Michal Dubovický

Neurobehavioral manifestations of developmental impairment of the brain

Neurobehavioral manifestations of developmental impairment of the brain Individual characteristics of human nature (e.g. introversion, extroversion, mood, activity, adaptability, aggressiveness, social ability, anxiety) do not need to be primarily innate. They can be determined by the action of various influences and their interactions on functional development of the brain. There is ample epidemiological and experimental evidence that chemical and/or physical factors acting during sensitive time windows of the brain development can cause mental, behavioral, emotional and/or cognitive disorders. Environmental pollutants, addictive substances, drugs, malnutrition, excessive stress and/or hypoxia-ischemia were reported to induce functional maldevelopment of the brain with consequent neurobehavioral disorders. The article provides review on most significant neurobehavioral manifestations of developmental impairment of the brain during prenatal, perinatal and early postnatal period. The most known adverse factors causing developmental neurobehavioral dysfunctions in humans as well as in experimental animals are discussed.

Evaluation of developmental neurotoxicity: some important issues focused on neurobehavioral development

Evaluation of developmental neurotoxicity: some important issues focused on neurobehavioral development Exposure of the developing organism to industrial chemicals and physical factors represents a serious risk factor for the development of neurobehavioral disorders, such as attention-deficit hyperactivity disorder, autism and mental retardation. Appropriate animal models are needed to test potentially harmful effects and mechanisms of developmental neurotoxicity of various chemical substances. However, there are significant human vs. rat differences in the brain developmental profile which should be taken into account in neurotoxicity studies. Subtle behavioral alterations are hard to detect by traditional developmental toxicity and teratogenicity studies, and in many cases they remain hidden. They can however be revealed by using special behavioral, endocrine and/or pharmacological challenges, such as repeated behavioral testing, exposure to single stressful stimulus or drugs. Further, current neurobehavioral test protocols recommend to test animals up to their adulthood. However some behavioral alterations, such as anxiety-like behavior or mental deficiency, may become manifest in later periods of development. Our experimental and scientific experiences are highly suggestive for a complex approach in testing potential developmental neurotoxicity. Strong emphasis should be given on repeated behavioral testing of animals up to senescence and on using proper pharmacological and/or stressful challenges.

Teratology – past, present and future

ABSTRACT Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development. The authors present an updated overview of the most important milestones and stages of the development of modern teratology. Development of knowledge and society led to the recognition that causes of congenital developmental disorders (CDDs) might be caused by various mechanical effects, foetal diseases, and retarded or arrested development of the embryo and foetus. Based on the analysis of the historical development of hypotheses and theories representing a decisive contribution to this field, we present a survey of the six Wilson´s fundamental principles of teratology. The aim of observing these principles is to get insight into developmental relations and to understand mechanisms of action on the level of cell populations (elementary morphogenetic processes), tissues and organs. It is important to realise that any negative intervention into the normal course of these processes, either on genetic or non-genetic basis, inevitably leads to a sequence of subsequent changes resulting in CDDs. Moreover, the classical toxicologic monotonic doseresponse paradigm recently has been challenged by the so-called “low dose-hypothesis”, particularly in the case of endocrine active substances. These include some pesticides, dioxins, polychlorobiphenyls (PCBs), and bisphenol A. Despite modern approaches of molecular biology and genetics, along with top diagnostic techniques, we are still not able to identify the actual cause in more than 65 to 70% of all congenital defects classified as having an unknown etiology. Today CDDs include any birth defect, either morphological, biochemical, or behavioural.

Experimental modeling of hypoxia in pregnancy and early postnatal life

Experimental modeling of hypoxia in pregnancy and early postnatal life The important role of equilibrium of environmental factors during the embryo-fetal period is undisputable. Women of reproductive age are increasingly exposed to various environmental risk factors such as hypoxia, prenatal viral infections, use of drugs, smoking, complications of birth or stressful life events. These early hazards represent an important risk for structural and/or functional maldevelopment of the fetus and neonates. Impairment of oxygen/energy supply during the pre- and perinatal period may affect neuronal functions and induce cell death. Thus when death of the newborn is not occurring following intrauterine hypoxia, various neurological deficits, including hyperactivity, learning disabilities, mental retardation, epilepsy, cerebral palsy, dystonia etc., may develop both in humans and in experimental animals. In our animal studies we used several approaches for modeling hypoxia in rats during pregnancy and shortly after delivery, i.e. chronic intrauterine hypoxia induced by the antiepileptic drug phenytoin, neonatal anoxia by decreased oxygen saturation in 2-day-old pups. Using these models we were able to test potential protective properties of natural (vitamin E, melatonin) and synthetic (stobadine) compounds. Based on our results, stobadine was also able to reduce hypoxia-induced hyperactivity and the antioxidant capacity of stobadine exceeded that of vitamin E and melatonin, and contrary to vitamin E, stobadine had no adverse effects on developing fetus and offspring.

