Impaired Oligodendrocyte Development Following Preterm Birth: Promoting GABAergic Action to Improve Outcomes

Preterm birth is associated with poor long-term neurodevelopmental and behavioral outcomes, even in the absence of obvious brain injury at the time of birth. In particular, behavioral disorders characterized by inattention, social difficulties and anxiety are common among children and adolescents who were born moderately to late preterm (32–37 weeks' gestation). Diffuse deficits in white matter microstructure are thought to play a role in these poor outcomes with evidence suggesting that a failure of oligodendrocytes to mature and myelinate axons is responsible. However, there remains a major knowledge gap over the mechanisms by which preterm birth interrupts normal oligodendrocyte development. In utero neurodevelopment occurs in an inhibitory-dominant environment due to the action of placentally derived neurosteroids on the GABAA receptor, thus promoting GABAergic inhibitory activity and maintaining the fetal behavioral state. Following preterm birth, and the subsequent premature exposure to the ex utero environment, this action of neurosteroids on GABAA receptors is greatly reduced. Coinciding with a reduction in GABAergic inhibition, the preterm neonatal brain is also exposed to ex utero environmental insults such as periods of hypoxia and excessive glucocorticoid concentrations. Together, these insults may increase levels of the excitatory neurotransmitter glutamate in the developing brain and result in a shift in the balance of inhibitory: excitatory activity toward excitatory. This review will outline the normal development of oligodendrocytes, how it is disrupted under excitation-dominated conditions and highlight how shifting the balance back toward an inhibitory-dominated environment may improve outcomes.

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Long-term dynamic changes of NMDA receptors following an excitotoxic challenge

10.1101/2022.01.03.474836 ◽

2022 ◽

Author(s):

Alberto Granzotto ◽

Marco d'Aurora ◽

Manuela Bomba ◽

Valentina Gatta ◽

Marco Onofrj ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Neuronal Death ◽

Oxygen Species ◽

Dynamic Changes ◽

Dynamic Regulation ◽

Excitatory Neurotransmitter ◽

Neurotransmitter Glutamate ◽

Nmdar Activation ◽

Sustained Activation

Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons [also known as nNOS (+) neurons] are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (-) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a key divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we demonstrate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings.

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Negative emotionality and discipline as long-term predictors of behavioral outcomes in African American and European American children.

Developmental Psychology ◽

10.1037/dev0000306 ◽

2017 ◽

Vol 53 (6) ◽

pp. 1013-1026 ◽

Cited By ~ 10

Author(s):

Cara Streit ◽

Gustavo Carlo ◽

Jean M. Ispa ◽

Francisco Palermo

Keyword(s):

African American ◽

Behavioral Outcomes ◽

Negative Emotionality ◽

European American ◽

American Children

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Oral melatonin as a new tool for neuroprotection in preterm newborns: study protocol for a randomized controlled trial

Trials ◽

10.1186/s13063-021-05034-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Francesca Garofoli ◽

Stefania Longo ◽

Camilla Pisoni ◽

Patrizia Accorsi ◽

Micol Angelini ◽

...

Keyword(s):

Preterm Birth ◽

Preterm Infants ◽

Neurodevelopmental Outcome ◽

Lipid Peroxidation Product ◽

Cerebral Magnetic Resonance Imaging ◽

Neurodevelopmental Impairment ◽

Anti Oxidant ◽

Preterm Newborns

Abstract Background Prevention of neurodevelopmental impairment due to preterm birth is a major health challenge. Despite advanced obstetric and neonatal care, to date there are few neuroprotective molecules available. Melatonin has been shown to have anti-oxidant/anti-inflammatory effects and to reduce brain damage, mainly after hypoxic ischemic encephalopathy. The planned study will be the first aiming to evaluate the capacity of melatonin to mitigate brain impairment due to premature birth. Method In our planned prospective, multicenter, double-blind, randomized vs placebo study, we will recruit, within 96 h of birth, 60 preterm newborns with a gestational age ≤ 29 weeks + 6 days; these infants will be randomly allocated to oral melatonin, 3 mg/kg/day, or placebo for 15 days. After the administration period, we will measure plasma levels of malondialdehyde, a lipid peroxidation product considered an early biological marker of melatonin treatment efficacy (primary outcome). At term-equivalent age, we will evaluate neurological status (through cerebral ultrasound, cerebral magnetic resonance imaging, vision and hearing evaluations, clinical neurological assessment, and screening for retinopathy of prematurity) as well as the incidence of bronchodysplasia and sepsis. We will also monitor neurodevelopmental outcome during the first 24 months of corrected age (using the modified Fagan Test of Infant Intelligence at 4–6 months and standardized neurological and developmental assessments at 24 months). Discussion Preterm birth survivors often present long-term neurodevelopmental sequelae, such as motor, learning, social-behavioral, and communication problems. We aim to assess the role of melatonin as a neuroprotectant during the first weeks of extrauterine life, when preterm infants are unable to produce it spontaneously. This approach is based on the supposition that its anti-oxidant mechanism could be useful in preventing neurodevelopmental impairment. Considering the short- and long-term morbidities related to preterm birth, and the financial and social costs of the care of preterm infants, both at birth and over time, we suggest that melatonin administration could lead to considerable saving of resources. This would be the first study addressing the role of melatonin in very low birth weight preterm newborns, and it could provide a basis for further studies on melatonin as a neuroprotection strategy in this vulnerable population. Trial registration ClinicalTrials.gov NCT04235673. Prospectively registered on 22 January 2020.

