Molecular hydrogen affords neuroprotection in a new translational piglet model of hypoxic-ischemic encephalopathy

Németh János
Molecular hydrogen affords neuroprotection in a new translational piglet model of hypoxic-ischemic encephalopathy.
Doctoral thesis (PhD), University of Szeged.
(2017) (Unpublished)

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Abstract in foreign language

Summary Perinatal asphyxia (PA) is one of the leading causes of neonatal mortality and morbidity worldwide. Despite the adequate neonatal resuscitation techniques, hypoxic-ischemic encephalopathy (HIE) may develop in survivors. Controlled therapeutic hypothermia (TH) became the gold standard care of asphyxiated babies, but its efficacy to prevent long-term disabilities is limited, therefore, additional neuroprotective interventions are required urgently. The newborn pig is regarded as one of the best models for human PA/HIE pathology and testing putative therapeutic interventions. The best methodology to elicit pathophysiologically/clinically relevant PA insult in animals is still being debated perhaps resulting in some of the failures of alleged neuroprotective therapies in clinical trials. Our major aim was to create a translationally relevant newborn piglet PA/HIE model. Accordingly, we investigated the effects of bilateral carotid artery occlusion (BCAO) on cortical blood flow (CoBF), a routinely applied method in the literature to augment hypoxic stress. Then we developed and extensively characterized our new PA/HIE model of PA/HIE and subsequently tested the neuroprotective potential of molecular H2 in our model. Newborn piglets were anesthetized, instrumented and mechanically ventilated. The effects of BCAO on CoBF were analysed through an implanted cranial window by laser speckle contrast imaging and analysis. PA (6%O2, 20%CO2, 20min) was induced in separate groups of animals to elicit HIE. One group served for testing the effects of H2 administered during reventilation (2.1%H2, 21%O2, 4h) on brain electrical activity, neuronal damage and oxidative stress at 24h survival). BCAO did not reduce CoBF. PA elicited clinically relevant severe alterations in cardiovascular and blood gas/metabolic parameters, resulting in depressed electroencephalogram (EEG), extensive neuronal damage associated with oxidative stress assessed by 8-OHdG immunoreactivity. Molecular H2 facilitated EEG recovery, ameliorated neonatal brain injury and alleviated oxidative stress. In conclusion, our new PA method was able to elicit reproducible, moderate/severe HIE without BCAO. The model was adequate to reveal the neuroprotective effect of molecular H2 administered in a clinically relevant, post-insult time window. The mechanism of neuroprotection appears to involve the reduction of oxidative stress. Encouraged by these promising results, to describe the effect of H2 administration combined with TH remains our future direction.

Item Type: Thesis (Doctoral thesis (PhD))
Creators: Németh János
Hungarian title: A molekuláris hidrogén neuroprotektív hatásának vizsgálata új hipoxiás-iszkémiás enkefalopátia transzlációs malac modellben
Position, academic title, institution
MTMT author ID
Domoki Ferenc
egyetemi docens, SZTE ÁOK Élettani Intézet
Subjects: 03. Medical and health sciences > 03.01. Basic medicine
Divisions: Doctoral School of Theoretical Medicine
Discipline: Medicine > Theoretical Medicine
Language: English
Date: 2017. September 25.
Item ID: 4072
MTMT identifier of the thesis: 3268493
Date Deposited: 2017. Oct. 02. 09:51
Last Modified: 2020. May. 28. 11:15
Defence/Citable status: Defended.

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