Dihydropteridine reductase activity in the brainstem of intrauterine growth-restricted rats

The aim of this study was to determine whether intrauterine growth restriction produces an increase of dihydropteridine reductase activity as a compensatory mechanism that maintains the necessary concentration of cofactor, tetrahydrobiopterin, during accelerated brain serotonin biosynthesis. Intrauterine growth-restricted offspring and controls were used. On days 1, 10, 15 and 21 of life, the brainstem was dissected and l-tryptophan, serotonin, tryptophan-5-hydroxylase and dihydropteridine reductase activities were determined. Intrauterine growth-restricted pups showed a significant increase of l-tryptophan, 5-hydroxytryptamine, tryptophan-5-hydroxylase and also dihydropteridine activity in the brainstem in comparison to normal pups. These results confirm that intrauterine growth restriction produces an increase of serotonin biosynthesis in the brainstem. This is accompanied by an increase in dihydropteridine activity that appears to be a compensatory mechanism to maintain sufficient tetrahydrobiopterin for the donation of electrons during the accelerated synthesis of brain serotonin in intrauterine growth-restricted rats.     

A strategy to treat neonatal hypoxic encephalopathy using glial cell line-derived neurotrophic factor

Hypoxic-ischemic encephalopathy is one of the main causes of neurological disabilities. It has been reported that the infarcted area can be reduced by injection of glial cell line-derived neurotrophic factor (GDNF) into the brain parenchyma after a hypoxic/ischemic insult in neonatal rats. We have shown that GDNF is expressed in neuronal and non-neuronal cells throughout all regions of the developing rat brain. We developed a system for the delivery of a constant supply of glial cell line-derived neurotrophic factor to the brain via implantation of GDNF secreting cells directly into the brain parenchyma. The aim of this study was to examine the neuroprotective effect of GDNF using this delivery system. We implanted a capsule containing GDNF secreting cells in 7 day old Wistar rats, and two days later, they underwent hypoxic-ischemic stress. The capsule provided strong neurological protection, as indicated by a reduction in the infarcted area and the severity of histological damage in the treated group compared with controls. We then investigated whether this new delivery method improved the long time learning and memory disability caused by hypoxic-ischemic stress. We examined the effect of implantation of the cells on three tasks:1) eight arm radial maze task for short memory; 2) choice reaction time task for reference memory; and 3) water maze task for long term memory. In all of the three tasks, implantation of the GDNF capsule improved learning and memory disability. Glial cell line-derived neurotrophic factor treatment is effective not only in reducing brain damage but also in preventing learning and memory impairment following hypoxic-ischemic insult in neonatal rats.     

Effects of maternal hyperhomocysteinemia induced by methionine intake on oxidative stress and apoptosis in pup rat brain

Maternal hyperhomocysteinemia is associated with a number of complications such as preeclampsia syndrome, thromboembolic events, repeated miscarriages, abruptio placentae, in utero fetal death, intrauterine fetal growth restriction and fetal neural tube defects. However, little is known about the mechanism of homocysteine on the degeneration of fetal brain. Thus, our study is aimed to investigate the effects of maternal hyperhomocysteinemia on oxidative stress and apoptosis in pup brain. Hyperhomocysteinemia was induced in female rats by way of administrating methionine dissolved in water at a dose of 1 g/kg body weight throughout the pregnancy. After delivery, level of lipid peroxidation (LPO; as malondialdehyde + 4-hydroxyalkenals) was determined in various fractions of pub brains. Furthermore, DNA fragmentation, levels of Bcl-2 protein and p53 mRNA expression were determined to evaluate apoptosis. Significant elevation was found in the levels of LPO in subcellular fractions of pup brains delivered from hyperhomocysteinemic mothers. DNA fragmentation, a hallmark of apoptosis was observed in the brain of pups of homocysteine group while significant reduction was seen in the levels of anti-apoptotic Bcl-2 levels. In addition, maternal hyperhomocysteinemia increased cerebral p53 mRNA expression above the control value. As a conclusion, we demonstrate and suggest that the pups of hyperhomocysteinemic mothers have an increased oxidative stress in brain tissues. The increased oxidative stress appears to cause apoptosis and cell death. These results may be significant to understand chronic pathology of the complications of hyperhomocysteinemia and congenital malformations of fetuses.     

