scholarly journals Magnesium induces preconditioning of the neonatal brain via profound mitochondrial protection

2017 ◽  
Vol 39 (6) ◽  
pp. 1038-1055 ◽  
Author(s):  
Gabriella Koning ◽  
Anna-Lena Leverin ◽  
Syam Nair ◽  
Leslie Schwendimann ◽  
Joakim Ek ◽  
...  
Keyword(s):  
Brain Injury ◽  
Preterm Labor ◽  
Serum Magnesium ◽  
High Energy ◽  
High Energy Phosphates ◽  
Clinical Implementation ◽  
Neonatal Brain ◽  
Immature Brain ◽  
Old Rats ◽  
The Brain

Magnesium sulphate (MgSO4) given to women in preterm labor reduces cerebral palsy in their offspring but the mechanism behind this protection is unclear, limiting its effective, safe clinical implementation. Previous studies suggest that MgSO4 is not neuroprotective if administered during or after the insult, so we hypothesised that MgSO4 induces preconditioning in the immature brain. Therefore, we administered MgSO4 at various time-points before/after unilateral hypoxia-ischemia (HI) in seven-day-old rats. We found that MgSO4 treatment administered as a bolus between 6 days and 12 h prior to HI markedly reduced the brain injury, with maximal protection achieved by 1.1 mg/g MgSO4 administered 24 h before HI. As serum magnesium levels returned to baseline before the induction of HI, we ascribed this reduction in brain injury to preconditioning. Cerebral blood flow was unaffected, but mRNAs/miRNAs involved in mitochondrial function and metabolism were modulated by MgSO4. Metabolomic analysis (H+-NMR) disclosed that MgSO4 attenuated HI-induced increases in succinate and prevented depletion of high-energy phosphates. MgSO4 pretreatment preserved mitochondrial respiration, reducing ROS production and inflammation after HI. Therefore, we propose that MgSO4 evokes preconditioning via induction of mitochondrial resistance and attenuation of inflammation.

scholarly journals New Antioxidant Drugs for Neonatal Brain Injury

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Maria Luisa Tataranno ◽  
Serafina Perrone ◽  
Mariangela Longini ◽  
Giuseppe Buonocore
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Postnatal Period ◽  
Limited Capacity ◽  
Neonatal Brain ◽  
Immature Brain ◽  
Beneficial Effects ◽  
Neurodevelopmental Impairment ◽  
The Brain

The brain injury concept covers a lot of heterogeneity in terms of aetiology involving multiple factors, genetic, hemodynamic, metabolic, nutritional, endocrinological, toxic, and infectious mechanisms, acting in antenatal or postnatal period. Increased vulnerability of the immature brain to oxidative stress is documented because of the limited capacity of antioxidant enzymes and the high free radicals (FRs) generation in rapidly growing tissue. FRs impair transmembrane enzyme Na+/K+-ATPase activity resulting in persistent membrane depolarization and excessive release of FR and excitatory aminoacid glutamate. Besides being neurotoxic, glutamate is also toxic to oligodendroglia, via FR effects. Neuronal cells die of oxidative stress. Excess of free iron and deficient iron/binding metabolising capacity are additional features favouring oxidative stress in newborn. Each step in the oxidative injury cascade has become a potential target for neuroprotective intervention. The administration of antioxidants for suspected or proven brain injury is still not accepted for clinical use due to uncertain beneficial effects when treatments are started after resuscitation of an asphyxiated newborn. The challenge for the future is the early identification of high-risk babies to target a safe and not toxic antioxidant therapy in combination with standard therapies to prevent brain injury and long-term neurodevelopmental impairment.

