X-Linked Inhibitor of Apoptosis Protein Expression After Ischemic Injury in the Human and Rat Developing Brain

Askalan, Rand; Salweski, Ryan; Tuor, Ursula I.; Hutchison, Jamie; Hawkins, Cynthia

doi:10.1203/pdr.0b013e3181894a25

Cited by 10 publications

(10 citation statements)

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“…It has also been shown to inhibit caspase-independent cell death [Silke et al, 2001[Silke et al, , 2002. We have shown that XIAP is upregulated in the penumbra of the ischemic rat and human developing brain, and this upregulation is prolonged for up to at least 1 week after injury [Askalan et al, 2009]. For these reasons, we have extended our investigation to determine the effect of hypothermia on XIAP expression in the ischemic neonatal rat brain.…”

Section: Discussionmentioning

confidence: 92%

“…Female rats were allowed to deliver vaginally, and all litters were culled to 10 pups within 48 h of birth. The well-established Rice-Vannucci stroke model [Yager and Ashwal, 2009] was used to induce hypoxic-ischemic injury in the neonatal rat brain as previously described [Askalan et al, 2009]. In brief, 7-day-old rat pups were randomly assigned to either the control or cerebral hypoxia-ischemia (HI) group.…”

Section: Neonatal Stroke Modelmentioning

confidence: 99%

“…One section from each brain was stained with HE to confirm the presence of an infarct. As we have previously described, normal brain parenchyma shown by HE staining directly adjacent to the ischemic 'core' was defined as the peri-infarct or 'penumbra' [Askalan et al, 2009]. Serial sections were then stained with commercially available specific primary antibodies for activated caspase 3 [rabbit polyclonal anti-cleaved caspase 3 (Asp175) antibody, 1: 400; Cell Signaling, Pickering, Ont., Canada], AIF (rabbit anti-AIF, 1: 100; Cell Signaling), X-linked inhibitor of apoptosis (XIAP; rabbit anti-XIAP, 1: 500; ProSci Inc., Burlington, Ont., Canada) and bromodeoxyuridine (BrdU; rat monoclonal, 1: 200; Santa Cruz) at 4 ° C overnight.…”

Section: Immunohistochemistry and Western Blotsmentioning

confidence: 99%

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The Effect of Postischemic Hypothermia on Apoptotic Cell Death in the Neonatal Rat Brain

et al. 2011

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Background and Objective: Hypothermia is the most effective neuroprotective therapy against ischemic injury in the developing brain. However, the mechanism of hypothermic neuroprotection is not well understood. We sought to investigate whether hypothermia mediates neuroprotection by modulating ischemia-induced apoptosis. Methods: Seven-day-old rat pups were randomly assigned to either control or hypoxia-ischemia (HI) groups. In the HI group, the internal carotid artery was ligated and cut. This was followed by transient hypoxia at 8% oxygen for 90 min. In the control rats, the internal carotid was isolated but not ligated. Immediately after the hypoxic episode, pups in the HI group were either placed in water baths maintained at 28°C for 24 h (core temperatures at 31°C) or they remained in a normothermic environment. Animals were sacrificed at 24, 48 and 72 h and 1 week after the HI insult. Brain sections were processed for immunohistochemistry and Western blots. Results: Caspase 3 expression was significantly higher in the core compared with the peri-infarct area at all time points in normothermic rats. Hypothermia reduced caspase 3 expression in the core but had little effect in the peri-infarct area. Hypothermia reduced apoptosis-inducing factor translocation to the nucleus in the core and peri-infarct area. Concurrently, X-linked inhibitor of apoptosis (XIAP) expression was significantly potentiated in the hypothermic-ischemic core but not in the peri-infarct area. Conclusion: Hypothermic modulation of caspase-dependent apoptosis may be mediated by upregulating XIAP. However, the effect of hypothermia on caspase-independent apoptosis may be mediated by XIAP-independent mechanisms. Importantly, these effects are mediated in both the core and the penumbral regions of ischemic lesion.

