Magnesium sulphate induces preconditioning in preterm rodent models of cerebral hypoxia‐ischemia

Koning, Gabriella; Lyngfelt, Ellinor; Svedin, Pernilla; Leverin, Anna-Lena; Jinnai, Masako; Gressèns, Pierre; Thornton, Claire; Wang, Xiaoyang; Mallard, Carina; Hagberg, Henrik

doi:10.1016/j.ijdevneu.2018.01.002

Cited by 14 publications

(11 citation statements)

References 52 publications

(74 reference statements)

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“…In conclusion, we showed for the first time that enhanced autophagy could mediate cell death in a premature model of excitotoxic brain damage. Autophagy inhibition in this severe model is very promising since the protective effect obtained is similar or even better to other previously described neuroprotectants such as caspases inhibitors 69 , erythropoietin 70 , 71 , BDNF 72 , 73 , melatonin 74 or magnesium sulfate 75 , 76 . Interestingly, we recently demonstrated that autophagy is enhanced in dying neurons in the ventrolateral nucleus of the thalamus and the lentiform nucleus of term newborns with severe HIE 31 , 60 .…”

Section: Discussionsupporting

confidence: 72%

Enhanced autophagy contributes to excitotoxic lesions in a rat model of preterm brain injury

et al. 2018

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Cystic periventricular leukomalacia is commonly diagnosed in premature infants, resulting from severe hypoxic-ischemic white matter injury, and also involving some grey matter damage. Very few is known concerning the cell death pathways involved in these types of premature cerebral lesions. Excitotoxicity is a predominant mechanism of hypoxic-ischemic injury in the developing brain. Concomitantly, it has been recently shown that autophagy could be enhanced in excitotoxic conditions switching this physiological intracellular degradation system to a deleterious process. We here investigated the role of autophagy in a validated rodent model of preterm excitotoxic brain damage mimicking in some aspects cystic periventricular leukomalacia. An excitotoxic lesion affecting periventricular white and grey matter was induced by injecting ibotenate, a glutamate analogue, in the subcortical white matter (subcingulum area) of five-day old rat pups. Ibotenate enhanced autophagy in rat brain dying neurons at 24 h as shown by increased presence of autophagosomes (increased LC3-II and LC3-positive dots) and enhanced autophagic degradation (SQSTM1 reduction and increased number and size of lysosomes (LAMP1- and CATHEPSIN B-positive vesicles)). Co-injection of the pharmacological autophagy inhibitor 3-methyladenine prevented not only autophagy induction but also CASPASE-3 activation and calpain-dependent cleavage of SPECTRIN 24 h after the insult, thus providing a strong reduction of the long term brain injury (16 days after ibotenate injection) including lateral ventricle dilatation, decreases in cerebral tissue volume and in subcortical white matter thickness. The autophagy-dependent neuroprotective effect of 3-methyladenine was confirmed in primary cortical neuronal cultures using not only pharmacological but also genetic autophagy inhibition of the ibotenate-induced autophagy. Strategies inhibiting autophagy could then represent a promising neuroprotective approach in the context of severe preterm brain injuries.

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Section: Discussionsupporting

confidence: 72%

Enhanced autophagy contributes to excitotoxic lesions in a rat model of preterm brain injury

et al. 2018

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“…Although this study focuses primarily on the effect of SFA on cortical brain cells, perinatal brain injury can take place, often simultaneously, in both gray and white matter [7][8][9]. A common cause for perinatal brain injury is HI induced rise in ROSs which lead to cell death through activation of apoptotic receptors or proteins, and mitochondrial dysfunction.…”

Section: Plos Onementioning

confidence: 99%

“…Excitotoxicty against oligodendrocytes works also by extracellular glutamate accumulation and results in an increase of ROSs causing oxidative stress. These processes are detrimental to the brain; by damaging oligodendrocytes they specifically reduce or attenuate the myelination process, thereby creating vulnerable neurons [2,7,9,30,31]. With all of these cellular constituents present in the co-culture, it is more likely to thrive compared to isolated neuron or astrocyte cultures; and their response to effects of SFA is more representative of what an in vivo response may look like.…”

Section: Plos Onementioning

confidence: 99%

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Sulforaphane (SFA) protects neuronal cells from oxygen & glucose deprivation (OGD)