Effect of Long-term Administration of Stobadine on Exploratory Behaviour and on Striatal Levels of Dopamine and Serotonin in Rats and their Offspring

Stobadine (STB), a cardioprotective drug, was evaluated for its effect on the intensity and habituation of exploratory behaviour in open field testing and on the levels of striatal dopamine (DA), serotonin (5‐HT) and their metabolites (3,4‐dihydroxyphenylacetic acid, homovanillic acid, 5‐hydroxyindole‐3‐acetic acid) in rats and their offspring. Dams were treated by oral gavage with STB (50 mg kg−1) for a total of 56 days from 14 days before mating to day 21 postpartum (pp). The first open field measurements of the dams were performed over 4 days at the beginning of the experiment, the second on days 21–24 pp and the third on days 49–52 pp (recovery period). Their offspring were tested on postnatal (pn) days 30–33 and 60–63. The biochemical analysis (HPLC with electrochemical detection) in the dams was performed at the same time schedule as given for the open field testing, but in their offspring only on pn day 60. Motor activity of the dams was decreased on days 21–24 pp. The increase of motor activity in female offspring was observed on pn days 30–33. Neurochemical analysis of the striatum of the dams revealed a significant increase of the levels of DA, 5‐HT and 5‐hydroxyindole‐3‐acetic acid. In male offspring the levels of DA were significantly decreased, whereas in females the levels were increased. These results suggest that maternal administration of STB resulted both in dams and their offspring in minor alterations in spontaneous behaviour components and changes in the dopaminergic and serotonergic system, but without inducing overtly detectable toxicity. © 1997 by John Wiley & Sons, Ltd.

Modulation of microglial function by the antidepressant drug venlafaxine 28 November 2014

ABSTRACT An increasing amount of data suggests that depression is an inflammatory disease. Depressed patients have higher peripheral blood levels of inflammatory markers which have been shown to access the brain and interact with the pathophysiological domain known to be involved in depression. Furthermore, microglia activation may play an important role in the inflammatory pathophysiology of depression. In BV-2 microglia cell line, the present study investigated the potential anti-inflammatory effects of venlafaxine, along with its potential influence on injury of lipopolysaccharide (LPS)-stimulated cells. Although venlafaxine showed only marginal influence on the majority of the pro-inflammatory parameters assessed (in particular NO release, phagocytosis and proliferation), it significantly suppressed superoxide production by the stimulated cells. In addition, venlafaxine exerted also a protective effect on mitochondrial membrane potential and lysosomes of the stimulated microglia. In conclusion, our results suggest that although VEN might have only a marginal effect on major pro-inflammatory parameters of microglia, its inhibitory effect on superoxide generation can contribute to the prevention of harmful effects of oxidative and nitrosative stress involved in the pathogenesis of depression. Moreover, the protective effect of VEN on viability of microglia can prevent a rapid reduction of these cells, thus avoiding limitations of several physiological processes in the brain and possibly also the progression of depression

Early assessment of the severity of asphyxia in term newborns using parameters of blood count

Early assessment of the severity of asphyxia in term newborns using parameters of blood count Acute perinatal asphyxia is a major cause of death and neurological injury in newborn infants. Severe asphyxia can occur in infants around the time of birth for several reasons. The aim of our study was to find the most sensitive, easily obtainable and fast assessable parameter of the presence and quantification of asphyxia. In our study 39 term newborns (15 healthy term newborns and 24 asphyxial term newborns), from vaginal deliveries admitted within 24 hours of life were monitored and parameters of blood count from venous blood were assessed. Laboratory findings of blood count parameters revealed significant differences between term asphyxial and healthy newborns in erythrocyte count and hemoglobin and hematocrit values. Hematological changes observed early after delivery can determine the duration of hypoxemia (acute vs. chronic) and asphyxia of short duration may be accompanied without occurrence of polyglobulia.