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The Long-Term Effect of Preterm Birth on Renal Function: A Meta-Analysis

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18062951 ◽

2021 ◽

Vol 18 (6) ◽

pp. 2951

Author(s):

Ju Sun Heo ◽

Jiwon M. Lee

Keyword(s):

Renal Function ◽

Preterm Birth ◽

Glomerular Filtration ◽

Renal Plasma Flow ◽

Meta Analysis ◽

Full Term ◽

Significant Difference ◽

Preterm Group ◽

Preterm Born

The preterm-born adult population is ever increasing following improved survival rates of premature births. We conducted a meta-analysis to investigate long-term effects of preterm birth on renal function in preterm-born survivors. We searched PubMed and EMBASE to identify studies that compared renal function in preterm-born survivors and full-term-born controls, published until 2 February 2019. A random effects model with standardized mean difference (SMD) was used for meta-analyses. Heterogeneity of the studies was evaluated using Higgin’s I2 statistics. Risk of bias was assessed using the Newcastle–Ottawa quality assessment scale. Of a total of 24,388 articles screened, 27 articles were finally included. Compared to full-term-born controls, glomerular filtration rate and effective renal plasma flow were significantly decreased in preterm survivors (SMD −0.54, 95% confidence interval (CI), −0.85 to −0.22, p = 0.0008; SMD −0.39, 95% CI, −0.74 to −0.04, p = 0.03, respectively). Length and volume of the kidneys were significantly decreased in the preterm group compared to the full-term controls (SMD −0.73, 95% CI, −1.04 to −0.41, p < 0.001; SMD −0.82, 95% CI, −1.05 to −0.60, p < 0.001, respectively). However, serum levels of blood urea nitrogen, creatinine, and cystatin C showed no significant difference. The urine microalbumin to creatinine ratio was significantly increased in the preterm group. Both systolic and diastolic blood pressures were also significantly elevated in the preterm group, although the plasma renin level did not differ. This meta-analysis demonstrates that preterm-born survivors may be subject to decreased glomerular filtration, increased albuminuria, decreased kidney size and volume, and hypertension even though their laboratory results may not yet deteriorate.

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Cytokine-Laden Extracellular Vesicles Predict Patient Prognosis after Cerebrovascular Accident

International Journal of Molecular Sciences ◽

10.3390/ijms22157847 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7847

Author(s):

Anthony Fringuello ◽

Philip D. Tatman ◽

Tadeusz Wroblewski ◽

John A. Thompson ◽

Xiaoli Yu ◽

...

Keyword(s):

Extracellular Vesicles ◽

Inflammatory Cytokines ◽

Hemorrhagic Stroke ◽

Term Outcome ◽

Long Term Outcome ◽

Interleukin 7 ◽

Poor Outcomes ◽

Patient Prognosis ◽

The Brain

Background: A major contributor to disability after hemorrhagic stroke is secondary brain damage induced by the inflammatory response. Following stroke, global increases in numerous cytokines—many associated with worse outcomes—occur within the brain, cerebrospinal fluid, and peripheral blood. Extracellular vesicles (EVs) may traffic inflammatory cytokines from damaged tissue within the brain, as well as peripheral sources, across the blood–brain barrier, and they may be a critical component of post-stroke neuroinflammatory signaling. Methods: We performed a comprehensive analysis of cytokine concentrations bound to plasma EV surfaces and/or sequestered within the vesicles themselves. These concentrations were correlated to patient acute neurological condition by the Glasgow Coma Scale (GCS) and to chronic, long-term outcome via the Glasgow Outcome Scale-Extended (GOS-E). Results: Pro-inflammatory cytokines detected from plasma EVs were correlated to worse outcomes in hemorrhagic stroke patients. Anti-inflammatory cytokines detected within EVs were still correlated to poor outcomes despite their putative neuroprotective properties. Inflammatory cytokines macrophage-derived chemokine (MDC/CCL2), colony stimulating factor 1 (CSF1), interleukin 7 (IL7), and monokine induced by gamma interferon (MIG/CXCL9) were significantly correlated to both negative GCS and GOS-E when bound to plasma EV membranes. Conclusions: These findings correlate plasma-derived EV cytokine content with detrimental outcomes after stroke, highlighting the potential for EVs to provide cytokines with a means of long-range delivery of inflammatory signals that perpetuate neuroinflammation after stroke, thus hindering recovery.

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Liposomal Encapsulated FSC231, a PICK1 Inhibitor, Prevents the Ischemia/Reperfusion-Induced Degradation of GluA2-Containing AMPA Receptors

Pharmaceutics ◽

10.3390/pharmaceutics13050636 ◽

2021 ◽

Vol 13 (5) ◽

pp. 636

Author(s):

Lindsay M. Achzet ◽

Fanny Astruc-Diaz ◽

Phillip H. Beske ◽

Nicholas R. Natale ◽

Travis T. Denton ◽

...

Keyword(s):

Intracellular Calcium ◽

Ampa Receptors ◽

Research Effort ◽

Ischemia Reperfusion ◽

Glucose Deprivation ◽

The United States ◽

Excitatory Neurotransmitter ◽

Protein Levels ◽

Neurotransmitter Glutamate ◽

Subsequent Degradation

Strokes remain one of the leading causes of disability within the United States. Despite an enormous amount of research effort within the scientific community, very few therapeutics are available for stroke patients. Cytotoxic accumulation of intracellular calcium is a well-studied phenomenon that occurs following ischemic stroke. This intracellular calcium overload results from excessive release of the excitatory neurotransmitter glutamate, a process known as excitotoxicity. Calcium-permeable AMPA receptors (AMPARs), lacking the GluA2 subunit, contribute to calcium cytotoxicity and subsequent neuronal death. The internalization and subsequent degradation of GluA2 AMPAR subunits following oxygen–glucose deprivation/reperfusion (OGD/R) is, at least in part, mediated by protein-interacting with C kinase-1 (PICK1). The purpose of the present study is to evaluate whether treatment with a PICK1 inhibitor, FSC231, prevents the OGD/R-induced degradation of the GluA2 AMPAR subunit. Utilizing an acute rodent hippocampal slice model system, we determined that pretreatment with FSC231 prevented the OGD/R-induced association of PICK1–GluA2. FSC231 treatment during OGD/R rescues total GluA2 AMPAR subunit protein levels. This suggests that the interaction between GluA2 and PICK1 serves as an important step in the ischemic/reperfusion-induced reduction in total GluA2 levels.

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An observational claims data analysis on the risk of maternal chronic kidney disease after preterm delivery and preeclampsia

Scientific Reports ◽

10.1038/s41598-021-92078-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Maren Goetz ◽

Mitho Müller ◽

Raphael Gutsfeld ◽

Tjeerd Dijkstra ◽

Kathrin Hassdenteufel ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Preterm Birth ◽

