Abstract
Neonatal hypoxic–ischemic encephalopathy (HIE) is increasingly recognized as a sexually dimorphic disease. Male infants are not only more vulnerable to ischemic insult; they also suffer more long-term cognitive deficits compared with females with comparable brain damage. The innate immune response plays a fundamental role in mediating acute neonatal HIE injury. However, the mechanism underlying the sex difference in chronic HIE is still elusive. The present study investigated the sex difference in HIE outcomes and inflammatory response in the chronic stage (30 days after HIE). Postnatal day 10 (P10) male and female C57BL/6 pups were subjected to 60-min Rice–Vanucci model (RVM) to induce HIE. Brain atrophy and behavioral deficits were analyzed to measure stroke outcomes at 30 days of HIE. Flow cytometry (FC) was performed to examine central (microglial activation) and peripheral immune responses. Serum levels of cytokines and sex hormones were determined by enzyme-linked immunosorbent assay (ELISA). Neurogenesis was quantified by 5-Bromo-2′-deoxyuridine (BrdU) incorporation with neurons. Results showed males had worse HIE outcomes than females at the endpoint. Female microglia exhibited a more robust anti-inflammatory response that was corresponding to an enhanced expression of CX3C chemokine receptor 1 (CX3CR1) than males. More infiltration of peripheral lymphocytes was seen in male vs. female HIE brains. Cytokine levels of tumor necrosis factor (TNF)-α and interleukin (IL)-10 were more upregulated in males and females respectively than their counterparts. Neurogenesis was more highly induced in females vs. males. No significant difference in circulating hormonal level was found between males and females after HIE. We conclude that a sex dichotomy in pro- and anti-inflammatory response underlies the sex-specific chronic HIE outcomes, and an enhanced neurogenesis in females also contribute to the sex difference.
Highlights
Perinatal hypoxic–ischemic encephalopathy (HIE) is a major cause of neonatal death and long-term disability
We examined outcomes at 30 days after HIE; the hypoxic– ischemic infarct becomes less visible at the chronic stage and the ischemic brains exhibit either cavitation or atrophy due to the tissue loss (Figure 1(a) and (b))
Sex differences exist in chronic HIE either in morphology or in behavior deficits, and sex hormones may not be determinants in inducing the sex difference as males and females have equivalent circulating hormone levels after chronic HIE
Summary
Perinatal hypoxic–ischemic encephalopathy (HIE) is a major cause of neonatal death and long-term disability. Clinical data showed about 15–20% of HIE infants will die in the postnatal period, and an additional 25% will develop severe and chronic neuropsychological sequelae, including mental retardation, visual motor or visual perceptive dysfunction, increased hyperactivity, cerebral palsy, and epilepsy[1]. Boys are more sensitive to the ischemic insult and have worse outcomes than girls[2]. Experimental studies have recapitulated the sex difference in acute HIE3. The chronic HIE outcomes reflect long-term sensorimotor/cognitive deficits and have not been well studied.
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