Transfection of the glial cell line-derived neurotrophic factor gene promotes neuronal differentiation简

Glial cell line-derived neurotrophic factor recombinant adenovirus vector-transfected bone marrow mesenchymal stem cells were induced to differentiate into neuron-like cells using inductive medium containing retinoic acid and epidermal growth factor. Cell viability, micro- tubule-associated protein 2-positive cell ratio, and the expression levels of glial cell line-derived neurotrophic factor, nerve growth factor and growth-associated protein-43 protein in the su- pernatant were significantly higher in glial cell line-derived neurotrophic factor/bone marrow mesenchymal stem cells compared with empty virus plasmid-transfected bone marrow mes- enchymal stem cells. Furthermore, microtubule-associated protein 2, glial cell line-derived neurotrophic factor, nerve growth factor and growth-associated protein743 mRNA levels in cell pellets were statistically higher in glial cell line-derived neurotrophic factor/bone marrow mesen- chymal stem cells compared with empty virus plasmid-transfected bone marrow mesenchymal stem cells. These results suggest that glial cell line-derived neurotrophic factor/bone marrow mesenchymal stem cells have a higher rate of induction into neuron-like cells, and this enhanced differentiation into neuron-like cells may be associated with up-regulated expression of glial cell line-derived neurotrophic factor, nerve growth factor and growth-associated protein-43.     

Intrauterine Growth-Restricted Neonates Born at Term or Preterm: How Different?

Late onset intrauterine growth restriction is a common form of growth restriction, mainly caused by placenta-vascular insufficiency. Whether the intrauterine or extrauterine environment offers a better long-term outcome for the growth-restricted fetus remains unclear. We compared the risk factors and long-term outcomes of late onset growth-restricted neonates delivered between 31-36 weeks of gestation vs those delivered at term. This prospective cohort study included 114 preterm and 193 term born growth-restricted neonates. They underwent a neurobehavioral examination (neonatal period), a neurodevelopmental assessment and the Bayley Scales of Infant Development (age 2 years), and neuromotor assessment and the Wechsler Preschool and Primary Scale of Intelligence (age 6 years). Growth-restricted neonates born prematurely exhibited a significantly higher incidence of maternal hypertension, a maternal history of abortions and stillbirths, increased intrapartum and postnatal complication rates, and abnormal neonatal neurobehavioral scores than expected. Both preterm and term born growth-restricted groups, however, exhibited comparable long-term neurodevelopmental and cognitive outcomes at ages 2 and 6 years. Although prematurely born neonates undergo an earlier growth restriction process and exhibit a higher perinatal risk factor profile, their long-term outcomes are comparable to those of growth-restricted neonates born at term.     

Intraspinal transplantation of motoneuron-like cell combined with delivery of polymer-based glial cell line-derived neurotrophic factor for repair of spinal cord contusion injury

To evaluate the effects of glial cell line-derived neurotrophic factor transplantation combined with adipose-derived stem cells-transdifferentiated motoneuron delivery on spinal cord con-tusion injury, we developed rat models of spinal cord contusion injury, 7 days later, injected adipose-derived stem cells-transdifferentiated motoneurons into the epicenter, rostral and caudal regions of the impact site and simultaneously transplanted glial cell line-derived neuro-trophic factor-gelfoam complex into the myelin sheath. Motoneuron-like cell transplantation combined with glial cell line-derived neurotrophic factor delivery reduced cavity formations and increased cell density in the transplantation site. The combined therapy exhibited superior promoting effects on recovery of motor function to transplantation of glial cell line-derived neurotrophic factor, adipose-derived stem cells or motoneurons alone. These ifndings suggest that motoneuron-like cell transplantation combined with glial cell line-derived neurotrophic factor delivery holds a great promise for repair of spinal cord injury.     

