Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia

Pierpaolo Cerullo, Paola Brancaccio, Serenella Anzilotti, Antonio Vinciguerra, Ornella Cuomo, Ferdinando Fiorino, Beatrice Severino, Paola Di Vaio, Gianfranco Di Renzo, Lucio Annunziato, Giuseppe Pignataro

Research output: Contribution to journalArticle

Abstract

Hypoxic-ischemic encephalopathy (HI) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since the plasmamembrane sodium/calcium exchanger (NCX) plays a fundamental role in maintaining ionic homeostasis during adult brain ischemia, in the present work we aimed to demonstrate (1)the involvement of NCX in the pathophysiology of neonatal HI and (2)a possible NCX-based pharmacological intervention. HI was induced in neonatal mice at postnatal day 7(P7) by unilateral cut of the right common carotid artery, followed by 60 min exposure to 8%O2. Expression profiles of NCX isoforms from embryos stage to adulthood was evaluated in the hippocampus of hypoxic-ischemic and control mice. To assess the effect of NCX pharmacological stimulation, brain infarct volume was evaluated in brain sections, obtained at several time intervals after systemic administration of the newly synthesized NCX activator neurounina. Moreover, the long term effect of NCX activation was evaluated in adult mice (P60) subjected to neonatal HI and daily treated with neurounina for three weeks. Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3 expression starting from day 7 until day 60. Notably, 8 weeks after HI induction in P7 mice, NCX pharmacological stimulation not only reduced infarct volume but improved also motor behaviour, spatial and visual memory. The present study highlights the significant role of NCX in the evolution of neonatal brain injury and in the learning and memory processes that are impaired in mice injured in the neonatal period.

Original languageEnglish
Pages (from-to)180-191
Number of pages12
JournalNeuropharmacology
Volume135
DOIs
Publication statusPublished - Jun 1 2018

Fingerprint

Brain Hypoxia-Ischemia
Brain Ischemia
Brain Injuries
Pharmacology
Sodium-Calcium Exchanger
Common Carotid Artery
Brain
Hippocampus
Protein Isoforms
Homeostasis
Embryonic Structures
Learning

Keywords

  • Learning and memory
  • Motor behaviour
  • Na+/Ca2+ exchanger
  • Neonatal hypoxia

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia. / Cerullo, Pierpaolo; Brancaccio, Paola; Anzilotti, Serenella; Vinciguerra, Antonio; Cuomo, Ornella; Fiorino, Ferdinando; Severino, Beatrice; Di Vaio, Paola; Di Renzo, Gianfranco; Annunziato, Lucio; Pignataro, Giuseppe.

In: Neuropharmacology, Vol. 135, 01.06.2018, p. 180-191.

Research output: Contribution to journalArticle

Cerullo, P, Brancaccio, P, Anzilotti, S, Vinciguerra, A, Cuomo, O, Fiorino, F, Severino, B, Di Vaio, P, Di Renzo, G, Annunziato, L & Pignataro, G 2018, 'Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia', Neuropharmacology, vol. 135, pp. 180-191. https://doi.org/10.1016/j.neuropharm.2018.03.017
Cerullo, Pierpaolo ; Brancaccio, Paola ; Anzilotti, Serenella ; Vinciguerra, Antonio ; Cuomo, Ornella ; Fiorino, Ferdinando ; Severino, Beatrice ; Di Vaio, Paola ; Di Renzo, Gianfranco ; Annunziato, Lucio ; Pignataro, Giuseppe. / Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia. In: Neuropharmacology. 2018 ; Vol. 135. pp. 180-191.
@article{b067a2125fc644ba97e03d1402974e56,
title = "Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia",
abstract = "Hypoxic-ischemic encephalopathy (HI) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since the plasmamembrane sodium/calcium exchanger (NCX) plays a fundamental role in maintaining ionic homeostasis during adult brain ischemia, in the present work we aimed to demonstrate (1)the involvement of NCX in the pathophysiology of neonatal HI and (2)a possible NCX-based pharmacological intervention. HI was induced in neonatal mice at postnatal day 7(P7) by unilateral cut of the right common carotid artery, followed by 60 min exposure to 8{\%}O2. Expression profiles of NCX isoforms from embryos stage to adulthood was evaluated in the hippocampus of hypoxic-ischemic and control mice. To assess the effect of NCX pharmacological stimulation, brain infarct volume was evaluated in brain sections, obtained at several time intervals after systemic administration of the newly synthesized NCX activator neurounina. Moreover, the long term effect of NCX activation was evaluated in adult mice (P60) subjected to neonatal HI and daily treated with neurounina for three weeks. Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3 expression starting from day 7 until day 60. Notably, 8 weeks after HI induction in P7 mice, NCX pharmacological stimulation not only reduced infarct volume but improved also motor behaviour, spatial and visual memory. The present study highlights the significant role of NCX in the evolution of neonatal brain injury and in the learning and memory processes that are impaired in mice injured in the neonatal period.",
keywords = "Learning and memory, Motor behaviour, Na+/Ca2+ exchanger, Neonatal hypoxia",
author = "Pierpaolo Cerullo and Paola Brancaccio and Serenella Anzilotti and Antonio Vinciguerra and Ornella Cuomo and Ferdinando Fiorino and Beatrice Severino and {Di Vaio}, Paola and {Di Renzo}, Gianfranco and Lucio Annunziato and Giuseppe Pignataro",
year = "2018",
month = "6",
day = "1",
doi = "10.1016/j.neuropharm.2018.03.017",
language = "English",
volume = "135",
pages = "180--191",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia

AU - Cerullo, Pierpaolo

AU - Brancaccio, Paola

AU - Anzilotti, Serenella

AU - Vinciguerra, Antonio

AU - Cuomo, Ornella

AU - Fiorino, Ferdinando

AU - Severino, Beatrice

AU - Di Vaio, Paola

AU - Di Renzo, Gianfranco

AU - Annunziato, Lucio

AU - Pignataro, Giuseppe

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Hypoxic-ischemic encephalopathy (HI) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since the plasmamembrane sodium/calcium exchanger (NCX) plays a fundamental role in maintaining ionic homeostasis during adult brain ischemia, in the present work we aimed to demonstrate (1)the involvement of NCX in the pathophysiology of neonatal HI and (2)a possible NCX-based pharmacological intervention. HI was induced in neonatal mice at postnatal day 7(P7) by unilateral cut of the right common carotid artery, followed by 60 min exposure to 8%O2. Expression profiles of NCX isoforms from embryos stage to adulthood was evaluated in the hippocampus of hypoxic-ischemic and control mice. To assess the effect of NCX pharmacological stimulation, brain infarct volume was evaluated in brain sections, obtained at several time intervals after systemic administration of the newly synthesized NCX activator neurounina. Moreover, the long term effect of NCX activation was evaluated in adult mice (P60) subjected to neonatal HI and daily treated with neurounina for three weeks. Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3 expression starting from day 7 until day 60. Notably, 8 weeks after HI induction in P7 mice, NCX pharmacological stimulation not only reduced infarct volume but improved also motor behaviour, spatial and visual memory. The present study highlights the significant role of NCX in the evolution of neonatal brain injury and in the learning and memory processes that are impaired in mice injured in the neonatal period.

AB - Hypoxic-ischemic encephalopathy (HI) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since the plasmamembrane sodium/calcium exchanger (NCX) plays a fundamental role in maintaining ionic homeostasis during adult brain ischemia, in the present work we aimed to demonstrate (1)the involvement of NCX in the pathophysiology of neonatal HI and (2)a possible NCX-based pharmacological intervention. HI was induced in neonatal mice at postnatal day 7(P7) by unilateral cut of the right common carotid artery, followed by 60 min exposure to 8%O2. Expression profiles of NCX isoforms from embryos stage to adulthood was evaluated in the hippocampus of hypoxic-ischemic and control mice. To assess the effect of NCX pharmacological stimulation, brain infarct volume was evaluated in brain sections, obtained at several time intervals after systemic administration of the newly synthesized NCX activator neurounina. Moreover, the long term effect of NCX activation was evaluated in adult mice (P60) subjected to neonatal HI and daily treated with neurounina for three weeks. Hypoxic-ischemic insult induced a reduction of NCX1 and NCX3 expression starting from day 7 until day 60. Notably, 8 weeks after HI induction in P7 mice, NCX pharmacological stimulation not only reduced infarct volume but improved also motor behaviour, spatial and visual memory. The present study highlights the significant role of NCX in the evolution of neonatal brain injury and in the learning and memory processes that are impaired in mice injured in the neonatal period.

KW - Learning and memory

KW - Motor behaviour

KW - Na+/Ca2+ exchanger

KW - Neonatal hypoxia

UR - http://www.scopus.com/inward/record.url?scp=85044149414&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044149414&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2018.03.017

DO - 10.1016/j.neuropharm.2018.03.017

M3 - Article

C2 - 29551690

AN - SCOPUS:85044149414

VL - 135

SP - 180

EP - 191

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -