Safety assessment of the pyridoindole derivative SMe1EC2: developmental neurotoxicity study in rats

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Safety assessment of the pyridoindole derivative SMe1EC2: developmental neurotoxicity study in rats

The present study deals with effect of prenatal and neonatal administration of the synthetic pyridoindole derivative SMe1EC2 (2-ethoxycarbonyl-8-methoxy-2,3,4,4a, 5,9b-hexahydro-1H-pyrido-[4,3b] indolinium chloride) on postnatal and neurobehavioral development of the rat offspring. The substance tested was administered to pregnant rats orally in the doses 5, 50 and 250 mg/kg from day 15 of gestation to day 10 post partum (PP). From the day 4 PP, the postnatal development and neurobehavioral characteritics of offspring were evaluated. The following variables were observed: body weight, pinna detachment, incisor eruption, ear opening, eye opening, testes descent and vaginal opening, righting reflex, negative geotaxia, startle reflex, dynamic air righting and exploratory behavior in a new environment. No maternal death, abortion or dead fetuses occurred either in the control or SMe1EC2 groups. Dynamic righting reflex was delayed one day in the groups of animals treated via their mothers with 5 and 50 mg/kg SMe1EC2. The delay in the development of this reflex was only transient. On day 20 PP, all pups tested had a positive score of the reflex. Administration of SMe1EC2 did not reveal any significant changes in other variables of somatic growth and maturation, reflex and neuromotor development and exploratory behavior, either of young or adult animals of both genders, assessed by analysis of variance.

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  • Balonová T Zeljenková D Ďurišová M Nosáľ R Jakubovský J Líška J Štolc S. (1991). Reproductive toxicity studies with cis-(-)-2344a 59b-hexahydro-28-dimethyl-1H-pyrido-[43-b]indole dipalmitate in rats. Arzneimittelforschung 41: 1-5.

  • Braquenier JB Quertemont E Tirelli E Plumier JC. (2010). Anxiety in adult female rats following perinatal exposure to chlorpyriforis. Neurotoxicol Teratol 32: 234-239.

  • Brucknerová I Benedeková M. (2000). Asphyxia of the newborn - the ever topical problem. Biologia 55: 23-26.

  • Cannon M Clarke MC. (2005). Risk for schizophrenia - broadening the concepts pushing back the boundaries. Schizophr Res 79: 5-13.

  • Cederberg J Eriksson UJ. (2005). Antioxidative treatment of pregnant diabetic rats diminished embryonic dysmorphogenesis. Birth Defects Res A Clin Mol Teratol. 73: 498-505.

  • Cohen-Kerem R Koren G. (2003). Antioxidants and fetal protection against ethanol teratogenicity. I. Review of the experimental data and implications to humas. Neurotoxicol Teratol 25: 1-9.

  • Dennery P. A. (2007). Effects of oxidative stress on embryonic development. Birth Defects Res C Embryo Today 81: 155-162.

  • Dubovický M Ujházy E Kovačovský P Rychlík I Janšák J. (1999). Evaluation of long-term administration of the antioxidant stobadine on exploratory behaviour in rats of both genders. J Appl Toxicol 19: 431-436.

  • Eriksson UJ Simán CM. (1996). Pregnant diabetic rats fed the antioxidant butylated hydroxytoluene show decreased occurrence of malformations in offspring. Diabetes 45: 1497-14502.

  • Ferguson SA Delclos KB Newbold RR Flynn KM. (2009). Few effects of generational dietary exposure to genistein or nonylphenol on sodium solution intake in male and female Sprague-Dawley rats. Neurotoxicol Teratol 31: 143-148.

  • Gajdošíková A Ujházy E Gajdošík A Chalupa I Blaško M Tomášková A Líška J Dubovický M Bauer V. (1995). Chronic toxicity and micronucleus assay of the new cardioprotective agent stobadine in rats. Arzneimittelforschung 45: 531-536.

