scholarly journals Melatonin and/or erythropoietin combined with hypothermia in a piglet model of perinatal asphyxia

2020 ◽  
Author(s):  
Raymand Pang ◽  
Adnan Avdic-Belltheus ◽  
Christopher Meehan ◽  
Kathryn Martinello ◽  
Tatenda Mutshiya ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Triple Therapy ◽  
Sensorimotor Cortex ◽  
Perinatal Asphyxia ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Resonance Spectroscopy ◽  
Periventricular White Matter ◽  
Deoxyuridine Triphosphate ◽  
Hypoxia Ischemia ◽  
Effective Adjunct

Abstract As therapeutic hypothermia is only partially protective for neonatal encephalopathy, safe and effective adjunct therapies are urgently needed. Melatonin and erythropoietin show promise as safe and effective neuroprotective therapies. We hypothesized that melatonin and erythropoietin individually augment 12-hour hypothermia (double therapies) and hypothermia + melatonin + erythropoietin (triple therapy) leads to optimal brain protection. Following carotid artery occlusion and hypoxia, 49 male piglets (<48 hours old) were randomized to: (i) hypothermia + vehicle (n = 12), (ii) hypothermia + melatonin (20 mg/kg over 2 hours) (n = 12), (iii) hypothermia + erythropoietin (3000 U/kg bolus) (n = 13) or (iv) triple therapy (n = 12). Melatonin, erythropoietin or vehicle were given at 1, 24 and 48 hours after hypoxia-ischemia. Hypoxia-ischemia severity was similar across groups. Therapeutic levels were achieved 3 hours after hypoxia-ischemia for melatonin (15-30mg/L) and within 30 minutes of erythropoietin administration (maximum concentration 10,000 mU/mL). Compared to hypothermia + vehicle, we observed faster amplitude integrated EEG recovery from 25-30 hours with hypothermia + melatonin (p = 0.02) and hypothermia + erythropoietin (p = 0.033) and from 55-60 hours with triple therapy (p = 0.042). Magnetic Resonance Spectroscopy Lactate/N-acetyl aspartate peak ratio was lower at 66 hours in hypothermia + melatonin (p = 0.012) and triple therapy (p = 0.032). With hypothermia + melatonin, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells were reduced in sensorimotor cortex (p = 0.017) and oligodendrocyte transcription factor 2 labelled-positive counts increased in hippocampus (p = 0.014) and periventricular white matter (p = 0.039). There was no reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells with hypothermia + erythropoietin, but increased oligodendrocyte transcription factor 2 labelled-positive cells in 5 of 8 brain regions (p < 0.05). Overall, melatonin and erythropoietin were safe and effective adjunct therapies to hypothermia. Hypothermia + melatonin double therapy led to faster amplitude integrated EEG recovery, amelioration of Lactate/N-acetyl aspartate rise and reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells in the sensorimotor cortex. Hypothermia + erythropoietin double therapy was association with EEG recovery and was most effective in promoting oligodendrocyte survival. Triple therapy provided no added benefit over the double therapies in this 72-hour study. Melatonin and erythropoietin influenced cell death and oligodendrocyte survival differently, reflecting distinct neuroprotective mechanisms which may become more visible with longer term studies. Staggering the administration of therapies with early melatonin and later erythropoietin (after hypothermia) may provide better protection; each therapy has complementary actions which may be time critical during the neurotoxic cascade after hypoxia-ischemia.

scholarly journals Immediate remote ischemic postconditioning after hypoxia ischemia in piglets protects cerebral white matter but not grey matter

2015 ◽  
Vol 36 (8) ◽  
pp. 1396-1411 ◽  
Author(s):  
Mojgan Ezzati ◽  
Alan Bainbridge ◽  
Kevin D Broad ◽  
Go Kawano ◽  
Aaron Oliver-Taylor ◽  
...  
Keyword(s):  
White Matter ◽  
Corpus Callosum ◽  
Grey Matter ◽  
Ischemia Reperfusion ◽  
Ischemic Postconditioning ◽  
White Female ◽  
Resonance Spectroscopy ◽  
Periventricular White Matter ◽  
Remote Ischemic Postconditioning ◽  
Hypoxia Ischemia

Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention whereby brief episodes of ischemia/reperfusion of one organ (limb) mitigate damage in another organ (brain) that has experienced severe hypoxia-ischemia. Our aim was to assess whether RIPostC is protective following cerebral hypoxia-ischemia in a piglet model of neonatal encephalopathy (NE) using magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry. After hypoxia-ischemia (HI), 16 Large White female newborn piglets were randomized to: (i) no intervention ( n = 8); (ii) RIPostC – with four, 10-min cycles of bilateral lower limb ischemia/reperfusion immediately after HI ( n = 8). RIPostC reduced the hypoxic-ischemic-induced increase in white matter proton MRS lactate/N acetyl aspartate ( p = 0.005) and increased whole brain phosphorus-31 MRS ATP ( p = 0.039) over the 48 h after HI. Cell death was reduced with RIPostC in the periventricular white matter ( p = 0.03), internal capsule ( p = 0.002) and corpus callosum ( p = 0.021); there was reduced microglial activation in corpus callosum ( p = 0.001) and more surviving oligodendrocytes in corpus callosum ( p = 0.029) and periventricular white matter ( p = 0.001). Changes in gene expression were detected in the white matter at 48 h, including KATP channel and endothelin A receptor. Immediate RIPostC is a potentially safe and promising brain protective therapy for babies with NE with protection in white but not grey matter.

scholarly journals Dexmedetomidine Combined with Therapeutic Hypothermia Is Associated with Cardiovascular Instability and Neurotoxicity in a Piglet Model of Perinatal Asphyxia

2017 ◽  
Vol 39 (1-4) ◽  
pp. 156-170 ◽  
Author(s):  
Mojgan Ezzati ◽  
Go Kawano ◽  
Eridan Rocha-Ferreira ◽  
Daniel Alonso-Alconada ◽  
Jane K. Hassell ◽  
...  
Keyword(s):  
Cell Death ◽  
Therapeutic Hypothermia ◽  
Perinatal Asphyxia ◽  
White Male ◽  
Brain Regions ◽  
Resonance Spectroscopy ◽  
Large White ◽  
Whole Brain ◽  
Effective Adjunct ◽  
Fentanyl Group

The selective α2-adrenoreceptor agonist dexmedetomidine has shown neuroprotective, analgesic, anti-inflammatory, and sympatholytic properties that may be beneficial in neonatal encephalopathy (NE). As therapeutic hypothermia is only partially effective, adjunct therapies are needed to optimize outcomes. The aim was to assess whether hypothermia + dexmedetomidine treatment augments neuroprotection compared to routine treatment (hypothermia + fentanyl sedation) in a piglet model of NE using magnetic resonance spectroscopy (MRS) biomarkers, which predict outcomes in babies with NE, and immunohistochemistry. After hypoxia-ischaemia (HI), 20 large White male piglets were randomized to: (i) hypothermia + fentanyl with cooling to 33.5°C from 2 to 26 h, or (ii) hypothermia + dexmedetomidine (a loading dose of 2 μg/kg at 10 min followed by 0.028 μg/kg/h for 48 h). Whole-brain phosphorus-31 and regional proton MRS biomarkers were assessed at baseline, 24, and 48 h after HI. At 48 h, cell death was evaluated over 7 brain regions by means of transferase-mediated d-UTP nick end labeling (TUNEL). Dexmedetomidine plasma levels were mainly within the target sedative range of 1 μg/L. In the hypothermia + dexmedetomidine group, there were 6 cardiac arrests (3 fatal) versus 2 (non-fatal) in the hypothermia + fentanyl group. The hypothermia + dexmedetomidine group required more saline (p = 0.005) to maintain blood pressure. Thalamic and white-matter lactate/N-acetylaspartate did not differ between groups (p = 0.66 and p = 0.21, respectively); the whole-brain nucleotide triphosphate/exchangeable phosphate pool was similar (p = 0.73) over 48 h. Cell death (TUNEL-positive cells/mm2) was higher in the hypothermia + dexmedetomidine group than in the hypothermia + fentanyl group (mean 5.1 vs. 2.3, difference 2.8 [95% CI 0.6-4.9], p = 0.036). Hypothermia + dexmedetomidine treatment was associated with adverse cardiovascular events, even within the recommended clinical sedative plasma level; these may have been exacerbated by an interaction with either isoflurane or low body temperature. Hypothermia + dexmedetomidine treatment was neurotoxic following HI in our piglet NE model, suggesting that caution is vital if dexmedetomidine is combined with cooling following NE.