Increased fiber outgrowth from xeno-transplanted human embryonic dopaminergic neurons with co-implants of polymer-encapsulated genetically modified cells releasing glial cell line-derived neurotrophic factor

We investigated whether a continuous supply of glial cell line-derived neurotrophic factor (GDNF) via encapsulated genetically modified cells can promote survival and fiber outgrowth from xenotransplanted human dopaminergic neurons. Cells genetically engineered to continuously secrete GDNF were confined in hollow fiber-based macrocapsules. Each hemiparkinsonian rat received either a single C2C12-hGDNF capsule (n=8) or a C2C12-control capsule (n=8) concomitantly with human embryonic ventral mesencephalic cell suspension transplants. Our results show that fiber outgrowth in the area between the capsule and the graft is more extensive in rats with GDNF-releasing capsules than in rats with control capsules. We suggest that continuous and safe delivery of GDNF to the brain could be a potential way to optimize neural transplantation as a therapy for Parkinson's disease.     

Developmental neurotoxicity of toluene: in vivo and in vitro effects on astroglial cells

Toluene, an inexpensive and available industrial solvent, has become increasingly popular as a drug of abuse. Inhaling toluene leads to a feeling of euphoria and several reports have shown that children born to women who had abused toluene during pregnancy present a syndrome (toluene embryopathy or fetal solvent syndrome) that is characterized by CNS effects (e.g. microencephaly), growth retardation and facial dysmorphologies. The characteristics of the fetal solvent syndrome are very similar to those observed in the fetal alcohol syndrome. As exposure of rats to ethanol during the brain growth spurt has been shown to cause microencephaly and to affect glial cell proliferation and maturation, the present study examines the effects of toluene administration (250, 500 and 750 mg/kg) in neonatal rats from postnatal day 4 to 10. This treatment resulted in a significant decrease in both brain and body weights, and in a significant reduction of levels of glial fibrillary acidic protein, but not of neuron-specific enolase in rat brain. In vitro experiments demonstrate that pharmacologically relevant concentrations of toluene (250-1,000 microM) significantly inhibit proliferation of rat cortical astrocytes without causing overt cytotoxicity. These results indicate that toluene does not cause selective microencephaly; however, it affects brain weight, and appears to target developing astrocytes, possibly by inhibiting their proliferation.     

Growth/differentiation factor 5 and glial cell line-derived neurotrophic factor enhance survival and function of dopaminergic grafts in a rat model of Parkinson's disease

Growth/differentiation factor 5 is a member of the transforming growth factor β superfamily, which has neurotrophic and neuroprotective effects on dopaminergic neurons both in vitro and in vivo. Here we investigate the effects of growth/differentiation factor 5 on foetal mesencephalic grafts transplanted into a rat model of Parkinson's disease, and compare them with those of glial cell line-derived neurotrophic factor. Mesencephalic tissue was suspended in solutions containing either growth/differentiation factor 5 or glial cell line-derived neurotrophic factor prior to transplantation into the left striatum of rats with 6-hydroxydopamine lesions of the left medial forebrain bundle. Both proteins enhanced graft-induced compensation of amphetamine-stimulated rotations. Positron emission tomography studies showed that both neurotrophins increased graft-induced recovery of striatal binding of [¹¹C]RTI-121, a marker for dopaminergic nerve terminals. Post mortem analysis at 8 weeks after transplantation showed that both neurotrophins significantly increased the survival of grafted dopaminergic neurons. This study shows that growth/differentiation factor 5 is at least as effective as glial cell line-derived neurotrophic factor in enhancing the survival and functional activity of mesencephalic grafts, and thus is an important candidate for use in the treatment of Parkinson's disease.     