TGFβ1: Friend or Foe During Recovery in Encephalopathy

2018 ◽  
Vol 25 (3) ◽  
pp. 192-198 ◽  
Author(s):  
Brian H. Kim ◽  
Steven W. Levison
Keyword(s):  
Brain Injury ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Neuronal Survival ◽  
Acute Stage ◽  
Tgfβ Signaling ◽  
Immature Brain ◽  
The Brain ◽  
Survival Mechanisms

The cytokine transforming growth factor (TGF)-β1 is highly induced after encephalopathic brain injury, with data showing that it can both contribute to the pathophysiology and aid in disease resolution. In the immature brain, sustained TGFβ-signaling after injury may prolong inflammation to both exacerbate acute stage damage and perturb the normal course of development. Yet in adult encephalopathy, elevated TGFβ1 may promote a reparative state. In this review, we highlight the context-dependent actions of TGFβ-signaling in the brain during resolution of encephalopathy and focus on neuronal survival mechanisms that are affected by TGFβ1. We discuss the mechanisms that contribute to the disparate actions of TGFβ1 toward elucidating the long-term neurological and neuropsychiatric consequences that follow encephalopathic injury.

Transient alterations of creatine, creatine phosphate, N-acetylaspartate and high-energy phosphates after mild traumatic brain injury in the rat

2009 ◽  
Vol 333 (1-2) ◽  
pp. 269-277 ◽  
Author(s):  
Stefano Signoretti ◽  
Valentina Di Pietro ◽  
Roberto Vagnozzi ◽  
Giuseppe Lazzarino ◽  
Angela M. Amorini ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Creatine Phosphate ◽  
High Energy ◽  
High Energy Phosphates

scholarly journals Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

1991 ◽  
Vol 277 (3) ◽  
pp. 697-703 ◽  
Author(s):  
R A Hawkins ◽  
J Jessy
Keyword(s):  
Amino Acids ◽  
Brain Function ◽  
Aromatic Amino Acids ◽  
Preceding Paper ◽  
Glucose Consumption ◽  
High Energy ◽  
High Energy Phosphates ◽  
Intermediary Metabolites ◽  
Glutamine Synthesis ◽  
The Brain

1. It has been established that chronic hyperammonaemia, whether caused by portacaval shunting or other means, leads to a variety of metabolic changes, including a depression in the cerebral metabolic rate of glucose (CMRGlc) increased permeability of the blood-brain barrier to neutral amino acids, and an increase in the brain content of aromatic amino acids. The preceding paper [Jessy, DeJoseph & Hawkins (1991) Biochem. J. 277, 693-696] showed that the depression in CMRGlc caused by hyperammonaemia correlated more closely with glutamine, a metabolite of ammonia, than with ammonia itself. This suggested that ammonia (NH3 and NH4+) was without effect. The present experiments address the question whether ammonia, in the absence of net glutamine synthesis, induces any of the metabolic symptoms of cerebral dysfunction associated with hyperammonaemia. 2. Small doses of methionine sulphoximine, an inhibitor of glutamine synthetase, were used to raise the plasma ammonia levels of normal rats without increasing the brain glutamine content. These hyperammonaemic rats, with plasma and brain ammonia levels equivalent to those known to depress brain function, behaved normally over 48 h. There was no depression of cerebral energy metabolism (i.e. the rate of glucose consumption). Contents of key intermediary metabolites and high-energy phosphates were normal. Neutral amino acid transport (tryptophan and leucine) and the brain contents of aromatic amino acids were unchanged. 3. The data suggest that ammonia is without effect at concentrations less than 1 mumol/ml if it is not converted into glutamine. The deleterious effect of chronic hyperammonaemia seems to begin with the synthesis of glutamine.

scholarly journals Circulating Tight-Junction Proteins Are Potential Biomarkers for Blood-Brain Barrier Function in a Model of Neonatal Hypoxic/Ischemic Brain Injury

2020 ◽  
Author(s):  
Axel Erik Andersson ◽  
Carina Mallard ◽  
Carl Joakim Ek
Keyword(s):  
Brain Injury ◽  
Blood Brain Barrier ◽  
Brain Injuries ◽  
Brain Barrier ◽  
Neonatal Brain ◽  
Ischemic Brain ◽  
Blood Brain ◽  
Hypoxia Ischemia ◽  
The Brain ◽  
Junction Proteins

