Limits...
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

Acute stroke outcomes at 1 day and 3 days after HIE. (A) Representative coronal brain sections of TTC-stained brains at 1 day and 3 days. The black dotted line outlines the border of the infarct; red-colored area: unaffected tissue; white-colored area: infarcted tissue. (B, C) Quantification of infarct volumes at 1 day (B) and 3 days (C) of HIE. *P < .05 vs. male. (D) Seizure scores at 1 day and 3 days of HIE. *P < .05. (E, F) Testosterone (E) and estradiol (F) levels in serum.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Acute stroke outcomes at 1 day and 3 days after HIE. (A) Representative coronal brain sections of TTC-stained brains at 1 day and 3 days. The black dotted line outlines the border of the infarct; red-colored area: unaffected tissue; white-colored area: infarcted tissue. (B, C) Quantification of infarct volumes at 1 day (B) and 3 days (C) of HIE. *P < .05 vs. male. (D) Seizure scores at 1 day and 3 days of HIE. *P < .05. (E, F) Testosterone (E) and estradiol (F) levels in serum.

Mentions: We first examined HIE outcomes in P10 neonatal mice with RVM model. One day after HIE, male and female exhibited equivalent histological changes in the brain; however, male pups had significantly larger infarct in the ipsilateral hemisphere compared to females at 3 days of HIE (Figure 1A, B, C). Correspondingly, male pups had higher seizure scores than females 3 days after HIE, whereas no differences were seen at 1 day (Figure 1D). To investigate whether differences in hormone levels could contribute to HIE outcomes, we measured serum levels of testosterone and estradiol at terminal endpoints. No significant differences in either testosterone (Figure 1E) or estradiol (Figure 1F) levels were seen between males and females at either time point, suggesting factors other than hormones are responsible for the differing HIE outcomes in male vs. female neonates.Figure 1


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

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

Acute stroke outcomes at 1 day and 3 days after HIE. (A) Representative coronal brain sections of TTC-stained brains at 1 day and 3 days. The black dotted line outlines the border of the infarct; red-colored area: unaffected tissue; white-colored area: infarcted tissue. (B, C) Quantification of infarct volumes at 1 day (B) and 3 days (C) of HIE. *P < .05 vs. male. (D) Seizure scores at 1 day and 3 days of HIE. *P < .05. (E, F) Testosterone (E) and estradiol (F) levels in serum.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Acute stroke outcomes at 1 day and 3 days after HIE. (A) Representative coronal brain sections of TTC-stained brains at 1 day and 3 days. The black dotted line outlines the border of the infarct; red-colored area: unaffected tissue; white-colored area: infarcted tissue. (B, C) Quantification of infarct volumes at 1 day (B) and 3 days (C) of HIE. *P < .05 vs. male. (D) Seizure scores at 1 day and 3 days of HIE. *P < .05. (E, F) Testosterone (E) and estradiol (F) levels in serum.
Mentions: We first examined HIE outcomes in P10 neonatal mice with RVM model. One day after HIE, male and female exhibited equivalent histological changes in the brain; however, male pups had significantly larger infarct in the ipsilateral hemisphere compared to females at 3 days of HIE (Figure 1A, B, C). Correspondingly, male pups had higher seizure scores than females 3 days after HIE, whereas no differences were seen at 1 day (Figure 1D). To investigate whether differences in hormone levels could contribute to HIE outcomes, we measured serum levels of testosterone and estradiol at terminal endpoints. No significant differences in either testosterone (Figure 1E) or estradiol (Figure 1F) levels were seen between males and females at either time point, suggesting factors other than hormones are responsible for the differing HIE outcomes in male vs. female neonates.Figure 1

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