Effect of Afobazole and Betaine on Cognitive Disorders in the Offspring of Rats with Streptozotocin-Induced Diabetes and Their Relationship with DNA Damage.

Cognitive activity in 60-day-old offspring of rats (intrauterine development in experimental streptozotocin-induced diabetes) was studied on the model of food-seeking behavior under conditions of free choice in a 6-arm maze. The formation of the food-procuring skill was significantly delayed, which attests to impairment of cognitive functions in these animals. Peroral administration of afobazole (10 and 50 mg/kg) and betaine (50 and 100 mg/kg) significantly and dose-dependently alleviated this disorder. Correlation analysis of the data on delayed formation of a food-procuring skill and results of DNA comet attests to a strong relationship between DNA damage in cells of the embryo and placenta during intrauterine development and cognitive dysfunction in the postnatal offspring of animals with streptozotocin-induced diabetes.

Effect of Afobazole and Betaine on DNA Damage in Placental and Embryonic Tissues of Rats with Experimental Streptozocin Diabetes.

DNA comet assay showed that the level of DNA damage in the placental and embryonic tissues of rats with streptozotocin-induced diabetes mellitus increased on gestation days 14 and 20. Afobazole and betaine administered per os effectively decreased the level of genotoxic damage; afobazole was most efficient in doses of 10 and 50 mg/kg and betaine in a dose of 100 mg/kg.

Impaired prenatal development and glycemic status in the offspring of rats with experimental streptozotocin-induced diabetes and their correction with afobazole.

Diabetes mellitus was simulated in rats on gestation day 1 by a single intraperitoneal injection of streptozotocin in doses of 40 and 50 mg/kg. Pregnant females showed increased glucose concentrations n the blood and urine, embryonic developmental disorders, such as tongue protrusion, edema, and skin hyperemia with concomitant vascular damage (hemorrhage, hematoma) as well as pre- and post-implantation embryo loss. Afobazole administered orally in doses of 10 and 50 mg/kg to pregnant rats with streptozotocin-induced diabetes significantly decreased prenatal developmental disorders and pre- and post-implantation embryo loss rate. Afobazole in a dose of 50 mg/kg produced maximum protective effect: in rats receiving 40 mg/kg streptozotocin, post-implantation embryo loss decreased by 14.7 times. Afobazole in doses of 10 and 50 mg/kg significantly reduced blood glucose concentration in pregnant rats and normalized glycemia in 90-day-old male offspring.

Afobazole modifies the neurotoxic and genotoxic effects in rat prenatal alcoholization model.

Prenatal ethanol leads to the formation of a wide spectrum of neurotoxic injuries to the brain in embryos by day 20 of intrauterine development. High levels of DNA aberrations and apoptotic comets were detected in tissues of 13-day embryos and placentas of rats receiving 40% ethanol orally (4 ml/kg) during gestation. The increase in the levels of DNA aberrations and apoptotic comets in the embryonic and placental tissues of alcoholic rats on day 13 of gestation correlated with the emergence of morphological abnormalities of the brain in the embryos on day 20 of intrauterine development. Afobazole (antimutagen) in doses of 1 and 10 mg/kg reduced the genotoxic effects of ethanol in embryonic and placental tissues and the relevant neurotoxic involvement of the brain.

[Association of genotoxic and teratogenic effects induced by cyclophosphamide and their modification with afobazole].

Intact rat embryonic and placental tissues were found to have a characteristic ratio of cells with different degrees of DNA fragmentation. The genotoxic effect of cyclophosphamide was shown to be accompanied by a quantitative deviation from the control group established ratio of different cell types. A relationship was found between the abnormal ratio of different cell types in the embryonic and placental tissues and the occurrence of embryonic morphological abnormalities. The antimutagen afobazole (1, 10, and 100 mg/kg) was ascertained to be able to lower genotoxic effects in the embryonic and placental tissues and their related malformations. It is presumed that it is promising to use DNA damage index in the embryonic and placental cells as a biomarker of the course of embryogenesis and as a basis for devising an indicator test for rapid screening of potential teratogens.

[Model study of afobazole distribution in pregnant and lactating female rats and infant rat pups].

Afobazole and M-11, its major metabolite were detected in placental and embryonic rat tissues after single peroral administration to pregnant female rats at a dose of 100 mg/kg. The anxiolytic drug and its metabolite are also detected in rat milk and body of the breast-fed infant rat pups after 4 days of daily administration (200 mg/kg, per os) to lactating female rats.

Evaluation of genotoxicity and reproductive toxicity of silicon nanocrystals.

Silicon crystal 2-5 nm nanoparticles in the form of 1-5-µ granules in water suspension were injected intraperitoneally in a single dose to male F(1)(CBA×C57Bl/6) mice or to outbred albino rats on days 1, 7, and 14 of gestation. Silicon crystal nanoparticles in doses of 5, 25, and 50 mg/kg exhibited no cytogenetic activity in mouse bone marrow cells after 24-h exposure and in doses of 5 and 25 mg/kg after 7 and 14-day exposure. A 24-h exposure to silicon nanoparticles in a dose of 5 mg/kg significantly increased DNA damage (detected by DNA comet assay) in bone marrow cells. In a dose of 50 mg/kg they considerably increased DNA damage in bone marrow and brain cells after exposure of the same duration. Silicon nanoparticles in doses of 5 and 50 mg/kg caused no genotoxic effects in the same cells after 3-h and in a dose of 5 mg/kg after 7-day exposure. Silicon crystal nanoparticles in a dose of 50 mg/kg caused death of 60-80% mice after exposure <24 h. Injected in a dose of 50 mg/kg on days 1, 7, and 14 of gestation, silicon crystal nanoparticles reduced body weight gain in pregnant rats and newborn rats at different stages of the experiment, but had no effect on other parameters of physical development of rat progeny and caused no teratogenic effects.