Kidney Disease ◽

Preterm Delivery ◽

Claims Data ◽

Maternal Risk ◽

Live Births ◽

Increased Risk ◽

History Of

AbstractWomen with complications of pregnancy such as preeclampsia and preterm birth are at risk for adverse long-term outcomes, including an increased future risk of chronic kidney disease (CKD) and end-stage kidney disease (ESKD). This observational cohort study aimed to examine the risk of CKD after preterm delivery and preeclampsia in a large obstetric cohort in Germany, taking into account preexisting comorbidities, potential confounders, and the severity of CKD. Statutory claims data of the AOK Baden-Wuerttemberg were used to identify women with singleton live births between 2010 and 2017. Women with preexisting conditions including CKD, ESKD, and kidney replacement therapy (KRT) were excluded. Preterm delivery (< 37 gestational weeks) was the main exposure of interest; preeclampsia was investigated as secondary exposure. The main outcome was a newly recorded diagnosis of CKD in the claims database. Data were analyzed using Cox proportional hazard regression models. The time-dependent occurrence of CKD was analyzed for four strata, i.e., births with (i) neither an exposure of preterm delivery nor an exposure of preeclampsia, (ii) no exposure of preterm delivery but exposure of at least one preeclampsia, (iii) an exposure of at least one preterm delivery but no exposure of preeclampsia, or (iv) joint exposure of preterm delivery and preeclampsia. Risk stratification also included different CKD stages. Adjustments were made for confounding factors, such as maternal age, diabetes, obesity, and dyslipidemia. The cohort consisted of 193,152 women with 257,481 singleton live births. Mean observation time was 5.44 years. In total, there were 16,948 preterm deliveries (6.58%) and 14,448 births with at least one prior diagnosis of preeclampsia (5.61%). With a mean age of 30.51 years, 1,821 women developed any form of CKD. Compared to women with no risk exposure, women with a history of at least one preterm delivery (HR = 1.789) and women with a history of at least one preeclampsia (HR = 1.784) had an increased risk for any subsequent CKD. The highest risk for CKD was found for women with a joint exposure of preterm delivery and preeclampsia (HR = 5.227). These effects were the same in magnitude only for the outcome of mild to moderate CKD, but strongly increased for the outcome of severe CKD (HR = 11.90). Preterm delivery and preeclampsia were identified as independent risk factors for all CKD stages. A joint exposure or preterm birth and preeclampsia was associated with an excessive maternal risk burden for CKD in the first decade after pregnancy. Since consequent follow-up policies have not been defined yet, these results will help guide long-term surveillance for early detection and prevention of kidney disease, especially for women affected by both conditions.

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Parenteral artemisinins are associated with reduced mortality and neurologic deficits and improved long-term behavioral outcomes in children with severe malaria

BMC Medicine ◽

10.1186/s12916-021-02033-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Andrea L. Conroy ◽

Robert O. Opoka ◽

Paul Bangirana ◽

Ruth Namazzi ◽

Allen E. Okullo ◽

...

Keyword(s):

Executive Function ◽

Hospital Mortality ◽

Cerebral Malaria ◽

Severe Malaria ◽

Behavioral Outcomes ◽

Artemisinin Derivatives ◽

Neurologic Deficits ◽

Adjusted Scores

Abstract Background In 2011, the World Health Organization recommended injectable artesunate as the first-line therapy for severe malaria (SM) due to its superiority in reducing mortality compared to quinine. There are limited data on long-term clinical and neurobehavioral outcomes after artemisinin use for treatment of SM. Methods From 2008 to 2013, 502 Ugandan children with two common forms of SM, cerebral malaria and severe malarial anemia, were enrolled in a prospective observational study assessing long-term neurobehavioral and cognitive outcomes following SM. Children were evaluated a week after hospital discharge, and 6, 12, and 24 months of follow-up, and returned to hospital for any illness. In this study, we evaluated the impact of artemisinin derivatives on survival, post-discharge hospital readmission or death, and neurocognitive and behavioral outcomes over 2 years of follow-up. Results 346 children received quinine and 156 received parenteral artemisinin therapy (artemether or artesunate). After adjustment for disease severity, artemisinin derivatives were associated with a 78% reduction in in-hospital mortality (adjusted odds ratio, 0.22; 95% CI, 0.07–0.67). Among cerebral malaria survivors, children treated with artemisinin derivatives also had reduced neurologic deficits at discharge (quinine, 41.7%; artemisinin derivatives, 23.7%, p=0.007). Over a 2-year follow-up, artemisinin derivatives as compared to quinine were associated with better adjusted scores (negative scores better) in internalizing behavior and executive function in children irrespective of the age at severe malaria episode. After adjusting for multiple comparisons, artemisinin derivatives were associated with better adjusted scores in behavior and executive function in children <6 years of age at severe malaria exposure following adjustment for child age, sex, socioeconomic status, enrichment in the home environment, and the incidence of hospitalizations over follow-up. Children receiving artesunate had the greatest reduction in mortality and benefit in behavioral outcomes and had reduced inflammation at 1-month follow-up compared to children treated with quinine. Conclusions Treatment of severe malaria with artemisinin derivatives, particularly artesunate, results in reduced in-hospital mortality and neurologic deficits in children of all ages, reduced inflammation following recovery, and better long-term behavioral outcomes. These findings suggest artesunate has long-term beneficial effects in children surviving severe malaria.

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