Evaluation of long-term administration of the antioxidant stobadine on exploratory behaviour in rats of both genders

Stobadine (STO) is a prospective neuro‐ and cardioprotective drug with high antioxidative properties. The aim of this study was to ascertain the effect of long‐term administration of STO on exploratory behaviour and habituation processes in adult virgin female and male rats. Stobadine was administered by oral gavage in a single dose of 50 mg kg−1 day−1 for a total of 56 days. The animals were tested for exploratory behaviour—intensity of motor and vertical activity in an open field test in three blocks of measurements (initial screening; after 56 days of STO administration; and 28 days after the last treatment). The rate of decline of motor activity was evaluated during four consecutive days of testing (interrupted habituation). Administration of STO resulted in transient inhibition of exploratory behaviour in female rats without overtly detectable toxicity. Exploratory behaviour of males was not affected by STO treatment. Copyright

Effect of prenatal administration of venlafaxine on postnatal development of rat offspring

Abstract About 3% of pregnant women are treated with antidepressant drugs during gestation. After delivery the number of treated women increases to 5 to 7%. Most prescribed antidepressants in pregnancy are selective serotonin re-uptake inhibitors and/or serotonin and noradrenaline re-uptake inhibitors, such as fluoxetine, paroxetine, sertraline, citalopram and venlafaxine (VENF). Despite the fact that VENF has been assigned to pregnancy category C by the FDA, experimental studies with this drug are rare. The aim of this pilot study was to investigate the effect of prenatal administration of VENF on early postnatal development of rat offspring and selected biochemical variables at weaning of pups. Pregnant female Wistar rats were treated with VENF from day 15 to 20 of gestation at the doses of 7.5, 37.5 and 70 mg/kg. Females were allowed to spontaneously deliver their pups. After delivery the pups were inspected for viability, gross malformation and they were weighed on day 0, 4 and 21 post partum. On day 21 post partum, the pups were killed, brains were removed from the skulls and blood samples were collected for biochemical assay (proteins, glucose-GOD, glucose-HEX, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and total antioxidant status). The study showed that prenatal VENF administration resulted in a mild maternal intoxication manifested by decreased body weight gain of pregnant females. There was no effect of the drug tested on the body and brain weights of offspring. No obvious morphological alterations were observed in the delivered pups. Similarly, there were no changes in the selected biochemical variables determined.

Anxiolytic activity of pyridoindole derivatives SMe1EC2 and SMe1M2: behavioral analysis using rat model

Anxiolytic activity of pyridoindole derivatives SMe1EC2 and SMe1M2: behavioral analysis using rat model Anxiety and mood disorders have become very significant affections in the last decades. According to WHO at least one mental disease occurred per year in 27% of EU inhabitants (more than 82 mil. people). It is estimated that by 2020, depression will be the main cause of morbidity in the developed countries. These circumstances call for research for new prospective drugs with anxiolytic and antidepressive properties exhibiting no toxicity and withdrawal effect and possessing beneficial properties, like antioxidant and/or neuroprotective effects. The aim of this study was to obtain information about psychopharmacological properties of pyridoindole derivatives SMe1EC2 and SMe1M2, using non-invasive behavioral methods in rats. The battery of ethological tests (open field, elevated plus-maze, light/dark box exploration, forced swim test) was used to obtain information about anxiolytic and antidepressant activity of the pyridoindole derivatives. The substances were administered intraperitoneally 30 minutes before the tests at doses of 1, 10 and 25 mg/kg. In the behavioral tests, SMe1EC2 was found to exert anxiolytic activity in elevated plus maze with no affection of locomotor activity. The highest dose of SMe1M2 increased the time spent in the lit part of the Light/Dark box, however this result was influenced by inhibition of motor activity of the rats. Similar findings were observed also in elevated plus-maze, although these results were not statistically significant. In conclusion, from the results of our study it is evident that both pyridoindoles acted on the CNS. In the highest dose, SMe1M2 was found to possess rather sedative than anxiolytic or antidepressant activity.