Mechanism of the sex difference in neuronal ischemic cell death

S. L. Fairbanks, J. M. Young, J. W. Nelson, Catherine Davis, Ines Koerner, Nabil Alkayed

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background: Stroke risk and outcome are different in men and women. We hypothesized that this is partly due to an inherent difference in susceptibility to ischemia between neurons from male vs. female brains. We tested whether neurons from male rodents are more susceptible to in-vitro ischemia than cells from females, and if this is related to increased expression of soluble epoxide hydrolase (sEH). sEH contributes to neuronal cell death by inactivating neuroprotective epoxyeicosatrienoic acids (EETs). Methods: Rodent cortical neurons were cultured, and exposed to oxygen-glucose deprivation (OGD); then cell death was measured. EETs levels were determined by LC-MS/MS. Expression of sEH-encoding ephx2 was determined by qRT-PCR. Western blotting, immunocytochemistry, and hydrolase activity assay assessed protein expression and activity. Results: Cell death after OGD was higher in neurons from males vs. females, which correlated with higher ephx2 mRNA and stronger sEH immunoreactivity. However, EETs levels were similar in both sexes and pharmacological inhibition of the hydrolase domain of sEH did not abolish the sex difference in cell death. Genetic knockout of sEH in mice abolished the sex difference observed in neurons isolated from these mice after OGD. Conclusions: Cultured cortical neurons from females are more resistant to ischemia than neurons from males. Neurons from females have less sEH activity compared to neurons from males at baseline, although sEH levels were not measured after OGD. While pharmacological inhibition of the hydrolase domain of sEH does not affect cell death, knockout of the gene encoding sEH eradicates the sex difference seen in wild-type neurons, suggesting a role for further study of the lesser-known phosphatase domain of sEH and its role in sexual dimorphism in neuronal sensitivity to ischemia.

Original languageEnglish (US)
Pages (from-to)183-191
Number of pages9
JournalNeuroscience
Volume219
DOIs
StatePublished - Sep 6 2012

Fingerprint

Epoxide Hydrolases
Sex Characteristics
Cell Death
Neurons
Hydrolases
Ischemia
Oxygen
Glucose
Rodentia
Pharmacology
Gene Knockout Techniques
Phosphoric Monoester Hydrolases
Western Blotting
Immunohistochemistry
Stroke

Keywords

  • Acute stroke
  • Brain ischemia
  • EETs
  • Gender
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mechanism of the sex difference in neuronal ischemic cell death. / Fairbanks, S. L.; Young, J. M.; Nelson, J. W.; Davis, Catherine; Koerner, Ines; Alkayed, Nabil.

In: Neuroscience, Vol. 219, 06.09.2012, p. 183-191.

Research output: Contribution to journalArticle

Fairbanks, S. L. ; Young, J. M. ; Nelson, J. W. ; Davis, Catherine ; Koerner, Ines ; Alkayed, Nabil. / Mechanism of the sex difference in neuronal ischemic cell death. In: Neuroscience. 2012 ; Vol. 219. pp. 183-191.
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