The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats

The GluN2B subunit of NMDA receptors represents a perspective therapeutic target in various CNS pathologies, including epilepsy. Because of its predominant expression in the immature brain, selective GluN2B antagonists are expected to be more effective early in postnatal development. The aim of this study was to identify age-dependent differences in the anticonvulsant activity of the GluN2B-selective antagonist Ro 25-6981 and assess the safety of this drug for the developing brain. Anticonvulsant activity of Ro 25-6981 (1, 3, and 10 mg/kg) was tested in a pentylenetetrazol (PTZ) model in infantile (12-day-old, P12) and juvenile (25-day-old, P25) rats. Ro 25-6981 (1 or 3 mg/kg/day) was administered from P7 till P11 to assess safety for the developing brain. Animals were then tested repeatedly in a battery of behavioral tests focusing on sensorimotor development, cognition, and emotionality till adulthood. Effects of early exposure to Ro 25-6981 on later seizure susceptibility were tested in the PTZ model. Ro 25-6981 was effective against PTZ-induced seizures in infantile rats, specifically suppressing the tonic phase of the generalized tonic–clonic seizures, but it failed in juveniles. Neither sensorimotor development nor cognitive abilities and emotionality were affected by early-life exposure to Ro 25-6981. Treatment cessation did not affect later seizure susceptibility. Our data are in line with the maturational gradient of the GluN2B-subunit of NMDA receptors and demonstrate developmental differences in the anti-seizure activity of the GluN2B-selective antagonist and its safety for the developing brain.

Early Neurodevelopmental Anomalies in Young Rats from Adult female Treated with Valproic Acid

Background: the influence of VPA on murine fertility, and on offspring is well documented: VPA decreases the fertility rate (by 25%) and the number of fœtus. Furthermore, VPA causes behavioral alterations in rodents similar to the symptoms observed in autism.Objective: in this study we investigated the effects of exposure of non-pregnant adult rats to VPA in the offspring of these animals.Material and methods: non-pregnant adult rats were divided into 3 groups; (1) distilled water group, (2) VPA 200 mg / kg group and (3) VPA 400 mg/kg group. The products were administered orally daily for 30 days. At the end of treatments, all rats were put into monogamous mating with breeding males. The zootechnical characteristics (gestation period, litter size, mortality rate) were then noted. The young rats were then subjected to a battery of behavioral tests (reversal and anti-gravity reflexes, cliff avoidance, suspension, motor coordination and eye opening), carried out at different stages of life to assess sensorimotor development. Morphological abnormalities were also sought, as well as the mortality rate on the 28th day of life.Results: An increase in the mortality rate and a decrease in the mean lifespan were found in female rats exposed to VPA. Young rats from female rats exposed to VPA showed decreased success rates and performance in behavioral testing. Morphodevelopmental abnormalities such as adictalia or stump necrosis were found in the VPA groups. The offspring mortality rate of female rats exposed to VPA 200 mg/kg was 100%.Conclusion: VPA administered to non-pregnant adult rats causes developmental abnormalities, decreased success rates for performance testing, deformities and increased mortality in young rats from the treated rats by VPA.

Differences in Sensorimotor Development Among U.S. Infants Receiving Breastmilk and/or Formula in the First 6-Months From the PediaTrac™ Project

Objectives Achieving sensorimotor (SEM) milestones is one measure of early infant brain development promoted through higher docosahexaenoic acid (DHA) levels. Both breastmilk and formula contain DHA, with a global level of 0.32% in breastmilk and many formula brands. However, a 2017 study of Midwestern U.S. mothers found significantly lower breastmilk DHA levels. It was thus hypothesized that infants fed formula would have higher SEM scores. The objective of this study was to measure differences in SEM development between infants fed breastmilk, formula, or a combination in participants of the PediaTrac™ Project. PediaTrac is a web-based measure providing longitudinal, real time, multidomain data on infant and toddler growth and development at time periods corresponding to well child visits. Methods Using PediaTrac, data were collected from 548 caregiver-infant dyads across multiple Midwestern sites. Caregivers reported the primary nutrition source as breastfeeding, formula or combination. Their responses to gross and fine motor function questions were used to create a SEM composite, Percent of Maximum Possible (POMP) score at newborn (NB), 2-, 4- and 6-months. Data were analyzed via ANOVA and Tukey test using SPSS. Results Infants fed formula had statistically higher mean SEM scores at NB (M = 0.618Formula, M = 0.590Breast, p = 0.017), 2- (M = 0.706Formula, M = 0.680Breast, p = 0.006) and 6-months (M = 0.727Formula, M = 0.696Breast, p = 0.014) compared to breastfed infants. Mean SEM scores of combination fed infants were higher than breastfed infants at 2- (M = 0.701Combination, M = 0.680Breast, p = 0.184), 4- (M = 0.684Combination, M = 0.673Breast, p = 0.573) and 6-months (M = 0.704Combination, M = 0.696Breast, p = 0.895), despite no significant differences between scores. Conclusions Formula fed infants showed consistently higher SEM scores than breastfed infants in the first 6-months. These findings contradict previous research, indicating a need for further investigation into variables contributing to these discrepancies such as maternal breastmilk DHA concentrations, socioeconomic factors, site specific confounds, accuracy of parent reports of motor development, etc. Funding Sources Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health. EMU College of Health & Human Services Research Support Award.