Ultrasound-induced release of GDNF from lipid coated microbubbles injected into striatum reduces hypoxic-ischemic injury in neonatal rats

Previous studies showed that inflammation and apoptosis were involved in the pathogenesis of hypoxic-ischemic brain injury. The immature brain is particularly vulnerable to damage. Intracerebral injection of glial cell line-derived neurotrophic factor (GDNF) has been shown to reduce the injury induced by hypoxia-ischemia (HI). In this study, the neuroprotective effect of intracerebral ultrasound-induced dissolution of lipid-coated GDNF microbubbles was investigated in a neonatal rat model of hypoxic-ischemic brain injury. Hypoxic-ischemic injury was induced in 7-day-old rats in the present study. The rats with hypoxia-ischemia received intracerebral injections of GDNF-containing microbubbles (0.5 mg/kg). They then received low frequency ultrasound stimulation (20 kHz, 2 h intervals for a total of 24 h and each time lasted for 1 min) to induce release of GDNF into the right striatum. We found that low frequency ultrasound stimulation can induce lipid-coated GDNF microbubbles to release GDNF. Ultrasound-induced dissolution of lipid-coated GDNF microbubbles treatment reduced infarction volume and improved neurological outcomes in neonatal rats. In the meanwhile, the microbubbles attenuated the production of inducible nitric oxide synthase, nitric oxide and tumor necrosis factor-alpha, as well as the activation of caspase-3 in insulted side of brain in neonatal rats. These data demonstrated that ultrasound-induced dissolution of lipid-coated GDNF microbubbles treatment can provide a neuroprotective effect against hypoxia-ischemia in neonatal rats.     

The biological basis of injury and neuroprotection in the fetal and neonatal brain

A compromised intrauterine environment that delivers low levels of oxygen and/or nutrients, or is infected or inflammatory, can result in fetal brain injury, abnormal brain development and in cases of chronic compromise, intrauterine growth restriction. Preterm birth can also be associated with injury to the developing brain and affect the normal trajectory of brain growth. This review will focus on the effects that episodes of perinatal hypoxia (acute, chronic, associated with inflammation or as an antecedent of preterm birth) can have on the developing brain. In animal models of these conditions we have found that relatively brief (acute) periods of fetal hypoxemia can have significant effects on the fetal brain, for example death of susceptible neuronal populations (cerebellum, hippocampus, cortex) and cerebral white matter damage. Chronic placental insufficiency which includes fetal hypoxemia, nutrient restriction and altered endocrine status can result in fetal growth restriction and long-term deficits in neural connectivity in addition to altered postnatal function, for example in the auditory and visual systems. Maternal/fetal inflammation can result in fetal brain damage, particularly but not exclusively in the white matter; injury is more pronounced when associated with fetal hypoxemia. In the baboon, in which the normal trajectory of growth is affected by preterm birth, there is a direct correlation between a higher flux in oxygen saturation and a greater extent of neuropathological damage. Currently, the only established therapy for neonatal encephalopathy in full term neonates is moderate hypothermia although this only offers some protection to moderately but not severely affected brains. There is no accepted therapy for injured preterm brains. Consequently the search for more efficacious treatments continues; we discuss neuroprotective agents (erythropoietin, N-acetyl cysteine, melatonin, creatine, neurosteroids) which we have trialed in appropriate animal models. The possibility of combining hypothermia with such agents or growth factors is now being considered. A deeper understanding of causal pathways in brain injury is essential for the development of efficacious strategies for neuroprotection.     

Fluoxetine promotes gliogenesis during neural differentiation in mouse embryonic stem cells

