Cyclophosphamide, a cancer chemotherapy drug-induced early onset of reproductive senescence and alterations in reproductive performance and their prevention in mice.

Although, cyclophosphamide (CP) treatment is known to cause degeneration of the ovarian follicular reserve, which may have a serious consequence of the onset of early reproductive senescence, thus far there is no experimental study either to demonstrate CP-induced early onset of reproductive senescence or its prevention. Intraperitoneal administration (ip) of CP [100 mg/kg body weight (bw)/mouse] resulted in a drastic reduction in reproductive life span as shown by the onset of reproductive senescence at a significantly early age (258 days) compared to controls (349 days), whereas treatment with the root extract of the herb Decalepis hamiltonii (DH) (200 mg/Kg bw/day for 7 days), a cocktail of anti-oxidants prior to CP administration maintained normal reproductive life span in mice. Further, the CP treated mice showed a significant increase in pre-coital interval and a significant reduction in parturition index coupled with regressive changes in the uterine endometrium, whereas DH co-treatment prevented these changes. The results for the first time, demonstrate that the ovarian toxicity of CP could be prevented by an anti-oxidant to maintain a normal reproductive life span as well as reproductive outcome using mice model.

Multiple dose treatment reduces cyclophosphamide-induced ovarian follicular loss in mice.

This study compares the effects of single dose and multiple dose treatment of cyclophosphamide (CP) on oxidative stress-mediated follicular damage in mouse ovary. In the first experiment, adult female mice were administered with a single dose of CP (100 mg/kg body weight/mouse) and autopsied 72 hr after treatment. In the second experiment, adult female mice were injected with multiple doses of CP (40 mg/kg body weight/day/mouse for 10 consecutive days) and sacrificed on Day 11. There was a 58, 48, 53, and 51% loss of primordial, primary, preantral, and antral follicles, respectively, following the administration of a single dose of CP, whereas, multiple dose of CP caused only 35% reduction in primordial follicles coupled with 28, 23, and 38%, loss of primary, preantral, and antral follicles, respectively. There was a decrease in activities of the ovarian antioxidant enzymes and increase in reactive oxygen species (ROS) and malondialdehyde (MDA) concentrations following single dose CP, whereas multiple dose treatment caused an increase in activities of these enzymes and decrease in ROS and MDA concentrations. The serum concentration of estradiol was significantly decreased following single or multiple dose treatment. The ovarian damage caused by a single high dose of CP administration is higher than that by multiple doses of smaller amount, though the total amount of CP administered was higher with multiple treatment. The results of the current study reveal the benefit of metronomic chemotherapy in cancer treatment, for its effectiveness in reducing ovarian toxicity, a major side effect in young female patients.

Mode of Action of the Natural Insecticide, Decaleside Involves Sodium Pump Inhibition.

Decalesides are a new class of natural insecticides which are toxic to insects by contact via the tarsal gustatory chemosensilla. The symptoms of their toxicity to insects and the rapid knockdown effect suggest neurotoxic action, but the precise mode of action and the molecular targets for decaleside action are not known. We have presented experimental evidence for the involvement of sodium pump inhibition in the insecticidal action of decaleside in the cockroach and housefly. The knockdown effect of decaleside is concomitant with the in vivo inhibition of Na+, K+ -ATPase in the head and thorax. The lack of insecticidal action by experimental ablation of tarsi or blocking the tarsal sites with paraffin correlated with lack of inhibition of Na+- K+ ATPase in vivo. Maltotriose, a trisaccharide, partially rescued the toxic action of decaleside as well as inhibition of the enzyme, suggesting the possible involvement of gustatory sugar receptors. In vitro studies with crude insect enzyme preparation and purified porcine Na+, K+ -ATPase showed that decaleside competitively inhibited the enzyme involving the ATP binding site. Our study shows that the insecticidal action of decaleside via the tarsal gustatory sites is causally linked to the inhibition of sodium pump which represents a unique mode of action. The precise target(s) for decaleside in the tarsal chemosensilla and the pathway linked to inhibition of sodium pump and the insecticidal action remain to be understood.

Decaleside: a new class of natural insecticide targeting tarsal gustatory sites.

Natural sources for novel insecticide molecules hold promise in view of their eco-friendly nature, selectivity, and mammalian safety. Recent progress in understanding the biology of insect olfaction and taste offers new strategies for developing selective pest control agents. We have isolated two natural insecticidal molecules from edible roots of Decalepis hamiltonii named Decalesides I and II, which are novel trisaccharides, highly toxic to household insect pests and stored-product insects. We have experimentally shown that insecticidal activity requires contact with tarsi on the legs but is not toxic orally. The insecticidal activity of molecules is lost by hydrolysis, and various sugars modify toxic response, showing that the insecticidal activity is via gustatory sites on the tarsi. Selective toxicity to insects by virtue of their gustatory site of action and the mammalian safety of the new insecticides is inherent in their chemical structure with 1-4 or 1-1 α linkage that is easily hydrolyzed by digestive enzymes of mammals. Decalesides represent a new chemical class of natural insecticides with a unique mode of action targeting tarsal chemosensory/gustatory system of insects.