Glutamate in Cerebral Tissue of Asphyxiated Neonates during the First Week of Life Demonstrated in vivo Using Proton Magnetic Resonance Spectroscopy

Groenendaal, Floris; Rijn, Ariadne M Roelants-van; Toet, Mona C.; Vries, Linda S. de

doi:10.1159/000047101

Cited by 36 publications

(3 citation statements)

References 21 publications

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“…In this case, energy failure will lead to neuronal cell death. The Glu/NAA ratio has been found closely related to excitotoxic brain damage in infants, and hypothermia has been shown to reduce the Glu/NAA ratio already at 6 hours post hypoxia in newborn piglets [ 27 , 28 ]. This is consistent with our findings of significantly reduced Glu/NAA in both cortex and hippocampus of hypothermic piglets (Figs 2 and 3 ).…”

Section: Discussionmentioning

confidence: 99%

DHA and therapeutic hypothermia in a short-term follow-up piglet model of hypoxia-ischemia: Effects on H+MRS biomarkers

et al. 2018

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BackgroundTherapeutic hypothermia has become the standard of care for newborns with hypoxic-ischemic encephalopathy in high and middle income countries. Docosahexaenoic acid (DHA) has neuroprotective properties of reducing excitotoxicity, neuroinflammation and apoptosis in rodent models. We aim to study whether post hypoxic administration of i.v. DHA will reduce H+MRS biomarkers and gene expression of inflammation and apoptosis both with and without hypothermia in a large animal model.MethodsFifty-five piglets were randomized to severe global hypoxia (N = 48) or not (Sham, N = 7). Hypoxic piglets were further randomized by factorial design: Vehicle (VEH), DHA, VEH + Hypothermia (HT), or DHA + HT. 5 mg/kg DHA was given intravenously 210 min after end of hypoxia. Two-way ANOVA analyses were performed with DHA and hypothermia as main effects.ResultsCortical lactate/N-acetylaspartate (Lac/NAA) was significantly reduced in DHA + HT compared to HT. DHA had significant main effects on increasing N-acetylaspartate and glutathione in hippocampus. Therapeutic hypothermia significantly reduced the Lac/NAA ratio and protein expression of IL-1β and TNFα in hippocampus and reduced Troponin T in serum. Neuropathology showed significant differences between sham and hypoxia, but no differences between intervention groups.ConclusionDHA and therapeutic hypothermia significantly improve specific H+MRS biomarkers in this short-term follow up model of hypoxia-ischemia. Longer recovery periods are needed to evaluate whether DHA can offer translational neuroprotection.

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Section: Discussionmentioning

confidence: 99%

DHA and therapeutic hypothermia in a short-term follow-up piglet model of hypoxia-ischemia: Effects on H+MRS biomarkers

et al. 2018

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“…In particular, the high concentration and activity of glutamate receptors aggravate the deleterious effects of this excitatory amino acid in the immature brain (Johnston et al, 2011 ; Drury et al, 2014 ; Juul and Ferriero, 2014 ). Among various approaches to quantify the increase in glutamate content in the immature brain after a hypoxic-ischemic insult, the Glu/NAA ratio has been observed to be closely related to excitotoxic brain damage (Groenendaal et al, 2001 ). The relative paucity of antioxidants and excess of pro-oxidant substances (in particular, iron) determine the particular susceptibility of the immature brain to oxidative stress (Johnston et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of Cannabidiol and Hypothermia on Short-Term Brain Damage in New-Born Piglets after Acute Hypoxia-Ischemia