scholarly journals Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia–ischemia

2021 ◽  
Author(s):  
Kathryn A. Martinello ◽  
Christopher Meehan ◽  
Adnan Avdic-Belltheus ◽  
Ingran Lingam ◽  
Tatenda Mutshiya ◽  
...  
Keyword(s):  
Cell Death ◽  
Microglial Activation ◽  
Acute Infection ◽  
Brain Cell ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Resonance Spectroscopy ◽  
List Type ◽  
Neonatal Encephalopathy ◽  
Perinatal Brain Injury ◽  
Hypoxia Ischemia

Abstract Background Perinatal inflammation combined with hypoxia–ischemia (HI) exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown. Methods Twelve newborn piglets received a 2 µg/kg bolus and 1 µg/kg/h infusion over 52 h of Escherichia coli lipopolysaccharide (LPS). HI was induced 4 h after LPS bolus. After HI, piglets were randomized to HT (33.5 °C 1–25 h after HI, n = 6) or normothermia (NT, n = 6). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48 h. At 48 h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured. Results Two HT piglets died. aEEG recovery, thalamic and white matter MRS lactate/N-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation/proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT. Conclusions We did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. Immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI. Impact Acute infection/inflammation is known to exacerbate perinatal brain injury and can worsen the outcomes in neonatal encephalopathy. Therapeutic HT is the current standard of care for all infants with NE, but the benefit in infants with coinfection/inflammation is unknown. In a piglet model of inflammation (LPS)-sensitized HI, we observed no evidence of neuroprotection with cooling for 24 h, based on our primary outcome measures: aEEG, MRS Lac/NAA, and histological brain cell death. Additional neuroprotective agents, with beneficial immunomodulatory effects, require exploration in IS-HI models.

scholarly journals GABA Levels in Left and Right Sensorimotor Cortex Correlate across Individuals

Biomedicines ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 80 ◽  
Author(s):  
Nicolaas Puts ◽  
Stefanie Heba ◽  
Ashley Harris ◽  
Christopher Evans ◽  
David McGonigle ◽  
...  
Keyword(s):  
Sensorimotor Cortex ◽  
Resonance Spectroscopy ◽  
Behavioral Performance ◽  
Gaba Level ◽  
Tissue Composition ◽  
Mr Images ◽  
Left And Right ◽  
Highly Correlated ◽  
Cortical Regions ◽  
Bulk Tissue

Differences in γ-aminobutyric acid (GABA) levels measured with Magnetic Resonance Spectroscopy have been shown to correlate with behavioral performance over a number of tasks and cortical regions. These correlations appear to be regionally and functionally specific. In this study, we test the hypothesis that GABA levels will be correlated within individuals for functionally related regions—the left and right sensorimotor cortex. In addition, we investigate whether this is driven by bulk tissue composition. GABA measurements using edited MRS data were acquired from the left and right sensorimotor cortex in 24 participants. T1-weighted MR images were also acquired and segmented to determine the tissue composition of the voxel. GABA level is shown to correlate significantly between the left and right regions (r = 0.64, p < 0.03). Tissue composition is highly correlated between sides, but does not explain significant variance in the bilateral correlation. In conclusion, individual differences in GABA level, which have previously been described as functionally and regionally specific, are correlated between homologous sensorimotor regions. This correlation is not driven by bulk differences in voxel tissue composition.