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for treatment of mood disorders and depression, even during pregnancy and lactation. SSRIs are thought to be much safer than tricyclic antidepressants, with a low risk of embryonic toxicity. Several recent studies, however, have reported that fetal exposure to SSRIs increases the risk of adverse effects during fetal and neonatal development. This is consistent with our previous finding that fluoxetine, a prototypical SSRI, profoundly affected the viability of cultured embryonic stem (ES) cells as well as their ability to differentiate into cardiomyocytes. Furthermore, we found that fluoxetine induced fluctuations in ectodermal marker gene expression during ES cell differentiation, which suggests that fluoxetine may affect neural development. In the present study, we investigated the effects of fluoxetine on the process of differentiation from ES cells into neural cells using the stromal cell‐derived inducing activity (SDIA) method. Fluoxetine treatment was found to enhance the expression of glial marker genes following neural differentiation, as observed by immunocytochemical analysis or quantitative RT‐PCR. The promoter activity of glial marker genes was also significantly enhanced when cells were treated with fluoxetine, as observed by luciferase reporter assay. The expression of neuronal markers during ES cell differentiation into neural cells, on the other hand, was inhibited by fluoxetine treatment. In addition, FACS analysis revealed an increased population of glial cells in the differentiating ES cells treated with fluoxetine. These results suggest that fluoxetine could facilitate the differentiation of mouse ES cells into glial cell lineage, which may affect fetal neural development. © 2010 Wiley‐Liss, Inc.     

Ret expression in the central nervous system

The ret proto-oncogene product (Ret) has been shown to be one of the glial cell line-derived neurotrophic factor (GDNF) receptors in dopaminergic, norepinephric and motor neurons. We immunohistochemically examined the expression of Ret in the human central nervous system (CNS). The distribution of Ret was generally identical to that of myclin as stained using the Klüver-Barrera method. We further investigated the expression of Ret in human fetal brains (19, 29 and 39 weeks gestation) and various brain tumors. The Ret positivity was observed to be associated with the myelin sheath of the cerebral white matter in 29-and 39-week-old fetal brains. Ret is known to be expressed in neural crest-derived cells. We could immunohistochemically confirm the Ret expression in the pheochromocytomas and neuroblastomas of retroperitoneal space. As for the brain tumors, no Ret expression was observed in glioblastomas, oligodendrogliomas, and schwannomas examined, although the glial cells surrounding the tumor and the pre-existing myelin sheath revealed positivity for Ret. In the CNS, Ret expression appears to be closely associated with the myelin sheath; therefore, Ret immunostaining may be useful in ascertaining the demyelinating lesions in the CNS.     

Normalization of ventral tegmental area structure following acupuncture in a rat model of heroin relapse

Drugs can cause obvious damage to the brain. To verify the relationship between acupuncture, neurotrophic factor expression and brain cell structural changes, this study established a rat model of heroin relapse using intramuscular injection of increasing amounts of heroin. During the detoxification period, rat models received acupuncture at Baihui （DU20） and Dazhui （DU14）. Electron microscopy demonstrated that the structure of the ventral tegmental area in heroin relapse rats gradually became normalized after acupuncture treatment. Immunohistochem- ical staining exhibited that the expression of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor increased in the ventral tegmental area following acupuncture. Moreover, the effects were similar to that of methadone, a type of medicine called an opioid. Results suggested that acupuncture at Baihui and Dazhui protected brain neurons against injury in rats with heroin relapse by promoting brain-derived neurotrophic factor and glial cell line-de-rived neurotrophic factor expression.     

Adult neural stem and progenitor cells modified to secrete GDNF can protect, migrate and integrate after intracerebral transplantation in rats with transient forebrain ischemia