et al. 2016

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Hypothermia is a standard treatment for neonatal encephalopathy, but nearly 50% of treated infants have adverse outcomes. Pharmacological therapies can act through complementary mechanisms with hypothermia improving neuroprotection. Cannabidiol could be a good candidate. Our aim was to test whether immediate treatment with cannabidiol and hypothermia act through complementary brain pathways in hypoxic-ischemic newborn piglets. Hypoxic-ischemic animals were randomly divided into four groups receiving 30 min after the insult: (1) normothermia and vehicle administration; (2) normothermia and cannabidiol administration; (3) hypothermia and vehicle administration; and (4) hypothermia and cannabidiol administration. Six hours after treatment, brains were processed to quantify the number of damaged neurons by Nissl staining. Proton nuclear magnetic resonance spectra were obtained and analyzed for lactate, N-acetyl-aspartate and glutamate. Metabolite ratios were calculated to assess neuronal damage (lactate/N-acetyl-aspartate) and excitotoxicity (glutamate/Nacetyl-aspartate). Western blot studies were performed to quantify protein nitrosylation (oxidative stress), content of caspase-3 (apoptosis) and TNFα (inflammation). Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels in newborn piglets subjected to hypoxic-ischemic insult. Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio. The combined effect of hypothermia and cannabidiol on excitotoxicity, inflammation and oxidative stress, and on cell damage, was greater than either hypothermia or cannabidiol alone. The present study demonstrated that cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage if applied shortly after the insult.

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“…In this study, proton spectra were localized to the basal ganglia because previous studies using MRI have identified this area as vulnerable to hypoxia-ischemia injury in neonates (19). Spectra from this region are also less susceptible to interference arising from extracranial fat tissue (20).…”

Section: Discussionmentioning

confidence: 99%

A piglet model for detection of hypoxic-ischemic brain injury with magnetic resonance imaging

et al. 2008

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Munkeby BH, de Lange C, Emblem KE, Bjørnerud A, Kro GAB, Andresen J, Winther-Larssen EH, Løberg EM, Hald JK. A piglet model for detection of hypoxic-ischemic brain injury with magnetic resonance imaging. Acta Radiol 2008;49:1049–1057.BackgroundEarly detection of hypoxic-ischemic (HI) injury in the asphyxic newborn is important because present prognostic factors are inadequate. Furthermore, therapeutic interventions may have additional benefit if initiated in time.PurposeTo assess whether the use of a combined protocol including conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), and proton MR spectroscopy (MRS) could detect pathological findings in a piglet model 7 hours after HI.Material and MethodsTen piglets were submitted to HI for 30 min followed by reoxygenation with 21% O2 for 7 hours. MRI at 1.5T was done prior to and 7 hours after the HI. Single-voxel proton MRS was performed, and apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in the basal ganglia. MRS identified N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and lactate (Lac). Histology and microtubule-associated protein 2 (MAP-2) staining was performed in the basal ganglia at the end of the experiment.ResultsCompared to baseline, ADC, NAA/Cho, and NAA/Cr were significantly reduced after 7 hours (P < 0.001, P = 00.01, and P = 00.05, respectively) and FA values were increased (P <0.025). The ratios of Lac/Cho and Lac/NAA were significantly higher after 7 hours compared to baseline (P <0.001). Presence of necrosis correlated well with reduced ADC (RS = 0.91) and presence of Lac (RS = 0.80). Histology and MAP-2 staining showed more than 90% necrosis in eight piglets, 60% in one piglet, and no necrosis in one piglet.ConclusionDiffusion MRI and proton MRS can detect HI injury in the piglet brain 7 hours after hypoxia. DWI and MRS can be used to give useful prognostic information. This piglet model may potentially be used to mimic clinical situations and is suitable for further research investigating HI injury.

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Glutamate in Cerebral Tissue of Asphyxiated Neonates during the First Week of Life Demonstrated in vivo Using Proton Magnetic Resonance Spectroscopy

Cited by 36 publications

References 21 publications

DHA and therapeutic hypothermia in a short-term follow-up piglet model of hypoxia-ischemia: Effects on H+MRS biomarkers

DHA and therapeutic hypothermia in a short-term follow-up piglet model of hypoxia-ischemia: Effects on H+MRS biomarkers

Effects of Cannabidiol and Hypothermia on Short-Term Brain Damage in New-Born Piglets after Acute Hypoxia-Ischemia

A piglet model for detection of hypoxic-ischemic brain injury with magnetic resonance imaging

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