Neonatal Hypoxia Research Articles

Obstetric and Neonatal Outcomes in Mild Idiopathic Polyhydramnios.

Background: Idiopathic polyhydramnios is a controversial clinical condition, as data on perinatal outcomes are conflicting and vary depending on the severity of the condition. The aim of the present study was to compare obstetric and neonatal outcomes between pregnant women with mild idiopathic polyhydramnios and a control population. Methods: A retrospective cohort study was performed at a single university hospital comparing the obstetrics and neonatal outcomes of pregnancies with mild idiopathic polyhydramnios (n = 109) and control pregnancies (n = 2550). Results: Cesarean section (CS) was significantly increased in the group with polyhydramnios compared to controls (46% vs. 32%, respectively, p = 0.047) due to a higher rate of emergency CS in the polyhydramnios group (p = 0.041) because of abnormal cardiotocography (7.3% vs. 2.9%; p = 0.018) or labor dystocia (8.2% vs. 2.9%; p = 0.006). No statistically significant difference was found in the Apgar score, in the rate of neonatal hypoxia, or in the incidence of macrosomia between groups. In four cases, additional diagnoses of anomalies were made after birth, with a rate of 3.2%, which is comparable to the general population. Conclusion: Besides an increased risk of CS, patients with mild idiopathic polyhydramnios should be reassured regarding maternal and feto-neonatal outcomes. The management of pregnancies with stable mild idiopathic polyhydramnios should not differ from uncomplicated pregnancies, except for the need for increased labor surveillance.

Cerebral Palsy: Current Concepts and Practices in Musculoskeletal Care.

Cerebral palsy is a neurologic disorder characterized by a spectrum of motor and cognitive deficits resulting from insults to the developing brain. The etiologies are numerous and likely multifactorial; an increasing portion of cases may be attributable to genetic causes, although the exact mechanisms responsible remain poorly understood. Major risk factors include intrauterine stroke and prematurity and neonatal infection, trauma, and hypoxia, which may occur in the prenatal, perinatal, or postnatal period. The Gross Motor Function Classification System (GMFCS) is a widely used tool to establish a child's level of function and to guide treatment; however, additional metrics are necessary to formulate long-term prognoses. Goals of care are to maximize function and independence, which directly correlate with overall quality of life, and family participation is key to establishing goals early in treatment. Nonpharmaceutical treatments include physical, occupational, and speech therapy, as well as bracing, equipment, and technology. There is a breadth of medical interventions for managing hypertonia, including medications, botulinum toxin injections, intrathecal baclofen pumps, and selective dorsal rhizotomy. Orthopedic interventions are indicated for symptomatic or progressive musculoskeletal sequelae. Treatments for dysplastic hips and/or hip instability range from soft tissue releases to bony procedures. Neuromuscular scoliosis is managed with posterior spinal fusion because bracing is ineffective against these rapidly progressive curves. The degree of care varies considerably depending on the child's baseline GMFCS level and functional capabilities, and early screening, diagnosis, and appropriate referrals are paramount to initiating early care and maximizing the child's quality of life.

Neonatal intermittent hypoxia persistently impairs lung vascular development and induces long-term lung mitochondrial DNA damage.

Adults born preterm have an increased risk of pulmonary vascular disease. Extreme preterm infants often require supplemental oxygen but they also exhibit frequent intermittent hypoxemic episodes (IH). Here, we test the hypothesis that neonatal IH induces lung endothelial cell mitochondrial DNA (mitDNA) damage and contributes to long-term pulmonary vascular disease and pulmonary hypertension (PH). Newborn C57BL/6J mice were assigned to the following groups: 1) normoxia, 2) hyperoxia (O2 65%), 3) normoxia cycling with IH (O2 21% + O2 10%), and 4) hyperoxia cycling with IH (O2 65% + O2 10%) for 3 wk. IH episodes were initiated on postnatal day 7. Lung angiogenesis, PH, and mitDNA lesions were assessed at 3 wk and 3 mo. In vitro, the effect of IH on tubule formation and mitDNA lesions was evaluated in human pulmonary microvascular endothelial cells (HPMECs). Data were analyzed by ANOVA. In vitro, IH exposure reduced tubule formation and increased mitDNA lesions in HPMECs. This was most marked in HPMECs exposed to hyperoxia cycling with IH. In vivo, neonatal IH increased lung mitDNA lesions, impaired angiogenesis, and induced PH in 3-wk-old mice. These findings were pronounced in mice exposed to hyperoxia cycling with IH. At 3 mo follow-up, mice exposed to neonatal IH had persistently increased lung mitDNA lesions and impaired lung angiogenesis, even without concomitant hyperoxia exposure. Neonatal IH induces lung endothelial cell mitDNA damage and causes persistent impairment in lung angiogenesis. These findings provide important mechanistic insight into the pathogenesis of pulmonary vascular disease in preterm survivors.NEW & NOTEWORTHY Our current study demonstrates that neonatal intermittent hypoxia (IH) alters lung endothelial cell function, induces mitochondrial DNA lesions, and impairs lung vascular growth into adulthood. Moreover, when superimposed on hyperoxia, neonatal IH induces a severe lung vascular phenotype that is seen in preterm infants with PH. These findings suggest that neonatal IH contributes to PH in adults born preterm and importantly, that mitochondrial protection strategies may mitigate these deleterious effects.