Adult neural stem and progenitor cells (NSPCs) are important autologous transplantation tools in regenerative medicine, as they can secrete factors that protect the ischemic brain. We investigated whether adult NSPCs genetically modified to secrete more glial cell line-derived neurotrophic factor (GDNF) could protect against transient ischemia in rats. NSPCs were harvested from the subventricular zone of adult Wistar rats and cultured for 3 weeks in the presence of epidermal growth factor. The NSPCs were treated with fibre-mutant Arg-Gly-Asp adenovirus containing the GDNF gene (NSPC-GDNF) or enhanced green fluorescent protein (EGFP) gene (NSPC-EGFP; control group). In one experiment, cultured cells were transplanted into the right ischemic boundary zone of Wistar rat brains. One week later, animals underwent 90 min of intraluminal right middle cerebral artery occlusion followed by magnetic resonance imaging and behavioural tests. The NSPC-GDNF group had higher behavioural scores and lesser infarct volume than did controls at 1, 7 and 28 days postocclusion. In the second experiment, we transplanted NSPCs 3 h after ischemic insult. Compared to controls, rats receiving NSPC-GDNF had decreased infarct volume and better behavioural assessments at 7 days post-transplant. Animals were killed on day 7 and brains were collected for GDNF ELISA and morphological assessment. Compared to controls, more GDNF was secreted, more NSPC-GDNF cells migrated toward the ischemic core and more NSPC-GDNF cells expressed immature neuronal marker. Moreover, the NSPC-GDNF group showed more effective inhibition of microglial invasion and apoptosis. These findings suggest that NSPC-GDNF may be useful in treatment of cerebral ischemia.     

Recombinant adeno-associated virus vector expressing glial cell line-derived neurotrophic factor reduces ischemia-induced damage

To explore the potential of using the recombinant adeno-associated viral (rAAV) vector, expressing glial cell line-derived neurotrophic factor (GDNF) as the gene therapy for stroke, we injected rAAV vectors expressing GDNF (rAAV-GDNF) into the cortex of rats which had been experiencing transient bilateral common carotid artery ligation and right middle cerebral artery ligation for 90 min. GDNF levels in cortical tissues of rAAV-GDNF-injected animals were significantly higher than in the control animals injected with rAAV-expressing lacZ (rAAV-lacZ), indicating that rAAV can deliver and express the GDNF gene in cortical tissues. Triphenyltetrazolium chloride tissue stain analysis revealed that the rAAV-delivered GDNF gene could rescue the brain tissues from ischemia-induced injury. Cortical tissues which received rAAV-GDNF injections had both significantly smaller total volumes of infarction and smaller areas of infarction on each brain slice than those which were injected with rAAV-lacZ. An in situ labeling analysis demonstrated significantly less apoptotic cells in cortical tissues rescued by rAAV-GDNF, indicating prevention of apoptosis as the mechanism of cortical cell protection. Moreover, immunohistochemistry staining of Neu-N indicated that the rescued brain tissues contained the same number of Neu-N-positive neuronal cells as contralateral undamaged brain tissues. This provides strong evidence that cortical neuronal cells can be rescued by GDNF gene therapy. Indeed, these findings show that the rAAV is a potential delivery vector of GDNF gene for the therapy of stroke.     

Development of taurine biosynthesizing system in cerebral cortical neurons in primary culture

Developmental patterns of taurine biosynthesizing system were investigated using primary cultured neurons prepared from the neopallium of 15-day-old fetal mice by a trypsin treatment in comparison with those in cerebral cortices obtained from age-matched fetal and neonatal mice. The morphological observations by phase contrast and scanning electron micrographies indicated that the cells in primary culture used in the present study possessed typical features of neurons. In addition, the immunohistochemical studies using the antibody to glial fibrillary acidic protein (GFAP), a specific marker for astroglia, revealed that the contamination of astroglias was negligible. The contents of taurine and metabolic intermediates in taurine biosynthesis, cysteine sulfinic acid and cysteic acid, in primary cultured neurons showed decreases during their development, especially during the first week after the inoculation. Similar developmental patterns of these amino acids were observed in cerebral cortices in vivo during perinatal stage, which corresponded to the first week of neuronal growth in vitro. On the other hand, the activities of cysteine sulfinic acid decarboxylase and cysteine dioxygenase, both of which are involved in the biosynthesis of taurine, were found to be increased progressively both in primary cultured neurons and in cerebral cortices in vivo during their growth. The immunohistochemical study using antitaurine antibody obtained from rabbit clearly demonstrated that immunoreactive materials were localized in cell bodies and the processes of neurons, and the intensity of the immunoreactivity in primary cultured neurons also showed a reduction with time of culture. These results indicate that primary cultured neurons used in this study possess a similar capacity to synthesize taurine from cysteine as developing brains in vivo. The present results also strongly suggest the well known decrease in cerebral taurine content in vivo during neonatal stages may be predominantly due to the decrease of taurine in neuronal cells.     