  • Gaspárová Z Šnirc V Štolc S Dubovický M Mach M Ujházy E. (2010). Maternal treatment of rats with the new pyridoindole antioxidant during pregnancy and lactation resulting in improved off spring hippocampal resistance to ischemia in vitro.Neuro Endocrinol Lett 31: 348-352.

  • Hood D. (2006). Developmental and reproductive toxicology. Second edition CRC Taylor & Francis Group Boca Raton USA 1-1149.

  • Kinney DK Munir KM Crowley DJ Miller AM. (2008). Prenatal stress and risk for autism. Neuroscie Biobehav Res 32: 1519-1523.

  • Makatsori A Dubovický M Ujházy E Bakoš J Ježová D. (2005). Neuroendocrine changes in adult female rats prenatally exposed to phenytoin. Neurotoxicol Teratol 3: 509-514.

  • OECD. (2007). OECD guideline for the testing of chemicals. Test No. 426 - Developmental Neurotoxicity Study.

  • Park H Park B Kim Y Lee H Park E Ha E Chang N Lee B Hong Y. (2004). Protective effects of vitamin C against oxidative stress on birth weight. Epidemiology 15: S85-S86.

  • Penn JS Talmon BL Bullard LE. (1997). Effect of a water-soluble vitamin E analog trolox C on retinal vescular development in an animal model of retinopathy of prematurity. Free Radic Biol Med 22: 977-984.

  • Ponce PAC Monsalve RMC Garibay PMA Andrade IS. (2005). Effect of maternal diabetes on human and rat fetal development. Ginecol. Obstet. Mex 73: 544-552.

  • Štolc S Šnirc V Gajdošíková A Gajdošík A Gáspárová Z Ondrejičková O Sotníková R Viola A Rapta P Syneková I Vajdová M Zacharová S Nemček V Krchnárová V. (2008). New pyridoindoles with antioxidant and neuroprotective actions. In: Bauer V. (ed.) Trends in Pharmacological Research Institute of Experimental Pharmacology SASc. Bratislava Slovakia 118-136.

  • Tamura H Nakamura Y Terron MP Flores LJ Manchester LG Tan DX Sugino N Reiter RJ. (2008). Melatonin and pregnancy in the human. Reprod Toxicol. 25: 291-303.

  • Ujházy E Balonová T Vargová T Janšák J Derková Ľ. (1992). Teratological study of stobadine after single and repeated administration in rats. Teratogen Carcinogen Mutagen 12: 211-221.

  • Ujházy E Dubovický M Balonová T Janšák J Zeljenková D. (1994). Teratological assessment of stobadine after single and repeated administration in mice. J Appl Toxicol 14: 357-363.

  • Ujházy E Dubovický M Ponechalová V Navarová J Brucknerová I Šnirc V Mach M. (2008). Prenatal developmental toxicity study of the pyridoindole antioxidant SMe1EC2 in rats. Neuro Endocrinol Lett 29: 639-643 2008.

  • Ujházy E Mach M Dubovický M Navarová J Šoltés L Juránek I Brucknerová I Zeman M. (2004). Effect of melatonin and stobadine on maternal and embryofoetal toxicity in rats due to intrauterine hypoxia induced by phenytoin administration. Cent Eur J Public Health 12: Suppl: S83-S86.

  • Ujházy E Schmidtová M Dubovický M Navarová J Brucknerová I Mach M. (2006). Neurobehavioral changes in rats after neonatal anoxia: effect of antioxidant stobadine pretreatment. Neuro Endocrinol Lett 27: 82-85.

  • van Bel F Shadid M Moison RM Dorrepeal CA Fontjin J Monteiro L. (1998). Effect of allpurinol on postasphyxial free radical formation cerebral hemodynamics and electrical brain activity. Pediatrics 10: 185-193.

  • Verklan MT. (2009). The chilling details: hypoxic-ischemic encephalopathy. J Perinat Neonat Nurs 23: 59-68.

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