Spontaneous Intestinal Perforation in a Full Term Neonate: A Case Report

Spontaneous intestinal perforation suggests a perforation of the gastrointestinal tract of no demonstrable cause. Only few such cases have been described in full term newborns. Although some authors have suggested ischemia and fetal or neonatal hypoxia as the most likely cause, the etiology and pathogenesis of this disease are still widely unknown. Here, we present a case of Spontaneous intestinal perforation in a full term neonate who was born to a mother with chronic hypertension. Radiological images revealed pneumoperitoneum on a three day old baby with feeding intolerance and abdominal distention. There was no clinical evidence of Hirschsprung’s disease, necrotizing enterocolitis, anorectal malformations or bowel obstruction. An emergency laparotomy revealed a localized perforation in distal ileum. Histopathological examination failed to reveal any etiology for the perforation. The neonate recovered rapidly following a double barrel ileostomy, with no immediate gastrointestinal complications.

Retinal vascular recovery revealed by retinal imaging following neonatal hypoxia ischemia in mice: Is there a role for tyrosine kinase receptor modulation?

ObjectiveHypoxic ischemic encephalopathy (HIE) secondary to perinatal asphyxia leads to long-term visual disabilities. Dilated retinal exams in human newborns with HIE is an emerging diagnostic tool, but phenotypes of hypoxia ischemia (HI) related retinal vascular injury are unclear. 7,8-Dihydroxyflavone (7,8-DHF) is a TrkB agonist with protective effects on HI-related brain damage. We studied retinal vessels in a mouse model of neonatal HIE and the efficacy of 7,8-DHF in ameliorating HI-related retinal vascular injury. MethodsC57BL6/J mice at post-natal day (P) 9 received unilateral left carotid artery ligation followed by exposure to 10 % oxygen for 50 min. Phosphate buffered saline or 7,8-DHF (5 mg/kg) were administered daily for 7 days intraperitoneally. Control groups of naïve or carotid artery ligation only mice were studied. Fluorescein angiography was performed in acute (two weeks post-exposure) and chronic (four weeks post-exposure) time points. Retinal artery width, retinal vein width, and collateral vessel length were quantified. ResultsLigation of the common carotid artery alone caused retinal artery dilation in acute and chronic time points, but had no effect on retinal veins. At acute time point, HI caused increased retinal artery vasodilation, but was reversed by 7,8-DHF. HI caused short collateral vessel formation in ipsilateral eyes, rescued by 7,8-DHF treatment. ConclusionRetinal artery vasodilation and collateral vessel formation due to HI were rescued by 7,8-DHF treatment. Retinal and collateral vessel monitoring could be diagnostic biomarkers for HI severity. Studies to elucidate mechanisms of 7,8-DHF action on retinal vessels could aid development of therapies for neonatal HI.

