Effects of hypoxia-induced neonatal seizures on acute hippocampal injury and later-life seizure susceptibility and anxiety-related behavior in mice

Rodriguez-Alvarez, Natalia; Jiménez-Mateos, Eva M.; Dunleavy, Mark; Waddington, John L.; Boylan, Geraldine B.; Henshall, David C.

doi:10.1016/j.nbd.2015.08.023

Cited by 51 publications

(55 citation statements)

References 70 publications

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“…Vannucci et al, 1995Vannucci et al, , 1997Vannucci et al, , 2001) simply mimic the effects of the endogenous hypercapnia, which are always associated with BA. In contrast to this, in current rodent models of BA and/or HIE which are based on exposure of rat and mouse pups to pure hypoxia induced by a gas mixture with a low O 2 (typically 4-8 % O 2 in N 2 ) (Greggio et al, 2009;Jensen et al, 1991;Rakhade et al, 2011;Rodriguez-Alvarez et al, 2015;Zanelli et al, 2014;Zayachkivsky et al, 2015), seizures are triggered already during the insult. Moreover, pure hypoxia (which does not occur under reallife physiological or pathophysiological conditions) evokes an immediate brain-confined alkalosis (Pospelov et al, 2020), which is exactly the opposite of what happens during asphyxia.…”

Section: Discussionmentioning

confidence: 99%

A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia

Ala-Kurikka

Pospelov

Summanen

et al. 2020

Preprint

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Birth asphyxia (BA) is a pathologic condition that arises from severe perinatal hypoxia and hypercapnia.Recovery following BA is often associated with seizures which may exacerbate the ensuing hypoxicischemic encephalopathy (HIE). Drugs used to treat post-BA seizures are often ineffective and there are concerns over their safety. Therefore, novel seizure-suppressing therapies are urgently needed. Most rodent models of BA-induced seizures are based on exposing neonatal rats or mice to hypoxia (or hypoxiaischemia), and overlook the fact that the hypercapnic acidosis linked to asphyxia has brain-sparing effects by suppressing neuronal excitability and enhancing cerebral blood flow. Thus, the aim of the present study was to investigate the dependence of asphyxia-induced seizures on brain pH and oxygen (Po 2 ) levels in a rodent model of term BA based on postnatal day 11-12 rat pups. Cortical activity and electrographic seizures were recorded in freely-behaving animals using epidural electrodes. Simultaneous measurements of cortical local field potentials as well as intracortical pH and Po 2 were made using microelectrodes and microsensors in urethane-anesthesized animals. The pups were exposed either to steady asphyxia (duration 15 min; with ambient air containing 5 % O 2 plus 20 % CO 2 ) or to intermittent asphyxia (30 min; with repetitive 5 min steps from 9 % to 5 % O 2 at constant 20 % CO 2 ). Both protocols led to acidemia (blood pH <7.0) coupled to a fall in base excess by 20 mmol/l, and to a large increase in plasma copeptin (from 0.2 nM to about 5 nM), a biomarker of BA. Brain pH decreased from 7.3 to 6.7 by the end of intermittent asphyxia.Brain Po 2 was only transiently affected by 9% ambient O 2 , but it fell below the level of detection with steps to 5 % O 2 , during which neuronal activity was near-abolished. The Po 2 steps to 9% were associated with a moderate increase in pH (0.12 units) and a slight recovery (~10 % of baseline) in ongoing neuronal activity.Behavioral seizures spanning the entire Racine scale were triggered after intermittent but not steady asphyxia, and they were tightly associated with neocortical electrographic seizures. The seizures were strongly suppressed when the post-asphyxia brain pH recovery was slowed down by a low level (5 %) of ambient CO 2 . The post-asphyxia overshoot in brain Po 2 (from 30 to 85 mmHg) had no discernible effect on neuronal activity. Our data suggest that the recurring hypoxic episodes during intermittent asphyxia promote neuronal excitability, which becomes established as hyperexcitability and seizures once the suppressing effect of the hypercapnic acidosis is relieved. The present rodent model of BA is to our best knowledge the first one where, consistent with the clinical picture of BA, robust behavioral and electrographic seizures are triggered after and not during the asphyxic insult. HIGHLIGHTS Experimental asphyxia induced severe acidemia and abolished most cortical activity. Cortical activity during asphyxia was closely linked with changes in brai...

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Section: Discussionmentioning

confidence: 99%

A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia

Ala-Kurikka

Pospelov

Summanen

et al. 2020

Preprint

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“…However, there is little consensus over the direction or magnitude of changes (Decker M.J. et al, 2003; Decker et al, 2005). Hypoxia-only models have become an established model used to generate seizures in neonatal rats (Jensen et al, 1995; Applegate et al, 1996; Rodríguez-Alvárez et al, 2015; Sampath et al, 2015). In one such model, P6 rat pups were placed in chambers at 9% O 2 partial pressure and 20% CO 2 partial pressure for 60 min.…”

Section: Evaluation Of Available Animal Models Of Neonatal Hypoxia Ismentioning

confidence: 99%

Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges

Millar

Shi

Hoerder‐Suabedissen

et al. 2017

Front. Cell. Neurosci.

271

272

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Neonatal hypoxia-ischaemia (HI) is the most common cause of death and disability in human neonates, and is often associated with persistent motor, sensory, and cognitive impairment. Improved intensive care technology has increased survival without preventing neurological disorder, increasing morbidity throughout the adult population. Early preventative or neuroprotective interventions have the potential to rescue brain development in neonates, yet only one therapeutic intervention is currently licensed for use in developed countries. Recent investigations of the transient cortical layer known as subplate, especially regarding subplate’s secretory role, opens up a novel set of potential molecular modulators of neonatal HI injury. This review examines the biological mechanisms of human neonatal HI, discusses evidence for the relevance of subplate-secreted molecules to this condition, and evaluates available animal models. Neuroserpin, a neuronally released neuroprotective factor, is discussed as a case study for developing new potential pharmacological interventions for use post-ischaemic injury.

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“…It has reported that C57BL/6 series mice have a tolerance to hypoxia, which may protect the neurons from the harm of oxygen deficit-induced cell death and subsequently, protect the mice from spontaneous seizure occurrence [32]. However, report also shows that C57BL/6 mice subjected to hypoxia-induced neonatal seizure developed earlier, more frequent, and longer duration seizures when treated with KA in late life, although spontaneous seizures were not monitored [33]. Thus, status epilepticus induced by intraperitoneal injection of KA may not be a good model to trigger epileptogenesis in C57BL/ 6 mice.…”

Section: Discussionmentioning

confidence: 99%

Neural Progenitor Cells Rptor Ablation Impairs Development but Benefits to Seizure‐Induced Behavioral Abnormalities

Chen

Zhu

et al. 2016

CNS Neurosci Ther

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Effects of hypoxia-induced neonatal seizures on acute hippocampal injury and later-life seizure susceptibility and anxiety-related behavior in mice

Cited by 51 publications

References 70 publications

A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia

A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia

Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges

Neural Progenitor Cells Rptor Ablation Impairs Development but Benefits to Seizure‐Induced Behavioral Abnormalities

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