Treatment and Prevention of Neurocristopathies.

Neurocristopathies form a heterogeneous group of rare diseases caused by abnormal development of neural crest cells. Heterogeneity of neurocristopathies directly relates to the nature of these migratory and multipotent cells, which generate dozens of specialized cell types throughout the body. Neurocristopathies are thus characterized by congenital malformations of tissues/organs that otherwise appear to have very little in common, such as the craniofacial skeleton and enteric nervous system. Treatment options are currently very limited, mainly consisting of corrective surgeries. Yet, as reviewed here, analyses of normal and pathological neural crest development in model organisms have opened up the possibility for better treatment options involving cellular and molecular approaches. These approaches provide hope that some neurocristopathies might soon be curable or preventable.

Valproate and folate: Congenital and developmental risks.

Increasing awareness of the congenital and developmental risks associated with the use of sodium valproate (VPA) has led to recent European guidelines designed to avoid the use of this drug in pregnancy if effective alternative treatments are available. In the general population, it is well established that periconceptual folic acid reduces the risk of neural tube defects (NTDs) and possibly other congenital abnormalities. We here review the evidence 1) that VPA interferes with one-carbon metabolism, including the transport of methylfolate into the brain and the placenta by targeting folate receptors; 2) that VPA effects on the folate metabolic system contribute to congenital and developmental problems associated with VPA exposure; and 3) that genetic factors, notably polymorphisms related to one-carbon metabolism, contribute to the vulnerability to these VPA-induced risks. Based on these facts, we propose that the standard periconceptual use of 400 µg of folic acid may not adequately protect against VPA or other antiepileptic drug (AED)-induced congenital or developmental risks. Pending definitive studies to determine appropriate dose, we recommend up to 5 mg of folic acid periconceptually in at-risk women with the caveat that the addition of supplementary vitamin B12 may also be prudent because vitamin B12 deficiency is common in pregnancy in some countries and is an additional risk factor for developmental abnormalities.

Curcumin Prevents Cerebellar Hypoplasia and Restores the Behavior in Hyperbilirubinemic Gunn Rat by a Pleiotropic Effect on the Molecular Effectors of Brain Damage.

Bilirubin toxicity to the central nervous system (CNS) is responsible for severe and permanent neurologic damage, resulting in hearing loss, cognitive, and movement impairment. Timely and effective management of severe neonatal hyperbilirubinemia by phototherapy or exchange transfusion is crucial for avoiding permanent neurological consequences, but these therapies are not always possible, particularly in low-income countries. To explore alternative options, we investigated a pharmaceutical approach focused on protecting the CNS from pigment toxicity, independently from serum bilirubin level. To this goal, we tested the ability of curcumin, a nutraceutical already used with relevant results in animal models as well as in clinics in other diseases, in the Gunn rat, the spontaneous model of neonatal hyperbilirubinemia. Curcumin treatment fully abolished the landmark cerebellar hypoplasia of Gunn rat, restoring the histological features, and reverting the behavioral abnormalities present in the hyperbilirubinemic rat. The protection was mediated by a multi-target action on the main bilirubin-induced pathological mechanism ongoing CNS damage (inflammation, redox imbalance, and glutamate neurotoxicity). If confirmed by independent studies, the result suggests the potential of curcumin as an alternative/complementary approach to bilirubin-induced brain damage in the clinical scenario.

Assessing the utility of antivirals for preventing maternal-fetal transmission of zika virus in pregnant mice.

Zika virus (ZIKV) infection during pregnancy has been associated with adverse outcomes and birth defects such as microcephaly in newborn children. Congenital malformations associated with ZIKV are believed to occur via direct infection of the fetus. Unfortunately, there are no licensed therapeutic or preventative tools to block maternal-fetal transmission of ZIKV. In this study, we developed a mouse model of ZIKV infection that specifically establishes vertical maternal-fetal transmission of ZIKV in 40-60% of fetuses when the dams acquire ZIKV infection during pregnancy. This mouse model somewhat mirrors the experience in humans at the peak of the epidemic in the Americas. Using this model, we demonstrate that a well-documented directly acting antiviral (DAA) compound that targets flaviviral RNA synthesis can completely prevent fetal infection when the treatment is started at the time of infection. Notably, we show that the treatment commenced at the time of peak viremia is still able to reduce the risk of fetal infection concomitant with significant reduction in placental viral load. Our results show for the first time the potential for clinical development of antiviral drugs for preventing vertical maternal-fetal transmission of ZIKV.

Improving Folic Acid Supplementation Rates in Women of Childbearing Age With Epilepsy.

BACKGROUND: This study aims to improve the rate of folic acid supplementation to adolescent women with epilepsy on an antiepileptic drug (AED) regimen seen by the pediatric neurology providers at the Children's Hospital at Montefiore, in compliance with the 2009 American Academy of Neurology and American Epilepsy Society practice parameter. METHODS: We designed a quality improvement study with implementation of a series of interventions and compared folic acid supplementation rates before and after intervention. We made additional comparisons based on specific age groups (12 to 15 years and 16 to 21 years) and a diagnosis with or without developmental impairment. RESULTS: A review of 1850 charts from 2004 to 2015 showed an average folic acid prescription rate of 41%. Supplementation rates gradually increased to 52.2%, 58.5%, 60.3%, and finally up to 81.6% after this respective intervention: initial email reminder, provider education, posting signs in examination rooms, and implementation of an electronic medical record best practice advisory. There was improvement across all categories, in both age groups (12 to 15 years and 16 to 21 years) and in those with or without developmental impairment. There was a trend for higher compliance rates in adolescents without developmental impairment. CONCLUSIONS: Our interventions resulted in an increase in folic acid supplementation rates of adolescent women with epilepsy. These results are encouraging. We plan to extend education about the recommendations for folic acid supplementation to non-neurology providers, as well as expand to apply our interventions and assess adherence to other defined epilepsy quality measures.

Neurotrophic Factors and Maternal Nutrition During Pregnancy.

Maternal nutrition is one of the major determinants of pregnancy outcome. It has been suggested that reduced intakes or lack of specific nutrients during pregnancy influences the length of gestation, proper placental and fetal growth during pregnancy. Maternal nutrition, particularly micronutrients such as folate and vitamin B12, and long-chain polyunsaturated fatty acids (LCPUFA) are the major determinants of the one carbon cycle and are suggested to be at the heart of intrauterine programming of diseases in adult life. LCPUFA play a key role in the normal feto-placental development, as well as in the development and functional maturation of the brain and central nervous system and also regulate the levels of neurotrophic factors. These neurotrophic factors are known to regulate the development of the placenta at the materno-fetal interface and act in a paracrine and endocrine manner. Neurotrophic factors like brain-derived neurotrophic factor and nerve growth factor are proteins involved in angiogenesis and potentiate the placental development. This chapter mainly focuses on micronutrients since they play a main physiological role during pregnancy.

Antenatal taurine supplementation for improving brain ultrastructure in fetal rats with intrauterine growth restriction.

Changes in brain ultrastructure of fetal rats with intrauterine growth restriction (IUGR) were explored and the effects of antenatal taurine supplementation on their brain ultrastructure were determined. Fifteen pregnant rats were randomly divided into three groups: control group, IUGR model group and IUGR group given antenatal taurine supplements. Taurine was added to the diet of the taurine group at a dose of 300 mg/kg/d from 12 days after conception until natural delivery. Transmission electron microscopy was used to observe ultrastructural changes in the brains of the newborn rats. At the same time, brain cellular apoptosis was detected using TUNEL, and the changes in protein expression of neuron specific enolase and glial fibrillary acidic protein were analyzed using immunohistochemistry. The results showed that: 1) The average body weight and cerebral weight were significantly lower in the IUGR group than in the control group (p<0.01) and both of them were less so after taurine was supplemented (p<0.01). 2) Transmission electron microscopy revealed that brain cortex structures were sparse IUGR rats, showing many scattered apoptotic cells, decreased numbers of synapses, lower glial cell proliferation, and fewer neurons, more sparsely arranged, while these factors were significantly improved with taurine supplementation. 3) The results of TUNEL showed that the counts of apoptotic brain cells in IUGR groups were significantly increased from those in control groups and that taurine could significantly decrease brain cell apoptosis (p<0.001). 4) The results of immunohistochemistry showed that antenatal taurine-supplementation could significantly increase the counts of neuron specific enolase and glial fibrillary acidic protein immunoreactive cells in fetal rats with IUGR (p<0.001). It can be concluded that it IUGR has a significant detrimental influence on the development of fetal rat brains, and antenatal supplement of taurine can significantly improve the IUGR fetal brain development.

Central nervous system congenital malformations in a developing country: issues and challenges against their prevention.

BACKGROUND: Little efforts are geared towards prevention of CNS anomalies in the developing countries. METHODS: A 1-year prospective cross-sectional analysis of the cases of CNS congenital anomalies seen in a Nigerian neurosurgical unit. This included both the children's and parents' sociodemographics, the profiles of the CNS anomalies, and the maternal obstetric health behaviors toward primary and/or secondary prevention of the anomalies. Statistical analysis was done with the Pearson's chi-square (or Fishers' exact) test. Level of significance set at P < 0.05. RESULTS: There were 54 cases of cranial and spinal gross CNS anomalies, including 32 neural tube defects; two thirds of the parents were low-income earners, and half had only basic education. Thirty percent of the pregnancies were unbooked; the mean gestational age (GA) at booking and commencement of obstetric micronutrient supplementation was 4.6 months. No case had periconceptional folic acid supplementation. Obstetric ultrasonography was performed late in pregnancy (mean GA 6 months), made positive diagnosis of CNS anomaly in only 14%, and was performed mainly in unsupervised private clinic settings in 98%. CONCLUSIONS: Little or no attention is currently paid to the prevention of CNS congenital anomalies in much of the low- and middle-income countries of the world. There is a great need to regulate the practice of obstetric ultrasonography in Nigeria. There is even a much greater, more fiercely urgent need to ensure periconceptional folic acid supplementation for all women of childbearing age through appropriate food fortification in these societies.

Carbamazepine protects against megencephaly and abnormal expression of BDNF and Nogo signaling components in the mceph/mceph mouse.

Carbamazepine (CBZ) is a commonly used antiepileptic drug known to block voltage-gated sodium channels. Infants exposed to CBZ in utero show reduced head circumference, for reasons unknown. We investigated CBZ's effect on neural growth in megencephaly (mceph/mceph) mice lacking functional Kv1.1. Mice fed with CBZ were assessed for brain structure size, seizure behavior and expression of markers for neuronal plasticity and rescue in brain. CBZ counteracted brain overgrowth and the increased size of neurons in the mceph/mceph mouse. These effects of CBZ occurred at doses that did not fully suppress epileptic behavior. Furthermore, CBZ normalized Bdnf mRNA levels and mRNA species encoding Nogo signaling pathway proteins. In conclusion, CBZ protects efficiently against abnormal growth and abnormal expression patterns of nerve growth signaling systems in the mceph/mceph brain. These observations and the effect of CBZ in utero suggest that CBZ treatment might be advantageous in some types of human idiopathic megalencephaly.

Enriched environments, experience-dependent plasticity and disorders of the nervous system.