Abstract BackgroundNeonatal hypoxia-ischemia often leads to lifelong disabilities with limited treatments currently available. The brain vasculature is an important factor in many neonatal brain pathologies but there is a lack of diagnostic tools to evaluate the brain vascular health of neonates in a clinical setting. Measurement of blood-brain barrier tight-junction proteins have shown promise as biomarkers for brain injury in the adult. Here we tested the biomarker potential of tight-junctions in the context of neonatal brain injury.MethodsThe levels of TJ-proteins (occluding, claudin-5, and zonula occludens-1) in both blood plasma and cerebrospinal fluid (CSF) as well as blood-brain barrier function were measured in a clinically relevant hypoxia/ischemia model in neonatal rats.ResultsTemporally acute elevated levels of occludin and claudin-5 could be measured in blood and CSF after hypoxia/ischemia with males generally having higher levels than females. The levels of claudin-5 in CSF correlated with the severity of the brain injury at 24h post- hypoxia/ischemia. Simultaneously, we detected early increase in blood-brain barrier-permeability at 6 and 24h after hypoxia/ischemia.ConclusionsLevels of circulating claudin-5 and occludin are increased after hypoxic/ischemic brain injuries and blood-brain barrier-impairment and have promise as early biomarkers for cerebral vascular health and as a tool for risk assessment of neonatal brain injuries.

Cerebral Palsy

2017 ◽  
Author(s):  
Joan M. Jasien ◽  
Bruce K. Shapiro ◽  
Alexander H. Hoon
Keyword(s):  
Cerebral Palsy ◽  
Brain Injury ◽  
Human Brain ◽  
Selective Vulnerability ◽  
Postnatal Life ◽  
Organizational Changes ◽  
Immature Brain ◽  
The Brain ◽  
Compensatory Plasticity ◽  
Over Time

Cerebral palsy (CP) describes a group of disorders of movement/posture causing activity limitation that are attributed to nonprogressive disturbances in the immature brain that can change over time. The immature human brain undergoes organizational changes during intrauterine and postnatal life creating potential temporal periods of selective vulnerability to damage. Understanding the compensatory plasticity process after the brain injury may provide new insights into the pathogenesis of CP.

scholarly journals Clinical motivation for31P MRS studies on the myocardial energy metabolism of brain dead cats

2003 ◽  
Vol 17 (2-3) ◽  
pp. 503-510
Author(s):  
G. J. Brandon Bravo Bruinsma ◽  
C. J. A. Van Echteld
Keyword(s):  
Energy Metabolism ◽  
Brain Death ◽  
Hemodynamic Instability ◽  
High Energy ◽  
Exclusion Criterion ◽  
High Energy Phosphates ◽  
Myocardial Energy Metabolism ◽  
Brain Dead ◽  
The Brain ◽  
Death Group

Hemodynamic instability of the brain dead potential heart donor is an exclusion criterion for heart donation for transplantation. Based on the results of myocardial biopsies it has been reported that brain death-related catecholamine induced damage of the heart causes depletion of high-energy phosphates which could explain contractile dysfunction. Our group has shown in a series of31P MRS experiments in cats that neither the onset of brain death, nor the hemodynamic deterioration which follows, nor its treatment with high dosages of dopamine affect the heart energetically as expressed by PCr/ATP ratios. However, after cardioplegic arrest and explantation, an initial and prolonged lower ATP content and an anomalous higher PCr/ATP ratio in the brain death group was found when compared with controls during long-term unperfused cold storage of the hearts. During subsequent reperfusion of the hearts, ATP and PCr levels in the brain death group were lower than in controls but equal partial recovery of PCr/ATP ratios was observed in both groups. It was concluded that PCr/ATP ratios need to be interpreted with great caution. Secondly, brain death-related hemodynamic instability is not related to significant changes of myocardial energy metabolism. Thirdly, brain death does affect the myocardial energy metabolism but the impact became apparent only during hypothermic storage and subsequent reperfusion of the donor heart.

