The Role of Cytokines and Inflammatory Cells in Perinatal Brain Injury

Perinatal brain injury frequently complicates preterm birth and leads to significant long-term morbidity. Cytokines and inflammatory cells are mediators in the common pathways associated with perinatal brain injury induced by a variety of insults, such as hypoxic-ischemic injury, reperfusion injury, toxin-mediated injury, and infection. This paper examines our current knowledge regarding cytokine-related perinatal brain injury and specifically discusses strategies for attenuating cytokine-mediated brain damage.

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The orphan nuclear receptor Nr4a1 mediates perinatal neuroinflammation in a murine model of preterm labor

Cell Death and Disease ◽

10.1038/s41419-019-2196-7 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Sarah M. Estrada ◽

Andrew S. Thagard ◽

Mary J. Dehart ◽

Jennifer R. Damicis ◽

Elisabeth M. Dornisch ◽

...

Keyword(s):

Preterm Birth ◽

Brain Injury ◽

Murine Model ◽

Inflammatory Factors ◽

Orphan Nuclear Receptor ◽

Perinatal Brain Injury ◽

Reporter Mice ◽

Injury Screening ◽

Genetic Modulators

AbstractPrematurity is associated with perinatal neuroinflammation and injury. Screening for genetic modulators in an LPS murine model of preterm birth revealed the upregulation of Nr4a1, an orphan nuclear transcription factor that is normally absent or limited in embryonic brains. Concurrently, Nr4a1 was downregulated with magnesium sulfate (MgSO4) and betamethasone (BMTZ) treatments administered to LPS exposed dams. To understand the role of Nr4a1 in perinatal brain injury, we compared the preterm neuroinflammatory response in Nr4a1 knockout (KO) versus wild type (wt) mice. Key inflammatory factors Il1b, Il6 and Tnf, and Iba1+ microglia were significantly lower in Nr4a1 KO versus wt brains exposed to LPS in utero. Treatment with MgSO4/BMTZ mitigated the neuroinflammatory process in wt but not Nr4a1 KO brains. These results correspond with a reduction in cerebral hemorrhage in wt but not mutant embryos from dams given MgSO4/BMTZ. Further analysis with Nr4a1-GFP-Cre × tdTomato loxP reporter mice revealed that the upregulation of Nr4a1 with perinatal neuroinflammation occurs in the cerebral vasculature. Altogether, this study implicates Nr4a1 in the developing vasculature as a potent mediator of neuroinflammatory brain injury that occurs with preterm birth. It is also possible that MgSO4/BMTZ mitigates this process by direct or indirect inhibition of Nr4a1.

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Role of PPARs in Radiation-Induced Brain Injury

PPAR Research ◽

10.1155/2010/234975 ◽

2010 ◽

Vol 2010 ◽

pp. 1-12 ◽

Cited By ~ 23

Author(s):

Sriram Ramanan ◽

Weiling Zhao ◽

David R. Riddle ◽

Mike E. Robbins

Keyword(s):

Brain Injury ◽

Inflammatory Responses ◽

Current Knowledge ◽

Whole Brain Irradiation ◽

Brain Irradiation ◽

Ppar Agonists ◽

The Usa ◽

Radiation Induced

Whole-brain irradiation (WBI) represents the primary mode of treatment for brain metastases; about 200 000 patients receive WBI each year in the USA. Up to 50% of adult and 100% of pediatric brain cancer patients who survive >6 months post-WBI will suffer from a progressive, cognitive impairment. At present, there are no proven long-term treatments or preventive strategies for this significant radiation-induced late effect. Recent studies suggest that the pathogenesis of radiation-induced brain injury involves WBI-mediated increases in oxidative stress and/or inflammatory responses in the brain. Therefore, anti-inflammatory strategies can be employed to modulate radiation-induced brain injury. Peroxisomal proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the steroid/thyroid hormone nuclear receptor superfamily. Although traditionally known to play a role in metabolism, increasing evidence suggests a role for PPARs in regulating the response to inflammation and oxidative injury. PPAR agonists have been shown to cross the blood-brain barrier and confer neuroprotection in animal models of CNS disorders such as stroke, multiple sclerosis and Parkinson's disease. However, the role of PPARs in radiation-induced brain injury is unclear. In this manuscript, we review the current knowledge and the emerging insights about the role of PPARs in modulating radiation-induced brain injury.

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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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Role of Glucose-Lowering Medications in Erectile Dysfunction

Journal of Clinical Medicine ◽

10.3390/jcm10112501 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2501

Author(s):

Angelo Cignarelli ◽

Valentina Annamaria Genchi ◽

Rossella D’Oria ◽

Fiorella Giordano ◽

Irene Caruso ◽

...