Hyperbaric oxygen treatment promotes neural stem cell proliferation in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage

Hyperbaric oxygen therapy for the treatment of neonatal hypoxic-ischemic brain damage has been used clinically for many years, but its effectiveness remains controversial. In addition, the mechanism of this potential neuroprotective effect remains unclear. This study aimed to investigate the influence of hyperbaric oxygen on the proliferation of neural stem cells in the subventricular zone of neonatal Sprague-Dawley rats (7 days old) subjected to hypoxic-ischemic brain damage. Six hours after modeling, rats were treated with hyperbaric oxygen once daily for 7 days. Immunohistochemistry revealed that the number of 5-bromo-2′-deoxyuridine positive and nestin positive cells in the subventricular zone of neonatal rats increased at day 3 after hypoxic-ischemic brain damage and peaked at day 5. After hyperbaric oxygen treatment, the number of 5-bromo-2′- deoxyuridine positive and nestin positive cells began to increase at day 1, and was significantly higher than that in normal rats and model rats until day 21. Hematoxylin-eosin staining showed that hyperbaric oxygen treatment could attenuate pathological changes to brain tissue in neonatal rats, and reduce the number of degenerating and necrotic nerve cells. Our experimental findings indicate that hyperbaric oxygen treatment enhances the proliferation of neural stem cells in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage, and has therapeutic potential for promoting neurological recovery following brain injury.     

Erythropoietin protects the developing brain against N-methyl-D-aspartate receptor antagonist neurotoxicity

Pharmacological blockade of NMDA receptor function induces apoptotic neurodegeneration in the developing rat brain. However, the use of NMDA receptor antagonists as anesthetics and sedatives represents a difficult-to-avoid clinical practice in pediatrics. This warrants the search for adjunctive neuroprotective measures that will prevent or ameliorate neurotoxicity of NMDA receptor antagonists. The NMDA receptor antagonist MK801 triggered apoptosis in the neonatal rat forebrain, most notably in cortex and thalamus. MK801 exposure reduced mRNA levels of erythropoietin (EPO) and the EPO receptor, suggesting that loss of endogenous EPO activity may contribute to MK801-induced apoptosis. Coadministration of recombinant EPO (rEPO) conferred 50% neuroprotection, partially restored MK801-induced reduction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) mRNA, and prevented decreased phosphorylation levels of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and Akt. These observations indicate that rEPO partly rescues newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways.     

Maternal personality traits and risk of preterm birth and fetal growth restriction

Background/AimsMaternal personality may increase vulnerability to stress, which could lead to an unfavourable intrauterine environment to the fetus. We sought to investigate the impact of maternal personality traits on adverse birth outcomes such as preterm birth, and fetal growth restriction in the mother-child cohort study (RHEA Study) in Crete, Greece 2007–2009.MethodsFive hundred and eighty pregnant women participating in “Rhea” cohort study completed the Eysenck Personality Questionnaire-Revised (EPQ-R) at 28–32 weeks of gestation. Information on anthropometric measures at birth was obtained from the hospital delivery logs and medical records. Fetal growth restriction was based on a customized model, and multivariate logistic regression models were used adjusting for confounders.ResultsA per unit increase in the EPQ Neuroticism scale increased the risk for fetal weight growth restriction by 9% [Odds Ratio (OR) = 1.09, 95 percent CI: 1.01, 1.19)], and for fetal head circumference growth restriction by 6% [OR = 1.06, 95 percent CI: 1.01, 1.18] after adjusting for maternal age, education, origin, marital status, working status, pre-pregnancy BMI, delivery type, parity, smoking, and alcohol intake during pregnancy.ConclusionsMaternal neuroticism, which predisposes to negative mood, may be a risk factor for fetal growth restriction.