AIF Overexpression Aggravates Oxidative Stress in Neonatal Male Mice After Hypoxia–Ischemia Injury

There are sex differences in the severity, mechanisms, and outcomes of neonatal hypoxia–ischemia (HI) brain injury, and apoptosis-inducing factor (AIF) may play a critical role in this discrepancy. Based on previous findings that AIF overexpression aggravates neonatal HI brain injury, we further investigated potential sex differences in the severity and molecular mechanisms underlying the injury using mice that overexpress AIF from homozygous transgenes. We found that the male sex significantly aggravated AIF-driven brain damage, as indicated by the injury volume in the gray matter (2.25 times greater in males) and by the lost volume of subcortical white matter (1.71 greater in males) after HI. As compared to females, male mice exhibited more severe brain injury, correlating with reduced antioxidant capacities, more pronounced protein carbonylation and nitration, and increased neuronal cell death. Under physiological conditions (without HI), the doublecortin-positive area in the dentate gyrus of females was 1.15 times larger than in males, indicating that AIF upregulation effectively promoted neurogenesis in females in the long term. We also found that AIF stimulated carbohydrate metabolism in young males. Altogether, these findings corroborate earlier studies and further demonstrate that AIF is involved in oxidative stress, which contributes to the sex-specific differences observed in neonatal HI brain injury.

Sirt2 promotes white matter oligodendrogenesis during development and in models of neonatal hypoxia

Delayed oligodendrocyte (OL) maturation caused by hypoxia (Hx)-induced neonatal brain injury results in hypomyelination and leads to neurological disabilities. Previously, we characterized Sirt1 as a crucial regulator of OL progenitor cell (OPC) proliferation in response to Hx. We now identify Sirt2 as a critical promoter of OL differentiation during both normal white matter development and in a mouse model of Hx. Importantly, we find that Hx reduces Sirt2 expression in mature OLs and that Sirt2 overexpression in OPCs restores mature OL populations. Reduced numbers of Sirt2+ OLs were also observed in the white matter of preterm human infants. We show that Sirt2 interacts with p27Kip1/FoxO1, p21Cip1/Cdk4, and Cdk5 pathways, and that these interactions are altered by Hx. Furthermore, Hx induces nuclear translocation of Sirt2 in OPCs where it binds several genomic targets. Overall, these results indicate that a balance of Sirt1 and Sirt2 activity is required for developmental oligodendrogenesis, and that these proteins represent potential targets for promoting repair following white matter injury.

Exercise and hypoxia unmask pulmonary vascular disease and right ventricular dysfunction in a 10- to 12-week-old swine model of neonatal oxidative injury.

Prematurely born young adults who experienced neonatal oxidative injury (NOI) of the lungs have increased incidence of cardiovascular disease. Here, we investigated the long‐term effects of NOI on cardiopulmonary function in piglets at the age of 10–12 weeks. To induce NOI, term‐born piglets (1.81 ± 0.06 kg) were exposed to hypoxia (10–12% FiO2), within 2 days after birth, and maintained for 4 weeks or until symptoms of heart failure developed (range 16–28 days), while SHAM piglets were normoxia raised. Following recovery (>5 weeks), NOI piglets were surgically instrumented to measure haemodynamics during hypoxic challenge testing (HCT) and exercise with modulation of the nitric‐oxide system. During exercise, NOI piglets showed a normal increase in cardiac index, but an exaggerated increase in pulmonary artery pressure and a blunted increase in left atrial pressure – suggesting left atrial under‐filling – consistent with an elevated pulmonary vascular resistance (PVR), which correlated with the duration of hypoxia exposure. Moreover, hypoxia duration correlated inversely with stroke volume (SV) during exercise. Nitric oxide synthase inhibition and HCT resulted in an exaggerated increase in PVR, while the PVR reduction by phosphodiesterase‐5 inhibition was enhanced in NOI compared to SHAM piglets. Finally, within the NOI piglet group, prolonged duration of hypoxia was associated with a better maintenance of SV during HCT, likely due to the increase in RV mass. In conclusion, duration of neonatal hypoxia appears an important determinant of alterations in cardiopulmonary function that persist further into life. These changes encompass both pulmonary vascular and cardiac responses to hypoxia and exercise. Key points Children who suffered from neonatal oxidative injury, such as very preterm born infants, have increased risk of cardiopulmonary disease later in life.Risk stratification requires knowledge of the mechanistic underpinning and the time course of progression into cardiopulmonary disease.Exercise and hypoxic challenge testing showed that 10‐ to 12‐week‐old swine that previously experienced neonatal oxidative injury had increased pulmonary vascular resistance and nitric oxide dependency.Duration of neonatal oxidative injury was a determinant of structural and functional cardiopulmonary remodelling later in life.Remodelling of the right ventricle, as a result of prolonged neonatal oxidative injury, resulted in worse performance during exercise, but enabled better performance during the hypoxic challenge test.Increased nitric oxide dependency together with age‐ or comorbidity‐related endothelial dysfunction may contribute to predisposition to pulmonary hypertension later in life.

