NMDA- and asphyxia induced alterations of neurovascular responses in the cerebral cortex of newborn pigs, implications for the pathomechanism of neonatal hypoxic-ischemic encephalopathy

Remzső Gábor
NMDA- and asphyxia induced alterations of neurovascular responses in the cerebral cortex of newborn pigs, implications for the pathomechanism of neonatal hypoxic-ischemic encephalopathy.
Doctoral thesis (PhD), University of Szeged.

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Abstract in foreign language

Perinatal asphyxia (PA) is a major cause of neonatal mortality and it can also lead to hypoxic-ischemic encephalopathy (HIE) in the surviving newborns. Despite the availability of therapeutic hypothermia, HIE still results in long term disability in many infants, as hypothermia alone is often not sufficient to fully mitigate the HIE caused neuronal damage. To find new adjunct therapies, further investigation of the neuronal and vascular pathomechanisms underlying HIE development is warranted, and the newborn pig used in our studies is one of the best large animal model for the preclinical translational study of PA/HIE. To enhance the mechanistic understanding of neuronal injury in our previously established translationally valid PA/HIE model, first we aimed to determine the magnitude, the dynamics, and the mechanisms of PA on the brain interstitial pH (pHbrain) both during asphyxia and HIE development. Second, we investigated the effects of excessive glutamatergic activation by NMDA on neurovascular unit function using hypercapnia induced vasodilation to test cerebrovascular reactivity. Third, we wanted to explore if NMDA could alter both the spontaneous and also the hypercapnia induced changes in cortical electrical activity. Anesthetized and mechanically ventilated piglets were fitted with either open or closed cranial windows. pHbrain, cortical blood flow (CoBF), and neuronal activity was determined, with pH sensitive microelectrodes, laser-speckle contrast imaging, and multi-channel intracortical microelectrodes, respectively. PA was elicited by ventilation with a hypoxic-hypercapnic gas mixture (6%O2, 20%CO2; 20min), then HIE development was observed up to 24h. NMDA was applied onto the cortical surface, graded (5-20%) hypercapnia was induced by ventilation with a normoxic-hypercapnic gas mixture. pHbrain dropped below 6.0 during PA exceeding by ~0.8 pH unit the acidosis in the blood highlighting its importance in neuronal injury. The respiratory component was responsible for only ~40% of the developing acidosis. pHbrain was restored quickly after PA and remained stable throughout the observation period. Both graded hypercapnia and NMDA caused increases in CoBF, but NMDA also attenuated the response to hypercapnia in an NMDA-receptor and nitric oxide synthase (nNOS) dependent manner shown with respective inhibitors. NMDA induced neurovascular dysfunction was also shown by NMDA induced perturbations in cortical neuronal activity and the altered electrophysiological response to graded hypercapnia as well. Our findings suggest that severe acidosis as well as excitotoxic neurovascular unit dysfunction may play an important role in PA/HIE pathpohysiology in our translational PA/HIE model.

Item Type: Thesis (Doctoral thesis (PhD))
Creators: Remzső Gábor
Hungarian title: NMDA- és aszfixia által létrehozott megváltozott neurovaszkuláris válaszkészség az újszülött malac agykéregben, adatok az újszülöttkori hipoxiás-iszkémiás enkefalopátia pathomechanizmusához
Position, academic title, institution
MTMT author ID
Domoki Ferenc
egyetemi docens, MD, PhD, Élettani Intézet SZTE / SZAOK
Subjects: 03. Medical and health sciences > 03.01. Basic medicine
Divisions: Doctoral School of Theoretical Medicine
Discipline: Medicine > Theoretical Medicine
Language: English
Date: 2021. June 24.
Item ID: 10834
MTMT identifier of the thesis: 32851087
doi: https://doi.org/10.14232/phd.10834
Date Deposited: 2021. Mar. 26. 09:05
Last Modified: 2022. May. 30. 15:28
URI: https://doktori.bibl.u-szeged.hu/id/eprint/10834
Defence/Citable status: Defended.

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