Uremic encephalopathy: role of brain energy metabolism

1984 ◽  
Vol 247 (3) ◽  
pp. F527-F532
Author(s):  
C. A. Mahoney ◽  
P. Sarnacki ◽  
A. I. Arieff
Keyword(s):  
Renal Failure ◽  
Redox State ◽  
Adenine Nucleotide ◽  
Energy Charge ◽  
High Energy ◽  
Normal Brain ◽  
High Energy Phosphates ◽  
Adenine Nucleotide Pool ◽  
The Brain ◽  
Brain Energy

Uremia is associated with decreased brain oxygen consumption in humans and with decreased brain energy consumption in rodent models of acute renal failure. We measured the levels of high-energy phosphates and glycolytic intermediates in the brain of dogs with acute or chronic renal failure. We used methods of rapid brain tissue fixation that trap these labile metabolites at their in vivo levels. Creatine phosphate, ATP, and glucose were normal in the brain of animals with renal failure, indicating a normal brain energy reserve. The brain energy charge, which is the fraction of the total adenine nucleotide pool that contains high-energy phosphates, (ATP + 1/2ADP)/(ATP + ADP + AMP), was also normal despite an 8% decrease in the total adenine nucleotide pool. Mild hypoxia failed to alter the level of any of these metabolites. The brain redox state, (NAD+)/(NADH), was normal to high in acute renal failure, suggesting that oxygen supply was not limiting oxygen consumption. In the face of normal brain energy reserves, energy charge, and redox state, the decreased energy consumption of uremic brain probably results from decreased demand rather than limited supply.

scholarly journals Circulating tight-junction proteins are potential biomarkers for blood–brain barrier function in a model of neonatal hypoxic/ischemic brain injury

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
E. Axel Andersson ◽  
Carina Mallard ◽  
C. Joakim Ek
Keyword(s):  
Brain Injury ◽  
Blood Brain Barrier ◽  
Brain Injuries ◽  
Vascular Dysfunction ◽  
Brain Barrier ◽  
Neonatal Brain ◽  
Ischemic Brain ◽  
Blood Brain ◽  
Hypoxia Ischemia ◽  
The Brain

Abstract Background Neonatal encephalopathy often leads to lifelong disabilities with limited treatments currently available. The brain vasculature is an important factor in many neonatal neurological disorders but there is a lack of diagnostic tools to evaluate the brain vascular dysfunction of neonates in the clinical setting. Measurement of blood–brain barrier tight-junction (TJ) proteins have shown promise as biomarkers for brain injury in the adult. Here we tested the biomarker potential of tight-junctions in the context of neonatal brain injury. Methods The levels of TJ-proteins (occluding, claudin-5, and zonula occludens protein 1) in both blood plasma and cerebrospinal fluid (CSF) as well as blood–brain barrier function via 14C-sucrose (342 Da) and Evans blue extravasation were measured in a hypoxia/ischemia brain-injury model in neonatal rats. Results Time-dependent changes of occludin and claudin-5 levels could be measured in blood and CSF after hypoxia/ischemia with males generally having higher levels than females. The levels of claudin-5 in CSF correlated with the severity of the brain injury at 24 h post- hypoxia/ischemia. Simultaneously, we detected early increase in blood–brain barrier-permeability at 6 and 24 h after hypoxia/ischemia. Conclusions Levels of circulating claudin-5 and occludin are increased after hypoxic/ischemic brain injuries and blood–brain barrier-impairment and have promise as early biomarkers for cerebral vascular dysfunction and as a tool for risk assessment of neonatal brain injuries.

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