Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

2017 ◽  
Vol 39 (1-4) ◽  
pp. 298-309 ◽  
Author(s):  
Kyra Y.Y. Chan ◽  
Domenic A. LaRosa ◽  
Mary Tolcos ◽  
Anqi Li ◽  
Valerie A. Zahra ◽  
...  

Erythropoietin (EPO) is being trialed in preterm neonates for neuroprotection. We have recently demonstrated that a single high bolus dose (5,000 IU/kg) of recombinant human EPO amplified preterm lung and brain ventilation-induced injury. We aimed to determine the optimal dose of EPO to reduce ventilation-induced cerebral white matter inflammation and injury in preterm lambs. Lambs (0.85 gestation) were ventilated with an injurious strategy for 15 min followed by conventional ventilation for 105 min. Lambs were randomized to no treatment (VENT; n = 8) or received a bolus dose of EPO (EPREX®): 300 IU/kg (EPO 300; n = 5), 1,000 IU/kg (EPO 1,000; n = 5), or 3,000 IU/kg (EPO 3,000; n = 5). Physiological parameters were measured throughout the study. After 2 h, brains were collected for analysis; real-time quantitative polymerase chain reaction and immunohistochemistry were used to assess inflammation, cell death, and vascular leakage in the periventricular and subcortical white matter (PVWM; SCWM). Molecular and histological inflammatory indices in the PVWM were not different between groups. EPO 300 lambs had higher IL-6 (p = 0.006) and caspase-3 (p = 0.025) mRNA expression in the SCWM than VENT lambs. Blood-brain barrier (BBB) occludin mRNA levels were higher in EPO 3,000 lambs in the PVWM and SCWM than VENT lambs. The number of blood vessels with protein extravasation in the SCWM was lower in EPO 1,000 (p = 0.010) and EPO 3,000 (p = 0.025) lambs compared to VENT controls but not different between groups in the PVWM. Early administration of EPO at lower doses neither reduced nor exacerbated cerebral white matter inflammation or injury. 3,000 IU/kg EPO may provide neuroprotection by improving BBB integrity.

2015 ◽  
Vol 36 (1) ◽  
pp. 187-198 ◽  
Author(s):  
Akihiro Shindo ◽  
Anna C Liang ◽  
Takakuni Maki ◽  
Nobukazu Miyamoto ◽  
Hidekazu Tomimoto ◽  
...  

Oligodendrocytes are one of the major cell types in cerebral white matter. Under normal conditions, they form myelin sheaths that encircle axons to support fast nerve conduction. Under conditions of cerebral ischemia, oligodendrocytes tend to die, resulting in white-matter dysfunction. Repair of white matter involves the ability of oligodendrocyte precursors to proliferate and mature. However, replacement of lost oligodendrocytes may not be the only mechanism for white-matter recovery. Emerging data now suggest that coordinated signaling between neural, glial, and vascular cells in the entire neurovascular unit may be required. In this mini-review, we discuss how oligodendrocyte lineage cells participate in signaling and crosstalk with other cell types to underlie function and recovery in various experimental models of subcortical white-matter injury.


2005 ◽  
Vol 105 (3) ◽  
pp. 458-465 ◽  
Author(s):  
Janyne E. Althaus ◽  
Scott M. Petersen ◽  
Harold E. Fox ◽  
Cynthia J. Holcroft ◽  
Ernest M. Graham

2019 ◽  
Author(s):  
Ziyi Wu ◽  
Qiushi Gao ◽  
Xingyue Li ◽  
Hang Xue ◽  
Ping Zhao

Abstract Background: General anesthetics may impose significant neurocognitive risks on the immature brain . Since preterm infants often need anesthesia for surgical or diagnostic procedures, exploring the appropriate anesthetic dose is necessary for procedural needs and for the safety of brain development. As brain injury in preterm neonates has a particular predilection for cerebral white matter, we studied the effects of different concentrations of sevoflurane on oligodendrocyte maturation and myelination in a preterm-equivalent rat model. Methods: Rats at postnatal day 2 were exposed to 3.3% (approximately 1 minimum alveolar concentration [MAC]) or 4.9% (approximately 1.5 MAC) sevoflurane for 2 hours. Changes in oligodendrocyte differentiation and myelin integrity in white matter were evaluated by immunofluorescence with stage-specific markers. Neurobehavioral function was examined by open field test and Morris water maze tests. As prominent hallmarks of white matter injury, microgliosis and astrogliosis were investigated in specific white matter regions. Results: In the 4.9% sevoflurane-treatment group, decreased differentiation of oligodendrocytes indicated arrested oligodendrocyte maturation, resulting in hypomyelination and axonal damage in the developing white matter of the rat brain. Treatment increased anxiety-like behaviour and caused learning and memory impairments in adolescent rats. Microglia activation and astrogliosis were also observed at 12 h post anesthesia. No differences were seen between the control and 3.3% sevoflurane groups. Conclusions: Sevoflurane exposure in preterm-equivalent rats dose-dependently disrupted oligodendrocyte maturation and hypomyelination and impaired function. Microgliosis and astrogliosis might contribute to white matter damage.


2013 ◽  
Vol 1495 ◽  
pp. 11-17 ◽  
Author(s):  
Yingzhu Chen ◽  
Qiong Yi ◽  
Gang Liu ◽  
Xue Shen ◽  
Lihui Xuan ◽  
...  

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Harun Yildiz ◽  
Erbu Yarci ◽  
Sefika Elmas Bozdemir ◽  
Nesrin Ozdinc Kizilay ◽  
Senay Mengi ◽  
...  

Author(s):  
Jennifer K Lee ◽  
Polan T Santos ◽  
May W Chen ◽  
Caitlin E O’Brien ◽  
Ewa Kulikowicz ◽  
...  

Abstract Neonatal hypoxia-ischemia (HI) causes white matter injury that is not fully prevented by therapeutic hypothermia. Adjuvant treatments are needed. We compared myelination in different piglet white matter regions. We then tested whether oleuropein (OLE) improves neuroprotection in 2- to 4-day-old piglets randomized to undergo HI or sham procedure and OLE or vehicle administration beginning at 15 minutes. All groups received overnight hypothermia and rewarming. Injury in the subcortical white matter, corpus callosum, internal capsule, putamen, and motor cortex gray matter was assessed 1 day later. At baseline, piglets had greater subcortical myelination than in corpus callosum. Hypothermic HI piglets had scant injury in putamen and cerebral cortex. However, hypothermia alone did not prevent the loss of subcortical myelinating oligodendrocytes or the reduction in subcortical myelin density after HI. Combining OLE with hypothermia improved post-HI subcortical white matter protection by preserving myelinating oligodendrocytes, myelin density, and oligodendrocyte markers. Corpus callosum and internal capsule showed little HI injury after hypothermia, and OLE accordingly had minimal effect. OLE did not affect putamen or motor cortex neuron counts. Thus, OLE combined with hypothermia protected subcortical white matter after HI. As an adjuvant to hypothermia, OLE may subacutely improve regional white matter protection after HI.


2008 ◽  
Vol 210 (2) ◽  
pp. 560-576 ◽  
Author(s):  
Manjeet K. Paintlia ◽  
Ajaib S. Paintlia ◽  
Miguel A. Contreras ◽  
Inderjit Singh ◽  
Avtar K. Singh

2004 ◽  
Vol 191 (6) ◽  
pp. S81
Author(s):  
Anadir Silva ◽  
Randi Smith ◽  
Christoph Lehmann ◽  
Cynthia Holcroft ◽  
Ernest Graham

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