Sex differences in cell genesis, hippocampal volume and behavioral outcomes in a rat model of neonatal HI

Waddell, Jaylyn; Hanscom, Marie; Edwards, N. Shalon; McKenna, Mary C.; McCarthy, Margaret M.

doi:10.1016/j.expneurol.2015.09.003

Cited by 50 publications

(54 citation statements)

References 78 publications

(85 reference statements)

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“…In this model, pups are exposed to hypoxic conditions for 3h or longer to create a severe model. However, not surprisingly, there are modified HI encephalopathy models in different laboratories, undergoing variable exposure times to hypoxia from several minutes to 2h or more in order to assimilate situations that would occur in clinic setting (Chen et al, 2008; Waddell et al, 2015; Wang et al, 2009; Zeinieh et al, 2010). Studies have shown that based on the length of exposure to hypoxic conditions, the neonatal rat brains displayed diverse brain injuries such as brain infarct volume, edema, and neurological deficit with different HI model parameters.…”

Section: Discussionmentioning

confidence: 99%

Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats

Shi

Doycheva

et al. 2016

Neurobiology of Disease

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Objective Hypoxic ischemic (HI) encephalopathy remains the leading cause of perinatal brain injury resulting in long term disabilities. Stabilization of blood brain barrier (BBB) after HI is an important target, therefore, in this study we aim to determine the role of sestrin2, a stress inducible protein which is elevated after various insults, on BBB stabilization after moderate and severe HI injury. Methods Rat pups underwent common carotid artery ligation followed by either 150 min (severe model) or 100 min (moderate model) of hypoxia. 1h post HI, rats were intranasally administered with recombinant human sestrin2 (rh-sestrin2) and sacrificed for infarct area, brain water content, righting reflex and geotaxis reflex. Sestrin2 was silenced using siRNA and an activator/inhibitor of hypoxia inducible factor1α (HIF1α) were used to examine their roles on BBB permeability. Results Rats subjected to severe HI exhibited larger infarct area and higher sestrin2 expression compared to rats in the moderate HI group. rh-sestrin2 attenuated brain infarct and edema, while silencing sestrin2 reversed these protective effects after severe HI. HIF1α induced sestrin2 activation in severe HI but not in moderate HI groups. A HIF1a agonist was shown to increase permeability of the BBB via vascular endothelial growth factor (VEGF) after moderate HI. However, after severe HI, HIF1α activated both VEGF and sestrin2. But HIF1α dependent sestrin2 activation was the predominant pathway after severe HI which inhibited VEGF and attenuated BBB permeability. Conclusions rh-sestrin2 attenuated BBB permeability via upregulation of endogenous sestrin2 which was induced by HIF1α after severe HI. However, HIF1α’s effects as a prodeath or prosurvival signal were influenced by the severity of HI injury.

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Section: Discussionmentioning

confidence: 99%

Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats

Shi

Doycheva

et al. 2016

Neurobiology of Disease

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“…Though this is interpreted as a motivation to restore postural stability, interpretation of this behavioral tendency has been questioned [35]. We consistently observe that sham operated control pups quickly reorient their position to point their heads up the incline, and use this task because it is sensitive to HI, and detect injury induced deficits in very young male and female rats [31]. The time to turn to face up the slope was measured 3 times, with a 3 min interval between trials and the average was determined for each pup.…”

Section: Methodsmentioning

confidence: 99%

“…Manipulations that prevent or reduce HI-induced inhibition of PARP-mediated cell death are protective in male mice subjected to neonatal HI, but has no effect in female mice [30]. Similarly, mechanisms of repair differ between the sexes, also contributing to potential treatment efficacy [31]. Thus, preclinical screening of potential therapies following HI must determine efficacy in both males and females, as treatments that benefit one sex may not protect the other sex [31–34].…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotective Effects of Acetyl-<smlcap>L</smlcap>-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats

Tang

Lü

et al. 2016

Dev Neurosci

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Perinatal hypoxia ischemia (HI) is a significant cause of brain injury in surviving infants. Although hypothermia improves outcomes in some infants, additional therapies are needed since about 40% of infants still have a poor outcome. Acetyl-L-carnitine (ALCAR), an acetylated derivative of L-carnitine, protected against early changes in brain metabolites and mitochondrial function after HI on postnatal day (PND) 7 in a rat pup model of near-term HI injury. However, its efficacy in long-term structural and functional outcomes remains unexplored. We determined the efficacy of ALCAR therapy administered to rat pups after HI at PND 7, using both longitudinal in vivo magnetic resonance imaging and behavioral tests, in male and female rats. HI led to sex-specific behavioral impairment, with males exhibiting more global functional deficits than females. Interestingly, HI reduced the volume of the contralateral hemisphere in males only, suggesting that the brain injury is more diffuse in males than in females. Treatment with ALCAR improved both morphological and functional outcomes in both male and female rats. These results suggest that ALCAR may be a potential therapy for clinical use since the treatment attenuated the moderate injury produced under the experimental conditions used and improved the functional outcome in preclinical studies.

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“…These results, together with the present data suggest that the reversal of HI-induced cognitive impairment by C3a is independent of neuronal density. Similarly, estradiol therapy improved behavioral performance but did not reverse the HI-induced loss of hippocampal volume (Waddell et al, 2016). Adaptive neural plasticity responses that improve neuronal functioning thus may play a critical role in functional outcome after neonatal…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Intranasal C3a treatment ameliorates cognitive impairment in a mouse model of neonatal hypoxic–ischemic brain injury

Morán

Stokowska

Walker

et al. 2017

Experimental Neurology

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Pekna, M. (2017). Intranasal C3a treatment ameliorates cognitive impairment in a mouse model of neonatal hypoxic-ischemic brain injury. Experimental Neurology. DOI: 10.1016DOI: 10. /j.expneurol.2017 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain •You may freely distribute the URL identifying the publication in the Research Portal Take down policy If you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access to the work immediately and investigate your claim. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT

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Sex differences in cell genesis, hippocampal volume and behavioral outcomes in a rat model of neonatal HI

Cited by 50 publications

References 78 publications

Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats

Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats

Neuroprotective Effects of Acetyl-<smlcap>L</smlcap>-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats

Intranasal C3a treatment ameliorates cognitive impairment in a mouse model of neonatal hypoxic–ischemic brain injury

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