Neuroprotection from ischemic brain injury by hypoxic preconditioning in the neonatal rat

Gidday, Jeffrey M.; Fitzgibbons, Jill C.; Shah, Aarti R.; Park, T.S.

doi:10.1016/0304-3940(94)90455-3

Cited by 293 publications

(202 citation statements)

References 26 publications

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“…It is well established that hypoxic PC protects the neonatal brain from subsequent ischemic insults (9,11,21). However, the mechanisms of this protection remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic Preconditioning Reverses Protection After Neonatal Hypoxia-Ischemia in Glutathione Peroxidase Transgenic Murine Brain

et al. 2007

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ABSTRACT:The effect of hypoxic preconditioning (PC) on hypoxic-ischemic (HI) injury was explored in glutathione peroxidase (GPx)-overexpressing mice (human GPx-transgenic [hGPx-tg]) mice. Six-day-old hGPx-tg mice and wild-type (Wt) littermates were preconditioned with hypoxia for 30 min and subjected to the Vannucci procedure of HI 24 h after the PC stimulus. Histopathological injury was determined 5 d later (P12). Additional animals were killed 2 h or 24 h after HI and ipsilateral cerebral cortices assayed for GPx activity, glutathione (GSH), and hydrogen peroxide (H 2 O 2 ). In line with previous studies, hypoxic PC reduced injury in the Wt brain. Preconditioned Wt brain had increased GPx activity, but reduced GSH, relative to naive 24 h after HI. Hypoxic PC did not reduce injury to hGPx-tg brain and even reversed the protection previously reported in the hGPx-tg. GPx activity and GSH in hGPx-tg cortices did not change. Without PC, hGPx-tg cortex had less H 2 O 2 accumulation than Wt at both 2 h and 24 h. With PC, H 2 O 2 remained low in hGPx-tg compared with Wt at 2 h, but at 24 h, there was no longer a difference between hGPx-tg and Wt cortices. T he developing brain is particularly susceptible to oxidative stress, more so than the mature brain (1). One reason for this susceptibility may be the different developmental profiles of antioxidant enzymes in the newborn brain compared with the mature brain. For example, total GPx activity increases sharply between E18 and P1, declines in the early postnatal period, then stabilizes through P21 (2). GSH levels also increase between E18 and P1, but remain lower than P21 (2). One consequence of this difference is that the developing brain accumulates H 2 O 2 after HI, whereas the mature brain does not (3). H 2 O 2 accumulation has also been associated with increased injury in superoxide dismutase-overexpressing neonatal murine brain (4), and greater cell death is seen when immature neurons are exposed to H 2 O 2 compared with mature neurons (5). Increased H 2 O 2 accumulation may be the result of relative insufficiency of the endogenous enzyme GPx. Under physiologic circumstances, the brain has efficient antioxidant defense mechanisms, including GPx, which converts potentially harmful H 2 O 2 to oxygen and water at the expense of reduced GSH. Under oxidative stress, in the immature brain, endogenous levels of GPx may be inadequate for converting excess H 2 O 2 . Transgenic mice that overexpress GPx (hGPx-tg), when subjected to HI have less histologic brain injury than their Wt littermates (6). In addition, the cortex exhibits increased GPx enzyme activity at 24 h, whereas GPx activity remains unaltered in the Wt brain. In addition, neurons cultured from GPx-tg brain are resistant to injury from exogenously applied H 2 O 2 (7). Neurons cultured from hippocampus and cortex that are transfected with genes for catalase and GPx also show protection from neurotoxic insults and a corresponding decrease in H 2 O 2 accumulation (8). These findings indicate that adequate GPx ac...

