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Sexually dimorphic outcomes and inflammatory responses in hypoxic-ischemic encephalopathy.

Mirza MA, Ritzel R, Xu Y, McCullough LD, Liu F - J Neuroinflammation (2015)

Bottom Line: However, female neonates exhibited significantly smaller infarct size and fewer seizures compared to males 3 days after HIE.Females also had less brain tissue loss and behavioral deficits compared to males at the chronic stage of HIE.Male animals demonstrated increased microglial activation and up-regulated inflammatory response compared to females at day 3.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. memirza@uchc.edu.

ABSTRACT

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of motor and cognitive impairment in children. Clinically, male infants are more vulnerable to ischemic insults and suffer more long-term deficits than females; however, the mechanisms underlying this sex difference remain elusive. Inflammatory processes initiated by microglial activation are fundamental in the pathophysiology of ischemia. Recent studies report a sexual dimorphism in microglia numbers and expression of activation markers in the neonatal brain under normal conditions. How these basal sex differences in microglia affect HIE remains largely unexplored. This study investigated sex differences in ischemic outcomes and inflammation triggered by HIE. We hypothesize that ischemia induces sex-specific brain injury in male and female neonates and that microglial activation and inflammatory responses play an important role in this sexual dimorphism.

Methods: Male and female C57BL6 mice were subjected to 60-min Rice-Vanucci modeling (RVM) at post-natal day 10 (P10) to induce HIE. Stroke outcomes were measured 1, 3, 7, and 30 days after stroke. Microglial activation and inflammatory responses were evaluated by flow cytometry and cytokine analysis.

Results: On day 1 of HIE, no difference in infarct volumes or seizure scores was seen between male and female neonates. However, female neonates exhibited significantly smaller infarct size and fewer seizures compared to males 3 days after HIE. Females also had less brain tissue loss and behavioral deficits compared to males at the chronic stage of HIE. Male animals demonstrated increased microglial activation and up-regulated inflammatory response compared to females at day 3.

Conclusions: HIE leads to an equivalent primary brain injury in male and female neonates at the acute stage that develops into sexually dimorphic outcomes at later time points. An innate immune response secondary to the primary injury may contribute to sexual dimorphism in HIE.

No MeSH data available.


Related in: MedlinePlus

Chronic HIE outcomes.(A) Representative images of brain slices stained with cresyl violet (CV) 30 days after HIE. Note that the cavitation and atrophy can be seen in both the male and female brains. (B) Quantification of brain tissue loss at 30 days of HIE. *P < .05 vs. males. (C, D) Quantification of corner test scores at 7 days (B) and 30 days (C) of HIE. *P < .05 vs. males.
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Fig5: Chronic HIE outcomes.(A) Representative images of brain slices stained with cresyl violet (CV) 30 days after HIE. Note that the cavitation and atrophy can be seen in both the male and female brains. (B) Quantification of brain tissue loss at 30 days of HIE. *P < .05 vs. males. (C, D) Quantification of corner test scores at 7 days (B) and 30 days (C) of HIE. *P < .05 vs. males.

Mentions: We also examined outcomes at 7 days and 30 days after HIE; the infarct becomes less visible at the chronic stages and the ischemic brains exhibit either cavitation or atrophy due to the tissue loss (Figure 5A). Tissue loss was measured and quantified at the endpoint (30 days), and male animals had significantly more tissue loss than females (Figure 5B). We performed behavioral studies on HIE mice at the chronic stages to evaluate long-term outcomes. Female mice had significantly less forelimb asymmetry vs. males at both 7 days and 30 days after HIE (Figure 5C, D).Figure 5


Sexually dimorphic outcomes and inflammatory responses in hypoxic-ischemic encephalopathy.

Mirza MA, Ritzel R, Xu Y, McCullough LD, Liu F - J Neuroinflammation (2015)

Chronic HIE outcomes.(A) Representative images of brain slices stained with cresyl violet (CV) 30 days after HIE. Note that the cavitation and atrophy can be seen in both the male and female brains. (B) Quantification of brain tissue loss at 30 days of HIE. *P < .05 vs. males. (C, D) Quantification of corner test scores at 7 days (B) and 30 days (C) of HIE. *P < .05 vs. males.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359482&req=5

Fig5: Chronic HIE outcomes.(A) Representative images of brain slices stained with cresyl violet (CV) 30 days after HIE. Note that the cavitation and atrophy can be seen in both the male and female brains. (B) Quantification of brain tissue loss at 30 days of HIE. *P < .05 vs. males. (C, D) Quantification of corner test scores at 7 days (B) and 30 days (C) of HIE. *P < .05 vs. males.
Mentions: We also examined outcomes at 7 days and 30 days after HIE; the infarct becomes less visible at the chronic stages and the ischemic brains exhibit either cavitation or atrophy due to the tissue loss (Figure 5A). Tissue loss was measured and quantified at the endpoint (30 days), and male animals had significantly more tissue loss than females (Figure 5B). We performed behavioral studies on HIE mice at the chronic stages to evaluate long-term outcomes. Female mice had significantly less forelimb asymmetry vs. males at both 7 days and 30 days after HIE (Figure 5C, D).Figure 5

Bottom Line: However, female neonates exhibited significantly smaller infarct size and fewer seizures compared to males 3 days after HIE.Females also had less brain tissue loss and behavioral deficits compared to males at the chronic stage of HIE.Male animals demonstrated increased microglial activation and up-regulated inflammatory response compared to females at day 3.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. memirza@uchc.edu.

ABSTRACT

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of motor and cognitive impairment in children. Clinically, male infants are more vulnerable to ischemic insults and suffer more long-term deficits than females; however, the mechanisms underlying this sex difference remain elusive. Inflammatory processes initiated by microglial activation are fundamental in the pathophysiology of ischemia. Recent studies report a sexual dimorphism in microglia numbers and expression of activation markers in the neonatal brain under normal conditions. How these basal sex differences in microglia affect HIE remains largely unexplored. This study investigated sex differences in ischemic outcomes and inflammation triggered by HIE. We hypothesize that ischemia induces sex-specific brain injury in male and female neonates and that microglial activation and inflammatory responses play an important role in this sexual dimorphism.

Methods: Male and female C57BL6 mice were subjected to 60-min Rice-Vanucci modeling (RVM) at post-natal day 10 (P10) to induce HIE. Stroke outcomes were measured 1, 3, 7, and 30 days after stroke. Microglial activation and inflammatory responses were evaluated by flow cytometry and cytokine analysis.

Results: On day 1 of HIE, no difference in infarct volumes or seizure scores was seen between male and female neonates. However, female neonates exhibited significantly smaller infarct size and fewer seizures compared to males 3 days after HIE. Females also had less brain tissue loss and behavioral deficits compared to males at the chronic stage of HIE. Male animals demonstrated increased microglial activation and up-regulated inflammatory response compared to females at day 3.

Conclusions: HIE leads to an equivalent primary brain injury in male and female neonates at the acute stage that develops into sexually dimorphic outcomes at later time points. An innate immune response secondary to the primary injury may contribute to sexual dimorphism in HIE.

No MeSH data available.


Related in: MedlinePlus