title: Sexually dimorphic outcomes and inflammatory responses in hypoxic-ischemic encephalopathy.
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.
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. memirza@uchc.edu.
authors.forename: Mehwish A
authors.initials: MA
authors.lastname: Mirza
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. rritzel@uchc.edu.
authors.forename: Rodney
authors.initials: R
authors.lastname: Ritzel
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. yxu@uchc.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. lmccullough@uchc.edu.|Department of Neurology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. lmccullough@uchc.edu.
authors.forename: Louise D
authors.initials: LD
authors.lastname: McCullough
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. fliu@uchc.edu.
authors.forename: Fudong
authors.initials: F
authors.lastname: Liu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020925:Hypoxia-Ischemia, Brain / Q000150:complications*; D007249:Inflammation / Q000097:blood* / Q000209:etiology*; D007962:Leukocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012640:Seizures / Q000209:etiology; D012727:Sex Characteristics; D013997:Time Factors
chemical_list: D016207:Cytokines; D004958:Estradiol