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New Strategies of Neuroprotection and Repair in the Developing Brain

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 43724

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Special Issue Editor

Prof. Dr. Olivier Baud

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Guest Editor

1. Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Robert Debré Children’s Hospital, University Paris Diderot, Sorbonne Paris-Cité, 75019 Paris, France
2. PROTECT, Inserm 1141, Université Paris Diderot, Sorbonne Paris Cité, 75019 Paris, France
3. PremUP Foundation, 75014 Paris, France
Interests: perinatal brain damage; neonatal brain damage

Special Issue Information

Dear Colleagues,

Every year, 30 million infants worldwide are delivered after intra-uterine growth restriction (IUGR), and 15 million are born preterm. These two conditions are the leading causes of brain injury responsible for neurocognitive and behavioral disorders in more than 9 million children each year. Systemic inflammation, microglial activation, astroglial reaction, and their consequences on neuronal networks and connectivity have been identified as the main factors responsible for neurodevelopmental impairments. While strategies for protecting the developing brain and promoting its repair following injury have been extensively investigated in preclinical studies, most pharmacological candidates struggle to demonstrate a substantial beneficial effect to prevent brain lesions and their long-lasting neurodevelopmental consequences in infancy and adulthood. Several shortcomings impede clinical translation of preclinical promising strategies, including biological relevance in humans, dosage, timing, and outcomes used for assessing intervention. Nevertheless, many improvements have been observed in the last two decades, and neuroprotection of the developing brain has never appeared so closed, especially by refining new tools for assessing brain functions and by combining several strategies. This Special Issue will update the state-of-the-art in these strategies based on molecular mechanisms supporting their relevance.

Prof. Dr. Olivier Baud
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Immature brain
Neuroprotection
Neuroinflammation
Microglial activation
Oligodendroglial lineage
Brain imaging

Published Papers (10 papers)

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Research

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19 pages, 5381 KiB

Open AccessArticle

The Kynurenic Acid Analog SZR72 Enhances Neuronal Activity after Asphyxia but Is Not Neuroprotective in a Translational Model of Neonatal Hypoxic Ischemic Encephalopathy

by Viktória Kovács, Gábor Remzső, Tímea Körmöczi, Róbert Berkecz, Valéria Tóth-Szűki, Andrea Pénzes, László Vécsei and Ferenc Domoki

Int. J. Mol. Sci. 2021, 22(9), 4822; https://doi.org/10.3390/ijms22094822 - 01 May 2021

Cited by 2 | Viewed by 2200

Abstract

Hypoxic–ischemic encephalopathy (HIE) remains to be a major cause of long-term neurodevelopmental deficits in term neonates. Hypothermia offers partial neuroprotection warranting research for additional therapies. Kynurenic acid (KYNA), an endogenous product of tryptophan metabolism, was previously shown to be beneficial in rat HIE models. We sought to determine if the KYNA analog SZR72 would afford neuroprotection in piglets. After severe asphyxia (pHa = 6.83 ± 0.02, ΔBE = −17.6 ± 1.2 mmol/L, mean ± SEM), anesthetized piglets were assigned to vehicle-treated (VEH), SZR72-treated (SZR72), or hypothermia-treated (HT) groups (n = 6, 6, 6; Tcore = 38.5, 38.5, 33.5 °C, respectively). Compared to VEH, serum KYNA levels were elevated, recovery of EEG was faster, and EEG power spectral density values were higher at 24 h in the SZR72 group. However, instantaneous entropy indicating EEG signal complexity, depression of the visual evoked potential (VEP), and the significant neuronal damage observed in the neocortex, the putamen, and the CA1 hippocampal field were similar in these groups. In the caudate nucleus and the CA3 hippocampal field, neuronal damage was even more severe in the SZR72 group. The HT group showed the best preservation of EEG complexity, VEP, and neuronal integrity in all examined brain regions. In summary, SZR72 appears to enhance neuronal activity after asphyxia but does not ameliorate early neuronal damage in this HIE model. Full article

(This article belongs to the Special Issue New Strategies of Neuroprotection and Repair in the Developing Brain)

