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A Battery of Motor Tests in a Neonatal Mouse Model of Cerebral Palsy
Published on: November 3, 2016
Sex and the pathogenesis of cerebral palsy
Michael V Johnston1, Henrik Hagberg
1Kennedy Krieger Institute and the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Johnston@kennedykrieger.org
Insights
Sex differences in brain injury response are evident in neonates. Males are more vulnerable to hypoxic-ischemic injury, suggesting distinct neurobiological pathways in cerebral palsy pathogenesis.
Area of Science:
- Neurobiology
- Developmental Neuroscience
- Perinatal Medicine
Background:
- Cerebral palsy (CP) and related disorders disproportionately affect males.
- Males born very preterm exhibit increased vulnerability to brain injuries like white matter injury and intraventricular hemorrhage.
- Sex hormones, particularly estrogens, show neuroprotective effects in adult stroke models, but neonatal hormonal influences differ.
Purpose of the Study:
- To investigate sex-based neurobiological differences in response to neonatal brain injury.
- To explore the underlying mechanisms contributing to the higher incidence of CP in males.
- To inform the development of targeted neuroprotective strategies for vulnerable neonates.
Main Methods:
- Review of experimental studies in neonatal rodents subjected to hypoxia-ischemia.
- Analysis of data from knockout models, specifically the poly (ADP-ribose) polymerase (PARP-1) gene.
- Examination of sex differences in neuronal cell cultures regarding cell death pathways.
Main Results:
- Neonatal rodent models demonstrate significant sex differences in response to hypoxia-ischemia.
- Genetic manipulation (PARP-1 knockout) provided protection in male but not female mouse pups.
- In vitro studies reveal intrinsic differences in cell death pathways between male and female neurons.
Conclusions:
- There are crucial neurobiological distinctions between males and females in their susceptibility and response to brain injury.
- These sex differences are relevant to understanding the pathogenesis of cerebral palsy.
- Findings have implications for designing sex-specific neuroprotective therapies in clinical trials.
Abstract:
Cerebral palsy (CP) and related developmental disorders are more common in males than in females, but the reasons for this disparity are uncertain. Males born very preterm also appear to be more vulnerable to white matter injury and intraventricular hemorrhage than females. Experimental studies in adult animals and data from adult patients with stroke indicate that sex hormones such as estrogens provide protection against hypoxic-ischemic injury, and the neonatal brain is also influenced by these hormones. However, hormonal influences on the fetus and neonates are substantially different from those on adults. Recent data from neonatal rodents subjected to hypoxia-ischemia also demonstrate differences between males and females. Knockout of the gene for poly (ADP-ribose) polymerase (PARP-1), a major step in the cascade of injury, protected male but not female mouse pups from hypoxic-ischemic injury. Other reports demonstrated major differences between male and female neurons grown separately in cell culture, suggesting that sex differences in the fetal or neonatal period result from intrinsic differences in cell death pathways. This new information indicates that there are important neurobiological differences between males and females with respect to their response to brain injuries. This information is relevant to understanding the pathogenesis of CP as well as to the design of future clinical trials of potential neuroprotective strategies.
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