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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

Cytokine levels in serum. (A) IL-1β and (B) TNF-α levels are significantly higher in males than in females 3 days after HIE. **P < .01 vs. 3-day males; ***P < .001 vs. 3-day males.
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Fig2: Cytokine levels in serum. (A) IL-1β and (B) TNF-α levels are significantly higher in males than in females 3 days after HIE. **P < .01 vs. 3-day males; ***P < .001 vs. 3-day males.

Mentions: The innate immune response to ischemia induces secondary brain injury following acute ischemic damage [29]. To investigate whether sex differences in inflammatory responses contribute to the delayed sexual dimorphism in HIE outcomes, we measured IL-1β, TNF-α, and IL-6 levels in the serum of the mice in the infarct cohort. Interestingly, the results of IL-1β and TNF-α were consistent with the infarct data: although there were no sex differences in IL-1β and TNF-α levels at 1 day, males had significantly higher serum concentration of both cytokines compared to females 3 days after HIE (Figure 2A, B). No sex differences in IL-6 levels were seen at either 1 day or 3 days of HIE (data not shown).Figure 2


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

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

Cytokine levels in serum. (A) IL-1β and (B) TNF-α levels are significantly higher in males than in females 3 days after HIE. **P < .01 vs. 3-day males; ***P < .001 vs. 3-day males.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Cytokine levels in serum. (A) IL-1β and (B) TNF-α levels are significantly higher in males than in females 3 days after HIE. **P < .01 vs. 3-day males; ***P < .001 vs. 3-day males.
Mentions: The innate immune response to ischemia induces secondary brain injury following acute ischemic damage [29]. To investigate whether sex differences in inflammatory responses contribute to the delayed sexual dimorphism in HIE outcomes, we measured IL-1β, TNF-α, and IL-6 levels in the serum of the mice in the infarct cohort. Interestingly, the results of IL-1β and TNF-α were consistent with the infarct data: although there were no sex differences in IL-1β and TNF-α levels at 1 day, males had significantly higher serum concentration of both cytokines compared to females 3 days after HIE (Figure 2A, B). No sex differences in IL-6 levels were seen at either 1 day or 3 days of HIE (data not shown).Figure 2

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