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30 pages, 7635 KiB

Open AccessArticle

Effect of Neuroprotective Magnesium Sulfate Treatment on Brain Transcription Response to Hypoxia Ischemia in Neonate Mice

by Bérénice Le Dieu-Lugon, Nicolas Dupré, Céline Derambure, François Janin, Bruno J. Gonzalez, Stéphane Marret, Arnaud Arabo and Philippe Leroux

Int. J. Mol. Sci. 2021, 22(8), 4253; https://doi.org/10.3390/ijms22084253 - 20 Apr 2021

Cited by 2 | Viewed by 2724

Abstract

MgSO₄ is widely used in the prevention of preterm neurological disabilities but its modes of action remain poorly established. We used a co-hybridization approach using the transcriptome in 5-day old mice treated with a single dose of MgSO₄ (600 mg/kg), and/or exposed to hypoxia-ischemia (HI). The transcription of hundreds of genes was altered in all the groups. MgSO₄ mainly produced repressions culminating 6 h after injection. Bio-statistical analysis revealed the repression of synaptogenesis and axonal development. The putative targets of MgSO₄ were Mnk1 and Frm1. A behavioral study of adults did not detect lasting effects of neonatal MgSO₄ and precluded NMDA-receptor-mediated side effects. The effects of MgSO₄ plus HI exceeded the sum of the effects of separate treatments. MgSO₄ prior to HI reduced inflammation and the innate immune response probably as a result of cytokine inhibition (Ccl2, Ifng, interleukins). Conversely, MgSO₄ had little effect on HI-induced transcription by RNA-polymerase II. De novo MgSO₄-HI affected mitochondrial function through the repression of genes of oxidative phosphorylation and many NAD-dehydrogenases. It also likely reduced protein translation by the repression of many ribosomal proteins, essentially located in synapses. All these effects appeared under the putative regulatory MgSO₄ induction of the mTORC2 Rictor coding gene. Lasting effects through Sirt1 and Frm1 could account for this epigenetic footprint. Full article

(This article belongs to the Special Issue New Strategies of Neuroprotection and Repair in the Developing Brain)

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22 pages, 16318 KiB

Open AccessArticle

Pharmacodynamic Effects of Standard versus High Caffeine Doses in the Developing Brain of Neonatal Rats Exposed to Intermittent Hypoxia

by Kutilda Soontarapornchai, Charles L. Cai, Taimur Ahmad, Jacob V. Aranda, Ivan Hand and Kay D. Beharry

Int. J. Mol. Sci. 2021, 22(7), 3473; https://doi.org/10.3390/ijms22073473 - 27 Mar 2021

Cited by 7 | Viewed by 2215

Abstract

(1) Background: Caffeine citrate, at standard doses, is effective for reducing the incidence of apnea of prematurity (AOP) and may confer neuroprotection and decrease neonatal morbidities in extremely low gestational age neonates (ELGANs) requiring oxygen therapy. We tested the hypothesis that high-dose caffeine (HiC) has no adverse effects on the neonatal brain. (2) Methods: Newborn rat pups were randomized to room air (RA), hyperoxia (Hx) or neonatal intermittent hypoxia (IH), from birth (P0) to P14 during which they received intraperitoneal injections of LoC (20 mg/kg on P0; 5 mg/kg/day on P1-P14), HiC (80 mg/kg; 20 mg/kg), or equivalent volume saline. Blood gases, histopathology, myelin and neuronal integrity, and adenosine receptor reactivity were assessed. (3) Results: Caffeine treatment in Hx influenced blood gases more than treatment in neonatal IH. Exposure to neonatal IH resulted in hemorrhage and higher brain width, particularly in layer 2 of the cerebral cortex. Both caffeine doses increased brain width in RA, but layer 2 was increased only with HiC. HiC decreased oxidative stress more effectively than LoC, and both doses reduced apoptosis biomarkers. In RA, both caffeine doses improved myelination, but the effect was abolished in Hx and neonatal IH. Similarly, both doses inhibited adenosine 1A receptor in all oxygen environments, but adenosine 2A receptor was inhibited only in RA and Hx. (4) Conclusions: Caffeine, even at high doses, when administered in normoxia, can confer neuroprotection, evidenced by reductions in oxidative stress, hypermyelination, and increased Golgi bodies. However, varying oxygen environments, such as Hx or neonatal IH, may alter and modify pharmacodynamic actions of caffeine and may even override the benefits caffeine. Full article

