Active forms of Akt and ERK are dominant in the cerebral cortex of newborn pigs that are unaffected by asphyxia

Viktória Kovács, Valéria Tóth-Szűki, J. Németh, Viktória Varga, Gábor Remzső, F. Domoki

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Aims Perinatal asphyxia (PA) often results in hypoxic–ischemic encephalopathy (HIE) in term neonates. Introduction of therapeutic hypothermia improved HIE outcome, but further neuroprotective therapies are still warranted. The present study sought to determine the feasibility of the activation of the cytoprotective PI-3-K/Akt and the MAPK/ERK signaling pathways in the subacute phase of HIE development in a translational newborn pig PA/HIE model. Main methods Phosphorylated and total levels of Akt and ERK were determined by Western blotting in brain samples obtained from untreated naive, time control, and PA/HIE animals at 24–48 h survival (n = 3–3–6,respectively). PA (20 min) was induced in anesthetized piglets by ventilation with a hypoxic/hypercapnic (6%O220%CO2) gas mixture. Furthermore, we studied the effect of topically administered specific Akt1/2 and MAPK/ERK kinase inhibitors on Akt and ERK phosphorylation (n = 4–4) in the cerebral cortex under normoxic conditions. Key findings PA resulted in significant neuronal injury shown by neuropathology assessment of haematoxylin/eosin stained sections. However, there were no significant differences among the groups in the high phosphorylation levels of both ERK and Akt in the cerebral cortex, hippocampus and subcortical structures. However, the Akt1/2 and MAPK/ERK kinase inhibitors significantly reduced cerebrocortical Akt and ERK phosphorylation within 30 min. Significance The major finding of the present study is that the PI-3-K/Akt and the MAPK/ERK signaling pathways appear to be constitutively active in the piglet brain, and this activation remains unaltered during HIE development. Thus, neuroprotective strategies aiming to activate these pathways to limit apoptotic neuronal death may offer limited efficacy in this translational model.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalLife Sciences
Volume192
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Phosphorylation
Asphyxia
Brain Diseases
MAP Kinase Kinase 2
Cerebral Cortex
Swine
Brain
Chemical activation
Hypothermia
MAP Kinase Signaling System
Hematoxylin
Eosine Yellowish-(YS)
Gas mixtures
Ventilation
Animals
Induced Hypothermia
Hippocampus
Gases
Western Blotting
Wounds and Injuries

Keywords

  • Hypoxic-ischemic encephalopathy
  • Perinatal asphyxia
  • Translational piglet model

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Active forms of Akt and ERK are dominant in the cerebral cortex of newborn pigs that are unaffected by asphyxia. / Kovács, Viktória; Tóth-Szűki, Valéria; Németh, J.; Varga, Viktória; Remzső, Gábor; Domoki, F.

In: Life Sciences, Vol. 192, 01.01.2018, p. 1-8.

Research output: Contribution to journalArticle

Kovács, Viktória ; Tóth-Szűki, Valéria ; Németh, J. ; Varga, Viktória ; Remzső, Gábor ; Domoki, F. / Active forms of Akt and ERK are dominant in the cerebral cortex of newborn pigs that are unaffected by asphyxia. In: Life Sciences. 2018 ; Vol. 192. pp. 1-8.
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abstract = "Aims Perinatal asphyxia (PA) often results in hypoxic–ischemic encephalopathy (HIE) in term neonates. Introduction of therapeutic hypothermia improved HIE outcome, but further neuroprotective therapies are still warranted. The present study sought to determine the feasibility of the activation of the cytoprotective PI-3-K/Akt and the MAPK/ERK signaling pathways in the subacute phase of HIE development in a translational newborn pig PA/HIE model. Main methods Phosphorylated and total levels of Akt and ERK were determined by Western blotting in brain samples obtained from untreated naive, time control, and PA/HIE animals at 24–48 h survival (n = 3–3–6,respectively). PA (20 min) was induced in anesthetized piglets by ventilation with a hypoxic/hypercapnic (6{\%}O220{\%}CO2) gas mixture. Furthermore, we studied the effect of topically administered specific Akt1/2 and MAPK/ERK kinase inhibitors on Akt and ERK phosphorylation (n = 4–4) in the cerebral cortex under normoxic conditions. Key findings PA resulted in significant neuronal injury shown by neuropathology assessment of haematoxylin/eosin stained sections. However, there were no significant differences among the groups in the high phosphorylation levels of both ERK and Akt in the cerebral cortex, hippocampus and subcortical structures. However, the Akt1/2 and MAPK/ERK kinase inhibitors significantly reduced cerebrocortical Akt and ERK phosphorylation within 30 min. Significance The major finding of the present study is that the PI-3-K/Akt and the MAPK/ERK signaling pathways appear to be constitutively active in the piglet brain, and this activation remains unaltered during HIE development. Thus, neuroprotective strategies aiming to activate these pathways to limit apoptotic neuronal death may offer limited efficacy in this translational model.",
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AU - Kovács, Viktória

AU - Tóth-Szűki, Valéria

AU - Németh, J.

AU - Varga, Viktória

AU - Remzső, Gábor

AU - Domoki, F.

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AB - Aims Perinatal asphyxia (PA) often results in hypoxic–ischemic encephalopathy (HIE) in term neonates. Introduction of therapeutic hypothermia improved HIE outcome, but further neuroprotective therapies are still warranted. The present study sought to determine the feasibility of the activation of the cytoprotective PI-3-K/Akt and the MAPK/ERK signaling pathways in the subacute phase of HIE development in a translational newborn pig PA/HIE model. Main methods Phosphorylated and total levels of Akt and ERK were determined by Western blotting in brain samples obtained from untreated naive, time control, and PA/HIE animals at 24–48 h survival (n = 3–3–6,respectively). PA (20 min) was induced in anesthetized piglets by ventilation with a hypoxic/hypercapnic (6%O220%CO2) gas mixture. Furthermore, we studied the effect of topically administered specific Akt1/2 and MAPK/ERK kinase inhibitors on Akt and ERK phosphorylation (n = 4–4) in the cerebral cortex under normoxic conditions. Key findings PA resulted in significant neuronal injury shown by neuropathology assessment of haematoxylin/eosin stained sections. However, there were no significant differences among the groups in the high phosphorylation levels of both ERK and Akt in the cerebral cortex, hippocampus and subcortical structures. However, the Akt1/2 and MAPK/ERK kinase inhibitors significantly reduced cerebrocortical Akt and ERK phosphorylation within 30 min. Significance The major finding of the present study is that the PI-3-K/Akt and the MAPK/ERK signaling pathways appear to be constitutively active in the piglet brain, and this activation remains unaltered during HIE development. Thus, neuroprotective strategies aiming to activate these pathways to limit apoptotic neuronal death may offer limited efficacy in this translational model.

KW - Hypoxic-ischemic encephalopathy

KW - Perinatal asphyxia

KW - Translational piglet model

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