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“…It is well established that hypoxic PC protects the neonatal brain from subsequent ischemic insults (9,11,21). However, the mechanisms of this protection remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic Preconditioning Reverses Protection After Neonatal Hypoxia-Ischemia in Glutathione Peroxidase Transgenic Murine Brain

et al. 2007

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“…The pups were housed with the dam in the home cage under a 12:12 hr light /dark cycle, with food and water available ad libitum throughout the study. The neonatal H-I brain injury is based on the Levine procedure (Levine, 1960;Rice et al, 1981;Gidday et al, 1994;Cheng et al, 1997). Briefly, pups at P7 were anesthetized with 2.5% halothane (balance, room air), and the left common carotid artery was surgically exposed and permanently ligated.…”

Section: Methodsmentioning

confidence: 99%

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

Han¹,

2000

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Neurotrophins activate several different intracellular signaling pathways that in some way exert neuroprotective effects. In vitro studies of sympathetic and cerebellar granule neurons have demonstrated that the survival effects of neurotrophins can be mediated via activation of the phosphatidylinositol 3-kinase (PI3-kinase) pathway. Neurotrophin-mediated protection of other neuronal types in vitro can be mediated via the extracellular signalrelated protein kinase (ERK) pathway. Whether either of these pathways contributes to the neuroprotective effects of neurotrophins in the brain in vivo has not been determined. Brain-derived neurotrophic factor (BDNF) is markedly neuroprotective against neonatal hypoxic-ischemic (H-I) brain injury in vivo. We assessed the role of the ERK and PI3-kinase pathways in neonatal H-I brain injury in the presence and absence of BDNF. Intracerebroventricular administration of BDNF to postnatal day 7 rats resulted in phosphorylation of ERK1/2 and the PI3-kinase substrate AKT within minutes. Effects were greater on ERK activation and occurred in neurons. Pharmacological inhibition of ERK, but not the PI3-kinase pathway, inhibited the ability of BDNF to block H-Iinduced caspase-3 activation and tissue loss. These findings suggest that neuronal ERK activation in the neonatal brain mediates neuroprotection against H-I brain injury, a model of cerebral palsy.

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“…Finally, cobalt chloride had been previously shown to act as a hypoxia mimic and it, like DFO, stabilized HIF and protected neurons from oxidative death. Moreover, in vitro and in vivo studies using DFO or cobalt chloride in several models showed dramatic neuroprotection or reductions in infarct volume by pretreatment with DFO or cobalt chloride 24 hours before stroke onset (Sharp et al, 2004;Gidday et al, 1994;Bergeron et al, 2000;Semenza, 2000;Prass et al, 2002).…”

Section: Iron Chelators: a Window Into The Hypoxic Adaptive Responsementioning

confidence: 98%

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

Karuppagounder

Ratan

2012

J Cereb Blood Flow Metab

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A major challenge in developing stroke therapeutics that augment adaptive pathways to stress has been to identify targets that can activate compensatory programs without inducing or adding to the stress of injury. In this regard, hypoxia-inducible factor prolyl hydroxylases (HIF PHDs) are central gatekeepers of posttranscriptional and transcriptional adaptation to hypoxia, oxidative stress, and excitotoxicity. Indeed, some of the known salutary effects of putative 'antioxidant' iron chelators in ischemic and hemorrhagic stroke may derive from their abilities to inhibit this family of iron, 2-oxoglutarate, and oxygen-dependent enzymes. Evidence from a number of laboratories supports the notion that HIF PHD inhibition can improve histological and functional outcomes in ischemic and hemorrhagic stroke models. In this review, we discuss this evidence and highlight important gaps in our understanding that render HIF PHD inhibition a promising but not yet preclinically validated target for protection and repair after stroke.

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Neuroprotection from ischemic brain injury by hypoxic preconditioning in the neonatal rat

Cited by 293 publications

References 26 publications

Hypoxic Preconditioning Reverses Protection After Neonatal Hypoxia-Ischemia in Glutathione Peroxidase Transgenic Murine Brain

Hypoxic Preconditioning Reverses Protection After Neonatal Hypoxia-Ischemia in Glutathione Peroxidase Transgenic Murine Brain

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

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