(This article belongs to the Special Issue New Strategies of Neuroprotection and Repair in the Developing Brain)

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22 pages, 4004 KiB

Open AccessArticle

Regenerative Therapies to Restore Interneuron Disturbances in Experimental Models of Encephalopathy of Prematurity

by Josine E. G. Vaes, Chantal M. Kosmeijer, Marthe Kaal, Rik van Vliet, Myrna J. V. Brandt, Manon J. N. L. Benders and Cora H. Nijboer

Int. J. Mol. Sci. 2021, 22(1), 211; https://doi.org/10.3390/ijms22010211 - 28 Dec 2020

Cited by 10 | Viewed by 3437

Abstract

Encephalopathy of Prematurity (EoP) is a major cause of morbidity in (extreme) preterm neonates. Though the majority of EoP research has focused on failure of oligodendrocyte maturation as an underlying pathophysiological mechanism, recent pioneer work has identified developmental disturbances in inhibitory interneurons to contribute to EoP. Here we investigated interneuron abnormalities in two experimental models of EoP and explored the potential of two promising treatment strategies, namely intranasal mesenchymal stem cells (MSCs) or insulin-like growth factor I (IGF1), to restore interneuron development. In rats, fetal inflammation and postnatal hypoxia led to a transient increase in total cortical interneuron numbers, with a layer-specific deficit in parvalbumin (PV)+ interneurons. Additionally, a transient excess of total cortical cell density was observed, including excitatory neuron numbers. In the hippocampal cornu ammonis (CA) 1 region, long-term deficits in total interneuron numbers and PV+ subtype were observed. In mice subjected to postnatal hypoxia/ischemia and systemic inflammation, total numbers of cortical interneurons remained unaffected; however, subtype analysis revealed a global, transient reduction in PV+ cells and a long-lasting layer-specific increase in vasoactive intestinal polypeptide (VIP)+ cells. In the dentate gyrus, a long-lasting deficit of somatostatin (SST)+ cells was observed. Both intranasal MSC and IGF1 therapy restored the majority of interneuron abnormalities in EoP mice. In line with the histological findings, EoP mice displayed impaired social behavior, which was partly restored by the therapies. In conclusion, induction of experimental EoP is associated with model-specific disturbances in interneuron development. In addition, intranasal MSCs and IGF1 are promising therapeutic strategies to aid interneuron development after EoP. Full article

(This article belongs to the Special Issue New Strategies of Neuroprotection and Repair in the Developing Brain)

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Review

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13 pages, 770 KiB

Open AccessReview

Paracetamol (Acetaminophen) and the Developing Brain

by Christoph Bührer, Stefanie Endesfelder, Till Scheuer and Thomas Schmitz

Int. J. Mol. Sci. 2021, 22(20), 11156; https://doi.org/10.3390/ijms222011156 - 15 Oct 2021

Cited by 17 | Viewed by 10748

Abstract

Paracetamol is commonly used to treat fever and pain in pregnant women, but there are growing concerns that this may cause attention deficit hyperactivity disorder and autism spectrum disorder in the offspring. A growing number of epidemiological studies suggests that relative risks for these disorders increase by an average of about 25% following intrauterine paracetamol exposure. The data analyzed point to a dose–effect relationship but cannot fully account for unmeasured confounders, notably indication and genetic transmission. Only few experimental investigations have addressed this issue. Altered behavior has been demonstrated in offspring of paracetamol-gavaged pregnant rats, and paracetamol given at or prior to day 10 of life to newborn mice resulted in altered locomotor activity in response to a novel home environment in adulthood and blunted the analgesic effect of paracetamol given to adult animals. The molecular mechanisms that might mediate these effects are unknown. Paracetamol has diverse pharmacologic actions. It reduces prostaglandin formation via competitive inhibition of the peroxidase moiety of prostaglandin H2 synthase, while its metabolite N-arachidonoyl-phenolamine activates transient vanilloid-subtype 1 receptors and interferes with cannabinoid receptor signaling. The metabolite N-acetyl-p-benzo-quinone-imine, which is pivotal for liver damage after overdosing, exerts oxidative stress and depletes glutathione in the brain already at dosages below the hepatic toxicity threshold. Given the widespread use of paracetamol during pregnancy and the lack of safe alternatives, its impact on the developing brain deserves further investigation. Full article