Further Evidence of Neuroprotective Effects of Recombinant Human Erythropoietin and Growth Hormone in Hypoxic Brain Injury in Neonatal Mice.

Experimental in vivo data have recently shown complementary neuroprotective actions of rhEPO and growth hormone (rhGH) in a neonatal murine model of hypoxic brain injury. Here, we hypothesized that rhGH and rhEPO mediate stabilization of the blood–brain barrier (BBB) and regenerative vascular effects in hypoxic injury to the developing brain. Using an established model of neonatal hypoxia, neonatal mice (P7) were treated i.p. with rhGH (4000 µg/kg) or rhEPO (5000 IU/kg) 0/12/24 h after hypoxic exposure. After a regeneration period of 48 h or 7 d, cerebral mRNA expression of Vegf-A, its receptors and co-receptors, and selected tight junction proteins were determined using qRT-PCR and ELISA. Vessel structures were assessed by Pecam-1 and occludin (Ocln) IHC. While Vegf-A expression increased significantly with rhGH treatment (p < 0.01), expression of the Vegfr and TEK receptor tyrosine kinase (Tie-2) system remained unchanged. RhEPO increased Vegf-A (p < 0.05) and Angpt-2 (p < 0.05) expression. While hypoxia reduced the mean vessel area in the parietal cortex compared to controls (p < 0.05), rhGH and rhEPO prevented this reduction after 48 h of regeneration. Hypoxia significantly reduced the Ocln+ fraction of cortical vascular endothelial cells. Ocln signal intensity increased in the cortex in response to rhGH (p < 0.05) and in the cortex and hippocampus in response to rhEPO (p < 0.05). Our data indicate that rhGH and rhEPO have protective effects on hypoxia-induced BBB disruption and regenerative vascular effects during the post-hypoxic period in the developing brain.

Ten Women Who Changed Science and the World

Ten Women Who Changed Science and the World

Preconditioning in hypoxic-ischemic neonate mice triggers Na+-Ca2+ exchanger-dependent neurogenesis

To identify alternative interventions in neonatal hypoxic-ischemic encephalopathy, researchers’ attention has been focused to the study of endogenous neuroprotective strategies. Based on the preconditioning concept that a subthreshold insult may protect from a subsequent harmful event, we aimed at identifying a new preconditioning protocol able to enhance Ca2+-dependent neurogenesis in a mouse model of neonatal hypoxia ischemia (HI). To this purpose, we also investigated the role of the preconditioning-linked protein controlling ionic homeostasis, Na+/Ca2+ exchanger (NCX). Hypoxic Preconditioning (HPC) was reproduced by exposing P7 mice to 20’ hypoxia. HI was induced by isolating and cutting the right common carotid artery. A significant reduction in ischemic damage was observed in mice subjected to 20’ hypoxia followed,3 days later, by 60’ HI, thus suggesting that 20’ hypoxia functions as preconditioning stimulus. HPC promoted neuroblasts proliferation in the dentate gyrus mirrored by an increase of NCX1 and NCX3-positive cells and an improvement of behavioral motor performances in HI mice. An attenuation of HPC neuroprotection as well as a reduction in the expression of neurogenesis markers, including p57 and NeuroD1, was observed in preconditioned mice lacking NCX1 or NCX3. In summary, PC in neonatal mice triggers a neurogenic process linked to ionic homeostasis maintenance, regulated by NCX1 and NCX3.

The effects of fetal or neonatal hypoxia and genetic variants on age at onset of schizophrenia

IntroductionFetal or neonatal hypoxia (FoNH) is a known risk factor for schizophrenia. It has been hypothesized that FoNH induced expression of schizophrenia susceptibility genes (Schmidt-Kastner et al. 2012, Giannopoulou et al. 2018).ObjectivesTo test this hypothesis, we explore the effects of FoNH and some genetic variants on age at onset (AAO) of schizophrenia.MethodsThe study included 1670 patients (women 1021 (61.1%), mean age 34.6 (SD 13.6), mean age at disease onset 25.4 (10.5) years) with ICD-10 diagnosis of schizophrenia or schizoaffective psychosis. The effects of FoNH in interaction with sex, family history (FH) and genetic variants on AAO of schizophrenia were evaluated. Polymorphisms rs2514218 DRD2 (n=943), Val66Met BDNF (n=820) and VNTR AS3MT (n=804) were genotyped.ResultsAmong all patients studied 179 (10.8%) had experienced FoNH. Regression model showed that FoNH, sex and FH of schizophrenia contribute significantly (p=0.000) to AAO. In the FoNH group, AAO was lower compared to the group without FoNH (20.7 (6.2) vs 25.5 (10.) years). When comparing men and women, there was a difference between FoNH and non- FoNH subgroups only in women (p=0.000). No interaction between FH and FoNH was observed though positive FH had an effect on AAO. There was the interaction effect of VNTR AS3MT and FoNH on AAO. In the FoNH group, carriers of 2 repeats had younger AAO compared to the carriers homozygous for 3 repeat variant (19.6 (4.9) vs 22. (7.6) years).ConclusionsWe demonstrate the interaction effects of FoNH and VNTR AS3MT polymorphism on AAO of schizophrenia.DisclosureNo significant relationships.

Induction of Mitochondrial Fragmentation and Mitophagy after Neonatal Hypoxia-Ischemia.

Hypoxia–ischemia (HI) leads to immature brain injury mediated by mitochondrial stress. If damaged mitochondria cannot be repaired, mitochondrial permeabilization ensues, leading to cell death. Non-optimal turnover of mitochondria is critical as it affects short and long term structural and functional recovery and brain development. Therefore, disposal of deficient mitochondria via mitophagy and their replacement through biogenesis is needed. We utilized mt-Keima reporter mice to quantify mitochondrial morphology (fission, fusion) and mitophagy and their mechanisms in primary neurons after Oxygen Glucose Deprivation (OGD) and in brain sections after neonatal HI. Molecular mechanisms of PARK2-dependent and -independent pathways of mitophagy were investigated in vivo by PCR and Western blotting. Mitochondrial morphology and mitophagy were investigated using live cell microscopy. In primary neurons, we found a primary fission wave immediately after OGD with a significant increase in mitophagy followed by a secondary phase of fission at 24 h following recovery. Following HI, mitophagy was upregulated immediately after HI followed by a second wave at 7 days. Western blotting suggests that both PINK1/Parkin-dependent and -independent mechanisms, including NIX and FUNDC1, were upregulated immediately after HI, whereas a PINK1/Parkin mechanism predominated 7 days after HI. We hypothesize that excessive mitophagy in the early phase is a pathologic response which may contribute to secondary energy depletion, whereas secondary mitophagy may be involved in post-HI regeneration and repair.

Attenuated succinate accumulation relieves neuronal injury induced by hypoxia in neonatal mice

Hypoxia causes neonatal neuronal damage. However, the underlying mechanism remains unclear. This study aimed to explore the changes in succinate levels and identify the mechanisms underlying their contribution to hypoxia-induced damage in newborn mice. The neonatal C57BL/6J mouse hypoxia model was used in our study. We evaluated the levels of succinate, iron, reactive oxygen species (ROS), and mitochondrial ROS, and assessed mitophagy, neuronal damage, and learning and memory function, after hypoxia treatment. The neonatal mice showed increased succinate levels in the early hypoxia stage, followed by increased levels of oxidative stress, iron stress, neuronal damage, and cognitive deficits. Succinate levels were significantly reduced following treatment with inhibitors of succinate dehydrogenase (SDH), purine nucleotide cycle (PNC), and malate/aspartate shuttle (MAS), with the corresponding attenuation of oxidative stress, iron stress, neuronal damage, and cognitive impairment. Reversal catalysis of SDH through fumarate from the PNC and MAS pathways might be involved in hypoxia-induced succinate accumulation. Succinate accumulation in the early period after hypoxia may crucially contribute to oxidative and iron stress. Relieving succinate accumulation at the early hypoxia stage could prevent neuronal damage and cognitive impairment in neonatal hypoxia.

