bark extracts containing 60–75% Toosendanin were less deterrent than the pure compound in both bioassays. However, the 60% extract significantly inhibited growth of neonate larvae in a dose-dependent manner when incorporated into an artificial diet, with an EC50 (concentration reducing growth by 50% relative to controls) of 42.3 ppm at 7 days. Extracts containing 60% and 75% Toosendanin were more inhibitory than equivalent amounts of pure Toosendanin in this chronic growth bioassay, suggesting the presence of other minor constituents which must be significantly more inhibitory, though less deterrent to feeding, than Toosendanin itself.
CONCLUSIONS:
Nutritional analyses of 4th instar larvae following both oral and topical administration of Toosendanin or the 75% extract confirm that both materials possess a combination of antifeedant and growth inhibitory properties.

Toosendanin, a triterpenoid derivative, acts as a novel agonist of L-type Ca2+ channels in neonatal rat ventricular cells.[Pubmed: 15464064 ]

Eur J Pharmacol. 2004 Oct 6;501(1-3):71-8.

Toosendanin, a triterpenoid derivative extracted from Melia toosendan Sieb et Zucc, was demonstrated to be potentially useful in medical and scientific researches.
METHODS AND RESULTS:
Here, we investigated the effects of Toosendanin on L-type voltage-dependent Ca(2+) channels in cultured neonatal rat ventricular cells, using whole-cell patch-clamp method. Toosendanin irreversibly increased L-type Ca(2+) current (I(Ca(L))) in a concentration-dependent manner and shifted the maximum of the current/voltage relationship from 8.3+/-3.7 to 1.7+/-3.7 mV, without modifying the threshold potential of the current. Toosendanin shifted the steady-state activation and inactivation curves to the left. The deactivation kinetics of the I(Ca(L)) was significantly slowed by Toosendanin while the activation kinetics was not affected. The cells pretreated with 100 nM 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid methyl ester (S(-)-BayK8644) still respond to further addition of 87 microM Toosendanin, and vice versa.
CONCLUSIONS:
These results prove Toosendanin to be a novel L-type Ca(2+) channel agonist, which possesses a distinct binding site from BayK8644.

Toosendanin induces apoptosis through suppression of JNK signaling pathway in HL-60 cells.[Pubmed: 23111283]

Toosendanin induces outgrowth of neuronal processes and apoptosis in PC12 cells.[Pubmed: 12573469]

Neurosci Res. 2003 Feb;45(2):225-31.

METHODS AND RESULTS:
In the present study, the effects of Toosendanin on cell differentiation and apoptosis were investigated in PC12 cells. The results showed that after 24-48 h of culture in a medium containing Toosendanin (approximately 1-10x10(-7) M), cell differentiation and outgrowth of neuronal processes were promoted. Combined treatment with Toosendanin and a calcium channel blocker, nifedipine or omega-conotoxin GVIA, resulted in a significant inhibition of the Toosendanin-induced effects. Pretreatment of PC12 cells with BAPTA-AM also inhibited the Toosendanin-induced effects; however, these effects were not inhibited by pertussis toxin and H-7 in the medium. Toosendanin also induced cell apoptosis. Based on the DNA content determined by flow cytometric analysis, the number of apoptotic cells significantly increased when the incubation time in the Toosendanin-containing medium was lasted up to 72 h.
CONCLUSIONS:
Toosendanin at a higher concentration (> or =1 x 10(-6) M) caused cell death while it had no effect on cell division at concentrations lower than 1 x 10(-7) M.

Toxicol In Vitro. 2013 Feb;27(1):232-8.

Toosendanin (TSN), a triterpenoid isolated from Melia toosendan Sieb. et Zucc., has been found to suppress proliferation and induce apoptosis in a variety of human cancer cells. However, the mechanism how TSN induces apoptosis remains poorly understood.
METHODS AND RESULTS:
In this study, we examined the effects of TSN on the growth, cell cycle arrest, induction of apoptosis and the involved signaling pathway in human promyelocytic leukemia HL-60 cells. Proliferation of HL-60 cells was inhibited in a dose-dependent manner with the IC(50 (48 h)) of 28 ng/mL. The growth inhibition was due primarily to the S phase arrest and cell apoptosis. Cell apoptosis induced by TSN was confirmed by Annexin V-FITC/propidium iodide staining. The increase of the pro-apoptotic protein Bax, cleaved PARP and caspase-3, and the decrease of anti-apoptotic protein Bcl-2 were observed. Western blot analysis indicated that TSN inhibits the CDC42/MEKK1/JNK pathway.
CONCLUSIONS:
Taken together, our study suggested, for the first time, that the pro-apoptotic effects of TSN on HL-60 cells were mediated through JNK signaling pathway.