Behavioural, cellular and molecular studies have revealed significant effects of enriched environments on rodents and other species, and provided new insights into mechanisms of experience-dependent plasticity, including adult neurogenesis and synaptic plasticity. The demonstration that the onset and progression of Huntington's disease in transgenic mice is delayed by environmental enrichment has emphasized the importance of understanding both genetic and environmental factors in nervous system disorders, including those with Mendelian inheritance patterns. A range of rodent models of other brain disorders, including Alzheimer's disease and Parkinson's disease, fragile X and Down syndrome, as well as various forms of brain injury, have now been compared under enriched and standard housing conditions. Here, we review these findings on the environmental modulators of pathogenesis and gene-environment interactions in CNS disorders, and discuss their therapeutic implications.

Prevention by maternal pancreatic islet transplantation of hypothalamic malformation in offspring of diabetic mother rats is already detectable at weaning.

Exposure to gestational diabetes (GD) in rats leads to dysplasia of the ventromedial hypothalamic nucleus (VMN), decisively involved into the regulation of body weight and metabolism. Recently, we have shown here that VMN malformation is absent in adult offspring of GD mothers treated by pancreatic islet transplantation during gestation. We therefore now investigated whether VMN malformation and its prevention are already present at the early postnatal end of the critical hypothalamic differentiation period. Already at weaning, the total number of VMN neurons, the volume of the VMN relative to total brain volume, and the numerical density of neurons in the anterior subnucleus of the VMN were reduced in offspring of sham-transplanted mothers (all P<0.05), but did not differ between offspring of islet-transplanted mothers and controls. No morphometric alterations occurred in the paraventricular hypothalamic nucleus. In conclusion, prevention of VMN malformation in offspring of islet-transplanted diabetic mothers is a direct consequence of normalized maternal metabolism during critical perinatal development.

Pancreatic islet transplantation in diabetic pregnant rats prevents acquired malformation of the ventromedial hypothalamic nucleus in their offspring.

Exposure to a diabetic intrauterine environment leads to diabetogenic disturbances throughout later life in rats. This is accompanied by a fetally acquired dysplasia of the ventromedial hypothalamic nucleus (VMN) which is decisively involved in the regulation of metabolism. We investigated whether malformation of the VMN is preventable by normalization of gestational hyperglycaemia. Correction of hyperglycaemia in pregnant streptozotocin-diabetic rats was achieved by pancreatic islet transplantation. The number of neurons in the VMN was significantly reduced in adult offspring of non-treated, sham-transplanted mother rats (P<0.05), but did not differ between offspring of islet-transplanted mother rats and offspring of control mothers. In conclusion, prevention of VMN malformation in offspring of islet-transplanted diabetic mothers might be co-responsible for normalization of their glucose homeostasis during life.

N-methyl-D-aspartate receptor agonists modulate homocysteine-induced developmental abnormalities.

We showed previously that the induction of neural crest (NC) and neural tube (NT) defects is a general property of N-methyl-D-aspartate receptor (NMDAR) antagonists. Since homocysteine induces NC and NT defects and can also act as an NMDAR antagonist, we hypothesized that the mechanism of homocysteine-induced developmental defects is mediated by competitive inhibition of the NMDAR by homocysteine. If this hypothesis is correct, homocysteine-induced defects will be reduced by NMDAR agonists. To test the hypothesis, we treated chicken embryos during the process of neural tube closure with sufficient homocysteine thiolactone to induce NC and NT defects in approximately 40% of survivors or with homocysteine thiolactone in combination with each of a selected set of NMDAR agonists in 0. 05-5000 nmol doses. Glutamate site agonists selected were L-glutamate and N-methyl-D-aspartate. Glycine site agonists were glycine, D-cycloserine, and aminocyclopropane-carboxylic acid. Glycine was the most effective overall, reducing defects significantly at two different doses (each P>0.001). These results support the hypothesis that homocysteine may affect NC and NT development by its ability to inhibit the NMDAR. One potentially important consequence of this putative mechanism is that homocysteine may interact synergistically with other NMDAR antagonists to enhance its effect on development.