Evaluation of the effect of dexmedetomidine combined with ropivacaine in epidural labor analgesia: a systematic review and meta-analysis

This review and meta-analysis comprehensively elaborated the analgesic and sedative effects of ropivacaine combined with dexmedetomidine in epidural labor analgesia, and its possible resulting motor block and adverse reactions. PubMed, Web of science, Cochrane, China National Knowledge Infrastructure and WANFANG DATA were searched for randomized controlled trials (RCTs) on the efficacy and safety of ropivacaine combined with dexmedetomidine in epidural labor analgesia. Standard mean difference (SMD) and 95% confidence interval (CI) were calculated. As of September 10th, 17 articles were finally included for meta-analysis. The results showed that compared with the control group (ropivacaine alone or ropivacaine + sufentanil), singleton full-term pregnant patients treated with ropivacaine + dexmedetomidine had better analgesic and sedative effects, with lower VAS scores at 15 min (T<inf>1</inf>), 30 min (T<inf>2</inf>), 1 h (T<inf>3</inf>), 2 h (T<inf>4</inf>) after labor analgesia, and the moment of delivery (T<inf>5</inf>) (T<inf>1</inf>: SMD=-1.90, 95% CI: -2.39, -1.40; T<inf>2</inf>: SMD=-1.43, 95% CI: -1.92, -0.93; T<inf>3</inf>: SMD=-0.91, 95% CI: -1.41, -0.41; T<inf>4</inf>: SMD=-0.94, 95% CI: -1.54, -0.34; T<inf>5</inf>: SMD=-0.56, 95% CI: -1.02, -0.10) and higher Ramsay scores at 15 min (T<inf>1</inf>) and 30 min (T<inf>2</inf>) after labor analgesia (T<inf>1</inf>: SMD=1.17, 95% CI: 0.80, 1.53; T<inf>2</inf>: SMD=2.17, 95% CI: 1.30, 3.03). In patients with singleton full-term pregnancy, ropivacaine + dexmedetomidine have better analgesic and sedative effects than in the control group. Both groups have no significant motor block and neonatal asphyxia and hypoxia.

Inter-alpha Inhibitor Proteins Ameliorate Brain Injury and Improve Behavioral Outcomes in a Sex-Dependent Manner After Exposure to Neonatal Hypoxia Ischemia in Newborn and Young Adult Rats.

Hypoxic-ischemic (HI) brain injury is a major contributor to neurodevelopmental morbidities. Inter-alpha inhibitor proteins (IAIPs) have neuroprotective effects on HI-related brain injury in neonatal rats. However, the effects of treatment with IAIPs on sequential behavioral, MRI, and histopathological abnormalities in the young adult brain after treatment with IAIPs in neonates remain to be determined. The objective of this study was to examine the neuroprotective effects of IAIPs at different neurodevelopmental stages from newborn to young adults after exposure of neonates to HI injury. IAIPs were given as 11-sequential 30-mg/kg doses to postnatal (P) day 7-21 rats after right common carotid artery ligation and exposure to 90min of 8% oxygen. The resulting brain edema and injury were examined by T2-weighted magnetic resonance imaging (MRI) and cresyl violet staining, respectively. The mean T2 values of the ipsilateral hemisphere from MRI slices 6 to 10 were reduced in IAIP-treated HI males + females on P8, P9, and P10 and females on P8, P9, P10, and P14. IAIP treatment reduced hemispheric volume atrophy by 44.5 ± 29.7% in adult male + female P42 rats and improved general locomotor abilities measured by the righting reflex over time at P7.5, P8, and P9 in males + females and males and muscle strength/endurance measured by wire hang on P16 in males + females and females. IAIPs provided beneficial effects during the learning phase of the Morris water maze with females exhibiting beneficial effects. IAIPs confer neuroprotection from HI-related brain injury in neonates and even in adult rats and beneficial MRI and behavioral benefits in a sex-dependent manner.

Plinia trunciflora Extract Administration Prevents HI-Induced Oxidative Stress, Inflammatory Response, Behavioral Impairments, and Tissue Damage in Rats.