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Section: Discussionmentioning

confidence: 92%

Section: Neonatal Stroke Modelmentioning

confidence: 99%

Section: Immunohistochemistry and Western Blotsmentioning

confidence: 99%

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The Effect of Postischemic Hypothermia on Apoptotic Cell Death in the Neonatal Rat Brain

et al. 2011

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“…XIAP stops both intrinsic and extrinsic apoptosis by binding to the initiator caspase (caspase-9) and halting further cleavage of downstream caspases (caspases 3 and 7) [59]. XIAP has also been shown to bind and inhibit caspases 3 and 7 directly [for a review, see [57]], and its expression has been confirmed in both rodent and human brains following ischemic injury [60]. Because XIAP acts on the caspase-dependent pathway of cell death, it may play a selective role in the protection afforded to females following early HI injury.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of X-Linked Inhibitor of Apoptosis with Embelin Differentially Affects Male versus Female Behavioral Outcome following Neonatal Hypoxia-Ischemia in Rats

et al. 2011

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Hypoxia-ischemia (HI; concurrent oxygen/blood deficiency) and associated encephalopathy represent a common cause of neurological injury in premature/low-birth-weight infants and term infants with birth complications. Resulting behavioral impairments include cognitive and/or sensory processing deficits, as well as language disabilities, and clinical evidence shows that male infants with HI exhibit more severe cognitive deficits compared to females with equivalent injury. Evidence also demonstrates activation of sex-dependent apoptotic pathways following HI events, with males preferentially activating a caspase-independent cascade of cell death and females preferentially activating a caspase-dependent cascade following neonatal hypoxic and/or ischemic insults. Based on these combined data, the ‘female protection’ following HI injury may reflect the endogenous X-linked inhibitor of apoptosis (XIAP), which effectively binds effector caspases and halts downstream cleavage of effector caspases (thus reducing cell death). To test this theory, the current study utilized neonatal injections of vehicle or embelin (a small molecule inhibitor of XIAP) in male and female rats with or without induced HI injury on postnatal day 7 (P7). Subsequent behavioral testing using a clinically relevant task revealed that the inhibition of XIAP exacerbated HI-induced persistent behavioral deficits in females, with no effect on HI males. These results support sex differences in mechanisms of cell death following early HI injuries, and suggest a potential clinical benefit from the development of sex-specific neuroprotectants for the treatment of HI.

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“…95 In vitro studies have identified endogenous XIAP as a critical regulator of neuronal apoptosis, 96 and data from studies of mice overexpressing XIAP have shown that increased levels of this protein confer protection against hypoxia-ischemia-induced caspase activation in both the adult 97 and neonatal brain. 98 In a model of transient cerebral ischemia in rats, XIAP overexpression increased cell survival by 5 to 6-fold and improved functional recovery. 99 Pharmacological implementation of XIAP-based neurorescuing has been successfully reported by Fan et al 100 in a model of transient brain ischemia.…”

Section: Inhibitors Of Apoptosis Proteins: the Natural Caspase Inhibimentioning

confidence: 99%

Mitochondrial Damage: A Target for New Therapeutic Horizons

Soustiel

Larisch

2010

Neurotherapeutics

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Summary: Traumatic brain injury (TBI) represents a leading cause of death and morbidity, as well as a considerable social and economical burden in western countries, and has thus emerged as a formidable therapeutic challenge. Yet despite tremendous efforts enlightening the mechanisms of neuronal death, hopes for the "magic bullet" have been repeatedly deceived, and TBI management has remained focused on the control of increased intracranial pressure. Indeed, impairment of cerebral metabolism is traditionally attributed to impaired oxygen delivery mediated by reduced cerebral perfusion in the swollen cerebral parenchyma. Although intuitively appealing, this hypothesis is not entirely supported by physiological facts and does not take into consideration mitochondrial dysfunction that has been repeatedly reported in both human and animal TBI. Although the nature and origin of the events leading to mitochondrial damage may be different, most share a permeabilization of mitochondrial membrane, which therefore may represent a logical target for new therapeutic strategies. Therefore, the proteins mediating these events may represent promising targets for new TBI therapies. Furthermore, mimicking anti-apoptotic proteins, such as Bcl-2 or XIAP, or inhibiting mitochondrial pro-apoptotic proteins, such as Smac/DIABLO, Omi/HTRA2, and ARTS (septin 4 isoform 2) may represent useful novel therapeutic strategies. This review focuses on mechanisms of the mitochondrial membrane permeabilization and its consequences and discusses the current and possible future therapeutic implications of this key event of neuronal death.

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X-Linked Inhibitor of Apoptosis Protein Expression After Ischemic Injury in the Human and Rat Developing Brain

Cited by 10 publications

References 31 publications

The Effect of Postischemic Hypothermia on Apoptotic Cell Death in the Neonatal Rat Brain

The Effect of Postischemic Hypothermia on Apoptotic Cell Death in the Neonatal Rat Brain

Inhibition of X-Linked Inhibitor of Apoptosis with Embelin Differentially Affects Male versus Female Behavioral Outcome following Neonatal Hypoxia-Ischemia in Rats

Mitochondrial Damage: A Target for New Therapeutic Horizons

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