Mechanisms of neurodegeneration after severe hypoxic-ischemic injury in the neonatal rat brain

Askalan, Rand; Gabarin, Nadia; Armstrong, Edward A.; Liu, Yuan Fang; Couchman, Deema; Yager, Jerome Y.

doi:10.1016/j.brainres.2015.10.020

Cited by 41 publications

(38 citation statements)

References 47 publications

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“…As females are reported to have greater caspase-mediated apoptosis than male rats after moderate HI (Mirza et al, 2015), we explored differences between females and males within treatment groups in our severe HI model. Males and females had similar caspase 3 activation in the penumbra within all groups (n=2-4 per sex, per group, data not shown), similar to findings by other investigators in severe HI (Askalan et al, 2015). …”

Section: Resultssupporting

confidence: 89%

Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia

Nie

Lowe

Rollins

et al. 2016

Neuroscience Research

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Approximately half of moderate to severely hypoxic-ischemic (HI) newborns do not respond to hypothermia, the only proven neuroprotective treatment. N-Acetylcysteine (NAC), an antioxidant and glutathione precursor, shows promise for neuroprotection in combination with hypothermia, mitigating post-HI neuroinflammation due to oxidative stress. As mechanisms of HI injury and cell death differ in males and females, sex differences must be considered in translational research of neuroprotection. We assessed the potential toxicity and efficacy of NAC in combination with hypothermia, in male and female neonatal rats after severe HI injury. NAC 50 mg/kg/d administered 1h after initiation of hypothermia significantly decreased iNOS expression and caspase 3 activation in the injured hemisphere versus hypothermia alone. However, only females treated with hypothermia + NAC 50mg/kg showed improvement in short-term infarct volumes compared with saline treated animals. Hypothermia alone had no effect in this severe model. When NAC was continued for 6 weeks, significant improvement in long-term neuromotor outcomes over hypothermia treatment alone was observed, controlling for sex. Antioxidants may provide insufficient neuroprotection after HI for neonatal males in the short term, while long-term therapy may benefit both sexes.

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Section: Resultssupporting

confidence: 89%

Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia

Nie

Lowe

Rollins

et al. 2016

Neuroscience Research

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“…Three pathways of cell apoptosis have been described, i.e., the death receptor pathway in cytomembranes, the mitochondrial pathway in cytomembranes and stress pathways of the endoplasmic reticulum (13,33). The latter two pathways have been investigated via the measurement ofcaspase-3 and caspase-12 activities in a study on cell apoptosis in a neonatal hypoxia-ischemia rat model (34).…”

Section: Discussionmentioning

confidence: 99%

Curcumin attenuates hypoxic-ischemic brain injury in neonatal rats through induction of nuclear factor erythroid-2-related factor 2 and heme oxygenase-1

Cui

Song

Shi

2017

Experimental and Therapeutic Medicine

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Curcumin has previously demonstrated anti-inflammatory, anti-infective and immuno-suppressive effects. In the present study, whether the attenuating effects of curcumin against hypoxic-ischemic brain injury in neonatal rats are mediated via nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was investigated. A model of hypoxic-ischemic brain injury was created using 1-week-old Sprague Dawley rats (weight, 52±1 g). The model rats were treated with 150 mg/kg curcumin by gavage for 3 days. Malondialdehyde levels, and superoxide dismutase and caspase-3 activities were assayed using commercial kits and western blot analysis was used to measure inducible nitric oxide synthase (iNOS), Nrf2 and HO-1 expression levels. Treatment with curcumin effectively reduced the brain injury score, increased myelin basic protein (MBP) expression and increased the quantity of neuronal cells in neonatal rats with hypoxic-ischemic brain injury. Furthermore, treatment with curcumin significantly attenuated the changes in SOD activity and MDA levels and suppressed the iNOS protein expression induced in neonatal rats by hypoxic-ischemic brain injury. Treatment with curcumin significantly increased Nrf2 and HO-1 expression in the neonatal rats with hypoxic-ischemic brain injury. The present study indicated that curcumin attenuates hypoxic-ischemic brain injury in neonatal rats through the induction of Nrf2 and HO-1.

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“…Until recently, there have been no reported sex differences in lesion volume or magnitude of cell death following HI. Thus far, there has been one report of decreased lesion volume in female mice compared to males 3 days post-injury (Mirza et al, 2015), and only one report of increased cell death in the male brain at 7 days post-injury that is dependent on moderate injury severity (Askalan et al, 2015). The lack of consistent sex differences in histopathology is likely due to differences in species, severity of injury, and time point post-injury.…”

Section: Discussionmentioning

confidence: 99%

“…No sex differences in lesion volume have been found following HI in rats (Smith et al, 2014), but there is one recent report of increased lesion volume in male compared to female mice following HI (Mirza et al, 2015). Cell death proclivity in several brain injury models is sexually dimorphic (Du et al, 2004; Li et al, 2005, 2009, 2011; Yuan et al, 2009; Siegel et al, 2011; Manwani and McCullough, 2011; Hill et al, 2011a; Hill and Fitch, 2012; Siegel and McCullough, 2013) and a sex difference in cell death was also recently reported in moderate, but not severe hypoxia–ischemia (HI) injury in postnatal day 7 (PN7) rats (Askalan et al, 2015). The large body of clinical evidence demonstrating adult females have a better outcome after stroke than similarly aged males is commonly attributed to the presence of estrogen (reviewed in Turtzo and McCullough, 2010).…”

Section: Introductionmentioning

confidence: 94%

Sex-dependent mitophagy and neuronal death following rat neonatal hypoxia–ischemia

et al. 2016

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Males are more susceptible than females to long-term cognitive deficits following neonatal hypoxic-ischemic encephalopathy (HIE). Mitochondrial dysfunction is implicated in the pathophysiology of cerebral hypoxia–ischemia (HI), but the influence of sex on mitochondrial quality control (MQC) after HI is unknown. Therefore, we tested the hypothesis that mitophagy is sexually dimorphic and neuroprotective 20–24 h following the Rice–Vannucci model of rat neonatal HI at postnatal day 7 (PN7). Mitochondrial and lysosomal morphology and degree of co-localization were determined by immunofluorescence in the cerebral cortex. No difference in mitochondrial abundance was detected in the cortex after HI. However, net mitochondrial fission increased in both hemispheres of female brain, but was most extensive in the ipsilateral hemisphere of male brain following HI. Basal autophagy, assessed by immunoblot for the autophagosome marker LC3BI/II, was greater in males suggesting less intrinsic reserve capacity for autophagy following HI. Autophagosome formation, lysosome size, and TOM20/LAMP2 co-localization were increased in the contralateral hemisphere following HI in female, but not male brain. An accumulation of ubiquitinated mitochondrial protein was observed in male, but not female brain following HI. Moreover, neuronal cell death with NeuN/TUNEL co-staining occurred in both hemispheres of male brain, but only in the ipsilateral hemisphere of female brain after HI. In summary, mitophagy induction and neuronal cell death are sex dependent following HI. The deficit in elimination of damaged/dysfunctional mitochondria in the male brain following HI may contribute to male vulnerability to neuronal death and long-term neurobehavioral deficits following HIE.

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Mechanisms of neurodegeneration after severe hypoxic-ischemic injury in the neonatal rat brain

Cited by 41 publications

References 47 publications

Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia

Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia

Curcumin attenuates hypoxic-ischemic brain injury in neonatal rats through induction of nuclear factor erythroid-2-related factor 2 and heme oxygenase-1

Sex-dependent mitophagy and neuronal death following rat neonatal hypoxia–ischemia

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