The disruption of redox homeostasis and neuroinflammation are key mechanisms in the pathogenesis of brain hypoxia–ischemia (HI); medicinal plants have been studied as a therapeutic strategy, generally associated with the prevention of oxidative stress and inflammatory response. This study evaluates the neuroprotective role of the Plinia trunciflora fruit extract (PTE) in neonatal rats submitted to experimental HI. The HI insult provoked a marked increase in the lipoperoxidation levels and glutathione peroxidase (GPx) activity, accompanied by a decrease in the brain concentration of glutathione (GSH). Interestingly, PTE was able to prevent most of the HI-induced pro-oxidant effects. It was also observed that HI increased the levels of interleukin-1β in the hippocampus, and that PTE-treatment prevented this effect. Furthermore, PTE was able to prevent neuronal loss and astrocyte reactivity induced by HI, as demonstrated by NeuN and GFAP staining, respectively. PTE also attenuated the anxiety-like behavior and prevented the spatial memory impairment caused by HI. Finally, PTE prevented neural tissue loss in the brain hemisphere, the hippocampus, cerebral cortex, and the striatum ipsilateral to the HI. Taken together our results provide good evidence that the PTE extract has the potential to be investigated as an adjunctive therapy in the treatment of brain insult caused by neonatal hypoxia–ischemia.

Mentat® ameliorates hypoxia-induced attention deficyt hyperactivity disorder like behavior in rats

Introduction and aim. The objective of the study was to evaluate the effect of MentatR an herbal formulation in experimental models of hypoxia-induced attention deficit hyperactive disorder (ADHD) like behavior in rats. Material and methods. MentatR was evaluated at the dose of 100 and 200 mg/kg body weight. per oral., in two experimental models of hypoxia in Wistar rats. In the first model, after parturition, on a postnatal day 2 (PND-2), the pups were subjected to hypoxic exposure for 10 minutes to induce neonatal hypoxia. Pups were weaned from dams on PND-21 and subjected to drug treatments for 10 days. In the second model, phenytoin 150 mg/kg. b.wt. p.o. was administered orally to all pregnant animals throughout gestation to induce intrauterine hypoxia. Pups were subjected to assigned treatments after weaning. Behavioral and biochemical parameters relevant to ADHD were assessed. Results. In the positive control group, hypoxic exposure resulted in significant changes in cognitive and neurologic skills compared to normal control. Open field test, elevated plus maze test, and Acetylcholine esterase levels showed a significant increase in positive control compared to normal control. In treatment groups, there was a dose-dependent decrease in all the above parameters compared to positive control. Dopamine and Nor-epinephrine levels in brain homogenate were decreased in positive control which subsequently increased with MentatR treatment. Conclusion. MentatR showed a neuroprotective effect in different experimental models of ADHD. It may be recommended for the effective/preventive management of ADHD, especially associated with memory impairment and neurologic conditions.

Retinal Vascular Recovery Revealed by Retinal Imaging Following Neonatal Hypoxia Ischemia in Mice: Is There a Role for Tyrosine Kinase Receptor Modulation?

Retinal Vascular Recovery Revealed by Retinal Imaging Following Neonatal Hypoxia Ischemia in Mice: Is There a Role for Tyrosine Kinase Receptor Modulation?

Sildenafil improves hippocampal brain injuries and restores neuronal development after neonatal hypoxia\u2013ischemia in male rat pups

The hippocampus is a fundamental structure of the brain that plays an important role in neurodevelopment and is very sensitive to hypoxia–ischemia (HI). The purpose of this study was to investigate the effects of sildenafil on neonatal hippocampal brain injuries resulting from HI, and on neuronal development in this context. HI was induced in male Long–Evans rat pups at postnatal day 10 (P10) by a left common carotid ligation followed by a 2-h exposure to 8% oxygen. Rat pups were randomized to vehicle or sildenafil given orally twice daily for 7 days starting 12 h after HI. Hematoxylin and eosin staining was performed at P30 to measure the surface of the hippocampus; immunohistochemistry was performed to stain neurons, oligodendrocytes, and glial cells in the hippocampus. Western blots of the hippocampus were performed at P12, P17, and P30 to study the expression of neuronal markers and mTOR pathway. HI caused significant hippocampal atrophy and a significant reduction of the number of mature neurons, and induced reactive astrocytosis and microgliosis in the hippocampus. HI increased apoptosis and caused significant dysregulation of the normal neuronal development program. Treatment with sildenafil preserved the gross morphology of the hippocampus, reverted the number of mature neurons to levels comparable to sham rats, significantly increased both the immature and mature oligodendrocytes, and significantly reduced the number of microglia and astrocytes. Sildenafil also decreased apoptosis and reestablished the normal progression of post-natal neuronal development. The PI3K/Akt/mTOR pathway, whose activity was decreased after HI in the hippocampus, and restored after sildenafil treatment, may be involved. Sildenafil may have both neuroprotective and neurorestorative properties in the neonatal hippocampus following HI.