scholarly journals Exploring Perinatal Asphyxia by Metabolomics

Metabolites ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 141 ◽  
Author(s):  
Emanuela Locci ◽  
Giovanni Bazzano ◽  
Roberto Demontis ◽  
Alberto Chighine ◽  
Vassilios Fanos ◽  
...  
Keyword(s):  
Perinatal Asphyxia ◽  
Relevant Literature ◽  
Hypoxic Ischemic Encephalopathy ◽  
Health Concern ◽  
Resonance Spectroscopy ◽  
Industrialized Countries ◽  
Human Infants ◽  
Therapeutic Tools ◽  
Effective Use ◽  
Ischemic Encephalopathy

Brain damage related to perinatal asphyxia is the second cause of neuro-disability worldwide. Its incidence was estimated in 2010 as 8.5 cases per 1000 live births worldwide, with no further recent improvement even in more industrialized countries. If so, hypoxic-ischemic encephalopathy is still an issue of global health concern. It is thought that a consistent number of cases may be avoided, and its sequelae may be preventable by a prompt and efficient physical and therapeutic treatment. The lack of early, reliable, and specific biomarkers has up to now hampered a more effective use of hypothermia, which represents the only validated therapy for this condition. The urge to unravel the biological modifications underlying perinatal asphyxia and hypoxic-ischemic encephalopathy needs new diagnostic and therapeutic tools. Metabolomics for its own features is a powerful approach that may help for the identification of specific metabolic profiles related to the pathological mechanism and foreseeable outcome. The metabolomic profiles of animal and human infants exposed to perinatal asphyxia or developing hypoxic-ischemic encephalopathy have so far been investigated by means of 1H nuclear magnetic resonance spectroscopy and mass spectrometry coupled with gas or liquid chromatography, leading to the identification of promising metabolomic signatures. In this work, an extensive review of the relevant literature was performed.

scholarly journals Hnrnpk, a Protein Differentially Expressed in Immature Rat Ovarian Development, Is Required for Normal Primordial Follicle Assembly and Development

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 1024-1035 ◽  
Author(s):  
Ningling Wang ◽  
Ping Zhang ◽  
Xuejiang Guo ◽  
Zuomin Zhou ◽  
Jiahao Sha
Keyword(s):  
Transcription Factor ◽  
Ovarian Development ◽  
Ovarian Function ◽  
Subsequent Development ◽  
Primordial Follicle ◽  
Differentially Expressed ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Mrna Levels ◽  
Small Interfering Rnas ◽  
Female Reproduction

The formation of ovarian follicles and subsequent development after birth are critical processes for female reproduction, and inappropriate coordination of these processes contributes to ovarian pathologies, such as premature ovarian failure and infertility. Identification and functional investigation of the factors involved in follicular assembly and the initial recruitment will be of great significance to the understanding of the female reproduction process. In this study, we examined the roles of transcription factor heterogeneous nuclear ribonucleoprotein K (Hnrnpk) in rat primordial folliculogenesis using RNA interference knockdown strategies. Reducing Hnrnpk mRNA levels via Hnrnpk small interfering RNAs to neonatal ovaries resulted in a substantial loss of naked oocytes, primordial and primary follicles. Structure disorganization of the ovary characterized by groups of oocytes arranged in nests, clusters of somatic cells not associated with any oocytes and many highly condensed oocyte nuclei was observed. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay demonstrated that these abnormalities may be partially attributable to abnormal apoptosis of oocytes. Furthermore, the microarray analysis showed that 63 genes changed significantly (≥2-folds or ≤0.5-fold) between the ovaries treated with Hnrnpk small interfering RNAs and the controls, with 22 up-regulated genes and 41 down-regulated genes. These differentially expressed genes were involved in several critical biological processes in ovarian development. These results suggest that transcription factor Hnrnpk is a key regulator for primordial follicle assembly and development, which provides a new potential therapeutic target to regulate ovarian function and treat ovarian disease.

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