et al. 2021

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Background Perinatal brain injury results in neurodevelopmental disabilities (neuroDDs) that include cerebral palsy, autism, attention deficit disorder, epilepsy, learning disabilities and others. Commonly, injury occurs when placental circulation, that is responsible for transporting nutrients and oxygen to the fetus, is compromised. Placental insufficiency (PI) is a reduced supply of blood and oxygen to the fetus and results in a hypoxic-ischemic (HI) environment. A significant HI state in-utero leads to perinatal compromise, characterized by fetal growth restriction and brain injury. Given that over 80% of perinatal brain injuries that result in neuroDDs occur during gestation, prior to birth, preventive approaches are needed to reduce or eliminate the potential for injury and subsequent neuroDDs. Sulforaphane (SFA) derived from cruciferous vegetables such as broccoli sprouts (BrSps) is a phase-II enzyme inducer that acts via cytoplasmic Nrf2 to enhance the production of anti-oxidants in the brain through the glutathione pathway. We have previously shown a profound in vivo neuro-protective effect of BrSps/SFA as a dietary supplement in pregnant rat models of both PI and fetal inflammation. Strong evidence also points to a role for SFA as treatment for various cancers. Paradoxically, then SFA has the ability to enhance cell survival, and with conditions of cancer, enhance cell death. Given our findings of the benefit of SFA/Broccoli Sprouts as a dietary supplement during pregnancy, with improvement to the fetus, it is important to determine the beneficial and toxic dosing range of SFA. We therefore explored, in vitro, the dosing range of SFA for neuronal and glial protection and toxicity in normal and oxygen/glucose deprived (OGD) cell cultures. Methods OGD simulates, in vitro, the condition experienced by the fetal brain due to PI. We developed a cell culture model of primary cortical neuronal, astrocyte and combined brain cell co-cultures from newborn rodent brains. The cultures were exposed to an OGD environment for various durations of time to determine the LD50 (duration of OGD required for 50% cell death). Using the LD50 as the time point, we evaluated the efficacy of varying doses of SFA for neuroprotective and neurotoxicity effects. Control cultures were exposed to normal media without OGD, and cytotoxicity of varying doses of SFA was also evaluated. Immunofluorescence (IF) and Western blot analysis of cell specific markers were used for culture characterization, and quantification of LD50. Efficacy and toxicity effect of SFA was assessed by IF/high content microscopy and by AlamarBlue viability assay, respectively. Results We determined the LD50 to be 2 hours for neurons, 8 hours for astrocytes, and 10 hours for co-cultures. The protective effect of SFA was noticeable at 2.5 μM and 5 μM for neurons, although it was not significant. There was a significant protective effect of SFA at 2.5 μM (p<0.05) for astrocytes and co-cultures. Significant toxicity ranges were also confirmed in OGD cultures as ≥ 100 μM (p<0.05) for astrocytes, ≥ 50 μM (p<0.01) for co-cultures, but not toxic in neurons; and toxic in control cultures as ≥ 100 μM (p<0.01) for neurons, and ≥ 50 μM (p<0.01) for astrocytes and co-cultures. One Way ANOVA and Dunnett’s Multiple Comparison Test were used for statistical analysis. Conclusions Our results indicate that cell death shows a trend to reduction in neuronal and astrocyte cultures, and is significantly reduced in co-cultures treated with low doses of SFA exposed to OGD. Doses of SFA that were 10 times higher were toxic, not only under conditions of OGD, but in normal control cultures as well. The findings suggest that: 1. SFA shows promise as a preventative agent for fetal ischemic brain injury, and 2. Because the fetus is a rapidly growing organism with profound cell multiplication, dosing parameters must be established to insure safety within efficacious ranges. This study will influence the development of innovative therapies for the prevention of childhood neuroDD.

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“…Considering the options from the classes of drugs already being tested in models of EoP, we find that, despite many compounds being tested (with mixed results), most have not considered outcomes in the GM. There are some notable exceptions, such as MgSO 4 pre-treatment in a rat model of preterm HI (modeling antenatal treatment in at-risk mothers), significantly reduced tissue loss in the hippocampus and striatum and were associated with reduced neurological injury score (219). MgSO 4 has also been tested in a sheep model of perinatal asphyxia, reporting reduced seizure burden, but worse WM outcomes and no GM neuropathology (189).…”

Section: Gray Matter Targetsmentioning

confidence: 99%

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

2020

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Preterm-born infants frequently suffer from an array of neurological damage, collectively termed encephalopathy of prematurity (EoP). They also have an increased risk of presenting with a neurodevelopmental disorder (e.g., autism spectrum disorder; attention deficit hyperactivity disorder) later in life. It is hypothesized that it is the gray matter injury to the cortex, in addition to white matter injury, in EoP that is responsible for the altered behavior and cognition in these individuals. However, although it is established that gray matter injury occurs in infants following preterm birth, the exact nature of these changes is not fully elucidated. Here we will review the current state of knowledge in this field, amalgamating data from both clinical and preclinical studies. This will be placed in the context of normal processes of developmental biology and the known pathophysiology of neurodevelopmental disorders. Novel diagnostic and therapeutic tactics required integration of this information so that in the future we can combine mechanism-based approaches with patient stratification to ensure the most efficacious and cost-effective clinical practice.

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Magnesium sulphate induces preconditioning in preterm rodent models of cerebral hypoxia‐ischemia

Abstract: We have established a postnatal day 4 rat model of HI for the study of preterm brain injury. MgSO provides a marked preconditioning protection both in postnatal day 4 rats and in postnatal day 5 mice.

Cited by 14 publications

References 52 publications

Enhanced autophagy contributes to excitotoxic lesions in a rat model of preterm brain injury

Enhanced autophagy contributes to excitotoxic lesions in a rat model of preterm brain injury

Sulforaphane (SFA) protects neuronal cells from oxygen & glucose deprivation (OGD)

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

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