Keyword(s):

Erectile Dysfunction ◽

Current Knowledge ◽

Smooth Muscle Contractility ◽

Glucose Lowering ◽

Glycation End Products ◽

Altered Metabolism

Erectile dysfunction (ED) is a long-term complication of type 2 diabetes (T2D) widely known to affect the quality of life. Several aspects of altered metabolism in individuals with T2D may help to compromise the penile vasculature structure and functions, thus exacerbating the imbalance between smooth muscle contractility and relaxation. Among these, advanced glycation end-products and reactive oxygen species derived from a hyperglycaemic state are known to accelerate endothelial dysfunction by lowering nitric oxide bioavailability, the essential stimulus of relaxation. Although several studies have explained the pathogenetic mechanisms involved in the generation of erectile failure, few studies to date have described the efficacy of glucose-lowering medications in the restoration of normal sexual activity. Herein, we will present current knowledge about the main starters of the pathophysiology of diabetic ED and explore the role of different anti-diabetes therapies in the potential remission of ED, highlighting specific pathways whose activation or inhibition could be fundamental for sexual care in a diabetes setting.

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Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia

Cells ◽

10.3390/cells10071678 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1678

Author(s):

Liriopé Toupenet Marchesi ◽

Marion Leblanc ◽

Giovanni Stevanin

Keyword(s):

Nervous System ◽

Motor Neurons ◽

Neurological Disorders ◽

Hereditary Spastic Paraplegia ◽

Current Knowledge ◽

Spastic Paraplegia ◽

Functional Convergence ◽

The Common ◽

Hsp Genes

Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary. The role of several HSP genes/proteins is linked to the endolysosomal and autophagic pathways, suggesting a functional convergence. Furthermore, impairment of these pathways is particularly interesting since it has been linked to other neurodegenerative diseases, which would suggest that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems. In this review, we will summarize the involvement of HSP proteins in the endolysosomal and autophagic pathways in order to clarify their functioning and decipher some of the pathological mechanisms leading to HSP.

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Gestation-Based Viability–Difficult Decisions with Far-Reaching Consequences

Children ◽

10.3390/children8070593 ◽

2021 ◽

Vol 8 (7) ◽

pp. 593

Author(s):

Sumesh Thomas ◽

Elizabeth Asztalos

Keyword(s):

Decision Making ◽

Preterm Birth ◽

Current Knowledge ◽

First Trimester ◽

Perinatal Period ◽

Outcome Data ◽

Future Research ◽

Extremely Preterm ◽

Fetal Maturity

Most clinicians rely on outcome data based on completed weeks of gestational of fetal maturity for antenatal and postnatal counseling, especially for preterm infants born at the margins of viability. Contemporary estimation of gestational maturity, based on ultrasounds, relies on the use of first-trimester scans, which offer an accuracy of ±3–7 days, and depend on the timing of the scans and the measurements used in the calculations. Most published literature on the outcomes of babies born prematurely have reported on short- and long-term outcomes based on completed gestational weeks of fetal maturity at birth. These outcome data change significantly from one week to the next, especially around the margin of gestational viability. With a change in approach solely from decisions based on survival, to disability-free survival and long-term functional outcomes, the complexity of the parental and care provider’s decision-making in the perinatal and postnatal period for babies born at less than 25 weeks gestation remains challenging. While sustaining life following birth at the margins of viability remains our priority—identifying and mitigating risks associated with extremely preterm birth begins in the perinatal period. The challenge of supporting the normal maturation of these babies postnatally has far-reaching consequences and depends on our ability to sustain life while optimizing growth, nutrition, and the repair of organs compromised by the consequences of preterm birth. This article aims to explore the ethical and medical complexities of contemporary decision-making in the perinatal and postnatal periods. We identify gaps in our current knowledge of this topic and suggest areas for future research, while offering a perspective for future collaborative decision-making and care for babies born at the margins of viability.

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Potential Role of Adult Hippocampal Neurogenesis in Traumatic Brain Injury

Current Medicinal Chemistry ◽

10.2174/0929867328666210923143713 ◽

2021 ◽

Vol 28 ◽

Author(s):

Lucas Alexandre Santos Marzano ◽

Fabyolla Lúcia Macedo de Castro ◽

Caroline Amaral Machado ◽

João Luís Vieira Monteiro de Barros ◽

Thiago Macedo e Cordeiro ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Clinical Studies ◽

Molecular Mechanisms ◽

Hippocampal Neurogenesis ◽

Cognitive Outcomes ◽

Adult Hippocampal Neurogenesis ◽

The Brain

: Traumatic brain injury (TBI) is a serious cause of disability and death among young and adult individuals, displaying complex pathophysiology including cellular and molecular mechanisms that are not fully elucidated. Many experimental and clinical studies investigated the potential relationship between TBI and the process by which neurons are formed in the brain, known as neurogenesis. Currently, there are no available treatments for TBI’s long-term consequences being the search for novel therapeutic targets, a goal of highest scientific and clinical priority. Some studies evaluated the benefits of treatments aimed at improving neurogenesis in TBI. In this scenario, herein, we reviewed current pre-clinical studies that evaluated different approaches to improving neurogenesis after TBI while achieving better cognitive outcomes, which may consist in interesting approaches for future treatments.

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