Uticaj primene valproične kiseline tokom priploda i gestacije na animalnom modelu miša - efekat na psihomotorni razvoj kod potomaka
Influence of valproic acid application during breeding and gestation in the mouse animal model - effect on psychomotor development in offspring
Doctoral thesis (Published version)
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The aim of this study was to examine the effects of intrauterine exposure to different doses of valproate on the course of physical and psychomotor development of mouse. The effects of valproate in the CNS was evaluated at subtherapeutic doses and dose-dependent effect. The tests applied to the offspring in the literature are labeled as suitable for the assessment of motor and sensory system at a certain stage of postnatal development. Certain tests, in addition to general motor skills, allowed the assessment of behavioral state as anxiety / depression, hyper-and hypo-activity of offspring. The study was done on adult female NMRI mice. Four experimental and one control group was formed. Females were treated with subcutaneous injection of 50, 100, 200 and 400 mg/kg VPA (Valproic acid sodium salt – 2 propylpentanoic sodium, ≥98, P4543 Sigma Aldrich) or with saline (Natrii Chloridi Infundibule 0,9%, HemofarmhospitalLogica) (control group). All treatments were performed during breeding and whole gestation period. Mice were given ad libitum access to food and water. The offspring was examined in tests: (1) Righting test, (2) Tail suspension test, (3) Hot plate test, (4) Elevated plus maze test and (5) Open field test Results: Different doses of VPA (50, 100, 200 and 400 mg/kg) continuously applied on female NMRI mice during breeding and whole gestation caused female mortality and lower fertility dose-dependent effect. Treatment had no influence on female body weight. In utero exposure to valproate has a negative impact on body weight of individuals during postnatal development, including the adolescence. Treatment is associated with a delay in eye-opening at the 15th postnatal day (PND). Prenatal exposition to different doses of VPA significantly influence on offspring behaviour in righting reflex. Regarding the critical developmental postnatal points, treatment influence on type response and latency during righting reflex testing. VPA treatment during gestation affect outcome of tail suspension test at the 5th and 10th PND (regarding the doses of 200 and 400mg/kg). There are no concequences in treated groups in tst at 15th PND. VPA exposition in utero distinctly influence on outcome during hot plate testing at 25th and 32nd PND. Increased procent of inadequately response and extended latency in adequate response of treated mice was obtained in hot plate test. Offspring which mothers were treated with VPA shown different pattern of behaviour (dose- and gender- dependent) during adolescence in elevated plus maze test (PND 35). Mice prenataly exposed to VPA during adolescence (PND40), represent significant differences during locomotor, stereotipic and vertical activity in the open field test. Conclusion: Experimental model of continuous application of VPA during breeding and gestation on mice is congruent with therapeutic application in epilepsy treatment during pregnancy in human population. Obtained results in this study indicate that exposure to VPA induce the effect which is dose- and gender-dependent. A subtherapeutic doses applied during gestation significantly influence on the course of psychomotor development. Methodolically, this experiments had shown that the consequences of exposition to valproate in-utero must be examined during adequate postnatal period. Mice has higher rate of VPA metabolism compared with the human rate. Regarding this fact, critical approach must be considered in approximation of the results obtained from animal model of mice to human population.
Keywords:Valproate; Gestation; Psychomotor development; Animal model
Source:University of Kragujevac, Faculty of Medical Sciences, 2014, 1-133
- The effect of prenatal exposure to antiepileptic therapy on the neurological development (RS-175006)