Prenatal Alcohol and THC E-Cigarette Exposure Effects on Motor Development

It has been well established that prenatal alcohol exposure can lead to a wide range of neurological and behavioral deficits, including alterations in motor domains. However, much less is known about the effects of prenatal cannabis exposure on motor development, despite the fact that cannabis is the most commonly consumed illicit drug among women. Cannabis use among pregnant women has become increasingly popular given the wide-spread perception that consumption is safe during pregnancy. Moreover, alcohol and cannabis are commonly used together, even among pregnant women. Yet, few studies have explored the potential consequences of combined prenatal exposure on behavioral domains. Using our previously established model, pregnant Sprague-Dawley rats were exposed to vaporized alcohol, THC via e-cigarettes, the combination, or a vehicle from gestational days 5-20. Following birth, offspring were tested on early sensorimotor development, adolescent motor coordination, and adolescent activity levels. Prenatal e-cigarette THC exposure delayed sensorimotor development early in life and impaired motor coordination later in adolescence. However, combined prenatal alcohol and THC exposure produced hyperactivity among male offspring. These data suggest that prenatal cannabis exposure may lead to impaired motor skills throughout early development, and that combined exposure with alcohol during gestation may also lead to hyperactivity in adolescence. These findings have important implications for pregnant women and public policy.

Impact of Prenatal Hypoxia on the Development and Behavior of the Rat Offspring

The healthy development of the fetus depends on the exact course of pregnancy and delivery. Therefore, prenatal hypoxia remains between the greatest threats to the developing fetus. Our study aimed to assess the impact of prenatal hypoxia on postnatal development and behavior of the rats, whose mothers were exposed to hypoxia (10.5 % O2) during a critical period of brain development on GD20 for 12 h. This prenatal insult resulted in a delay of sensorimotor development of hypoxic pups compared to the control group. Hypoxic pups also had lowered postnatal weight which in males persisted up to adulthood. In adulthood, hypoxic males showed anxiety-like behavior in the OF, higher sucrose preference, and lower levels of grimace scale (reflecting the degree of negative emotions) in the immobilization chamber compared to the control group. Moreover, hypoxic animals showed hyperactivity in EPM and LD tests, and hypoxic females had reduced sociability compared to the control group. In conclusion, our results indicate a possible relationship between prenatal hypoxia and changes in sociability, activity, and impaired emotion regulation in ADHD, ASD, or anxiety disorders. The fact that changes in observed parameters are manifested mostly in males confirms that male sex is more sensitive to prenatal insults.

Impact of perinatal hypoxia on the developing brain

Perinatal hypoxia is still one of the greatest threats to the newborn child, even in developed countries. However, there is a lack of works which summarize up-to-date information about that huge topic. Our review covers a broader spectrum of recent results from studies on mechanisms leading to hypoxia-induced injury. It also resumes possible primary causes and observed behavioral outcomes of perinatal hypoxia. In this review, we recognize two types of hypoxia, according to the localization of its primary cause: environmental and placental. Later we analyze possible pathways of prenatal hypoxia-induced injury including gene expression changes, glutaminergic excitatory damage (and a role of NMDA receptors in it), oxidative stress with ROS and RNS production, inflammation and apoptosis. Moreover, we focus on the impact of these pathophysiological changes on the structure and development of the brain, especially on its regions: corpus striatum and hippocampus. These brain changes of the offspring lead to impairments in their postnatal growth and sensorimotor development, and in their motor functions, activity, emotionality and learning ability in adulthood. Later we compare various animal models used to investigate the impact of prenatal and postnatal injury (hypoxic, ischemic or combinatory) on living organisms, and show their advantages and limitations.