(This article belongs to the Special Issue New Strategies of Neuroprotection and Repair in the Developing Brain)

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25 pages, 1067 KiB

Open AccessReview

Connecting the Neurobiology of Developmental Brain Injury: Neuronal Arborisation as a Regulator of Dysfunction and Potential Therapeutic Target

by Ane Goikolea-Vives and Helen B. Stolp

Int. J. Mol. Sci. 2021, 22(15), 8220; https://doi.org/10.3390/ijms22158220 - 30 Jul 2021

Cited by 2 | Viewed by 3345

Abstract

Neurodevelopmental disorders can derive from a complex combination of genetic variation and environmental pressures on key developmental processes. Despite this complex aetiology, and the equally complex array of syndromes and conditions diagnosed under the heading of neurodevelopmental disorder, there are parallels in the neuropathology of these conditions that suggest overlapping mechanisms of cellular injury and dysfunction. Neuronal arborisation is a process of dendrite and axon extension that is essential for the connectivity between neurons that underlies normal brain function. Disrupted arborisation and synapse formation are commonly reported in neurodevelopmental disorders. Here, we summarise the evidence for disrupted neuronal arborisation in these conditions, focusing primarily on the cortex and hippocampus. In addition, we explore the developmentally specific mechanisms by which neuronal arborisation is regulated. Finally, we discuss key regulators of neuronal arborisation that could link to neurodevelopmental disease and the potential for pharmacological modification of arborisation and the formation of synaptic connections that may provide therapeutic benefit in the future. Full article

(This article belongs to the Special Issue New Strategies of Neuroprotection and Repair in the Developing Brain)

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14 pages, 1158 KiB

Open AccessReview

Treating Seizures after Hypoxic-Ischemic Encephalopathy—Current Controversies and Future Directions

by Kelly Q. Zhou, Alice McDouall, Paul P. Drury, Christopher A. Lear, Kenta H. T. Cho, Laura Bennet, Alistair J. Gunn and Joanne O. Davidson

Int. J. Mol. Sci. 2021, 22(13), 7121; https://doi.org/10.3390/ijms22137121 - 01 Jul 2021

Cited by 19 | Viewed by 5396

Abstract

Seizures are common in newborn infants with hypoxic-ischemic encephalopathy and are highly associated with adverse neurodevelopmental outcomes. The impact of seizure activity on the developing brain and the most effective way to manage these seizures remain surprisingly poorly understood, particularly in the era of therapeutic hypothermia. Critically, the extent to which seizures exacerbate brain injury or merely reflect the underlying evolution of injury is unclear. Current anticonvulsants, such as phenobarbital and phenytoin have poor efficacy and preclinical studies suggest that most anticonvulsants are associated with adverse effects on the developing brain. Levetiracetam seems to have less potential neurotoxic effects than other anticonvulsants but may not be more effective. Given that therapeutic hypothermia itself has significant anticonvulsant effects, randomized controlled trials of anticonvulsants combined with therapeutic hypothermia, are required to properly determine the safety and efficacy of these drugs. Small clinical studies suggest that prophylactic phenobarbital administration may improve neurodevelopmental outcomes compared to delayed administration; however, larger high-quality studies are required to confirm this. In conclusion, there is a distinct lack of high-quality evidence for whether and to what extent neonatal seizures exacerbate brain damage after hypoxia-ischemia and how best to manage them in the era of therapeutic hypothermia. Full article

(This article belongs to the Special Issue New Strategies of Neuroprotection and Repair in the Developing Brain)

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24 pages, 1299 KiB

Open AccessReview

Melatonin for Neonatal Encephalopathy: From Bench to Bedside

by Raymand Pang, Adnan Advic-Belltheus, Christopher Meehan, Daniel J. Fullen, Xavier Golay and Nicola J. Robertson

Int. J. Mol. Sci. 2021, 22(11), 5481; https://doi.org/10.3390/ijms22115481 - 22 May 2021

Cited by 9 | Viewed by 4254

Abstract

Neonatal encephalopathy is a leading cause of morbidity and mortality worldwide. Although therapeutic hypothermia (HT) is now standard practice in most neonatal intensive care units in high resource settings, some infants still develop long-term adverse neurological sequelae. In low resource settings, HT may not be safe or efficacious. Therefore, additional neuroprotective interventions are urgently needed. Melatonin’s diverse neuroprotective properties include antioxidant, anti-inflammatory, and anti-apoptotic effects. Its strong safety profile and compelling preclinical data suggests that melatonin is a promising agent to improve the outcomes of infants with NE. Over the past decade, the safety and efficacy of melatonin to augment HT has been studied in the neonatal piglet model of perinatal asphyxia. From this model, we have observed that the neuroprotective effects of melatonin are time-critical and dose dependent. Therapeutic melatonin levels are likely to be 15–30 mg/L and for optimal effect, these need to be achieved within the first 2–3 h after birth. This review summarises the neuroprotective properties of melatonin, the key findings from the piglet and other animal studies to date, and the challenges we face to translate melatonin from bench to bedside. Full article

(This article belongs to the Special Issue New Strategies of Neuroprotection and Repair in the Developing Brain)

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13 pages, 656 KiB

Open AccessReview

Neuroprotection of the Perinatal Brain by Early Information of Cerebral Oxygenation and Perfusion Patterns

by Filipe Gonçalves Costa, Naser Hakimi and Frank Van Bel

Int. J. Mol. Sci. 2021, 22(10), 5389; https://doi.org/10.3390/ijms22105389 - 20 May 2021

Cited by 9 | Viewed by 2968

Abstract

Abnormal patterns of cerebral perfusion/oxygenation are associated with neuronal damage. In preterm neonates, hypoxemia, hypo-/hypercapnia and lack of cerebral autoregulation are related to peri-intraventricular hemorrhages and white matter injury. Reperfusion damage after perinatal hypoxic ischemia in term neonates seems related with cerebral hyperoxygenation. Since biological tissue is transparent for near infrared (NIR) light, NIR-spectroscopy (NIRS) is a noninvasive bedside tool to monitor brain oxygenation and perfusion. This review focuses on early assessment and guiding abnormal cerebral oxygenation/perfusion patterns to possibly reduce brain injury. In term infants, early patterns of brain oxygenation helps to decide whether or not therapy (hypothermia) and add-on therapies should be considered. Further NIRS-related technical advances such as the use of (functional) NIRS allowing simultaneous estimation and integrating of heart rate, respiration rate and monitoring cerebral autoregulation will be discussed. Full article

(This article belongs to the Special Issue New Strategies of Neuroprotection and Repair in the Developing Brain)

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17 pages, 1784 KiB

Open AccessReview

Perinatal Infection: A Major Contributor to Efficacy of Cooling in Newborns Following Birth Asphyxia

by Jibrin Danladi and Hemmen Sabir

Int. J. Mol. Sci. 2021, 22(2), 707; https://doi.org/10.3390/ijms22020707 - 12 Jan 2021

Cited by 8 | Viewed by 5100

Abstract

Neonatal encephalopathy (NE) is a global burden, as more than 90% of NE occurs in low- and middle-income countries (LMICs). Perinatal infection seems to limit the neuroprotective efficacy of therapeutic hypothermia. Efforts made to use therapeutic hypothermia in LMICs treating NE has led to increased neonatal mortality rates. The heat shock and cold shock protein responses are essential for survival against a wide range of stressors during which organisms raise their core body temperature and temporarily subject themselves to thermal and cold stress in the face of infection. The characteristic increase and decrease in core body temperature activates and utilizes elements of the heat shock and cold shock response pathways to modify cytokine and chemokine gene expression, cellular signaling, and immune cell mobilization to sites of inflammation, infection, and injury. Hypothermia stimulates microglia to secret cold-inducible RNA-binding protein (CIRP), which triggers NF-κB, controlling multiple inflammatory pathways, including nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes and cyclooxygenase-2 (COX-2) signaling. Brain responses through changes in heat shock protein and cold shock protein transcription and gene-expression following fever range and hyperthermia may be new promising potential therapeutic targets. Full article

(This article belongs to the Special Issue New Strategies of Neuroprotection and Repair in the Developing Brain)

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