17β-Estradiol increases expression of the oxidative stress response and DNA repair protein apurinic endonuclease (Ape1) in the cerebral cortex of female mice following hypoxia

Abstract

While it is well established that 17β-estradiol (E2) protects the rodent brain from ischemia-induced damage, it has been unclear how this neuroprotective effect is mediated. Interestingly, convincing evidence has also demonstrated that maintaining or increasing the expression of the oxidative stress response and DNA repair protein apurinic endonuclease 1 (Ape1) is instrumental in reducing ischemiainduced damage in the brain. Since E2 increases expression of the oxidative stress response proteins Cu/Zn superoxide dismutase and thioredoxin in the brain, we hypothesized that E2 may also increase Ape1 expression and that this E2-induced expression of Ape1 may help to mediate the neuroprotective effects of E2 in the brain. To test this hypothesis, we utilized three model systems including primary cortical neurons, brain slice cultures, and whole animals. Although estrogen receptor α and Ape1 were expressed in primary cortical neurons, E2 did not alter Ape1 expression in these cells. However, immunofluorescent staining and quantitative Western blot analysis demonstrated that estrogen receptor α and Ape1 were expressed in the nuclei of cortical neurons in brain slice cultures and that E2 increased Ape1 expression in the cerebral cortex of these cultures. Furthermore, Ape1 expression was increased and oxidative DNA damage was decreased in the cerebral cortices of ovariectomized female C57Bl/6J mice that had been treated with E2 and exposed to hypoxia. Taken together, our studies demonstrate that the neuronal microenvironment may be required for increased Ape1 expression and that E2 enhances expression of Ape1 and reduces oxidative DNA damage, which may in turn help to reduce ischemia-induced damage in the cerebral cortex and mediate the neuroprotective effects of E2.

Expression of estrogen receptor α in the mouse cerebral cortex

“…2A, boxed regions). As shown earlier using brain slice cultures and whole mouse brains (Rao et al 2011, Dietrich et al 2013), ERα protein colocalized with NeuN and DAPI (Fig. 2B) demonstrating that the receptor was expressed in the nuclei of cortical neurons.…”

Gender and Cell-Type-Specific Effects of the Transcription-Coupled Repair Protein, ERCC6/CSB, on Repeat Expansion in a Mouse Model of the Fragile X-Related Disorders

“…Increased contractions during female germline transmission have been reported for mouse models of CAG/CTG REDs, but this does not seem to follow a period of significant expansion as in the FX PM mouse [Mangiarini et al., ; Wheeler et al., ; Kovtun et al., ]. A number of DNA repair genes, including those involved in DNA damage signaling, in mismatch repair, and in the repair of oxidative DNA damage, are regulated by estrogen [Kirk, ; Murdoch and Van Kirk, ; Cabanes et al., ; Likhite et al., ; Araneda et al., ; Miyamoto et al., ; Jin et al., ; Medunjanin et al., ; Schultz‐Norton et al., ; Berger et al., ; Dietrich et al., ]. It may be that an age‐related decline in estrogen contributes to the drop in maternally transmitted expansions, thus allowing the contraction process to become more apparent.…”

“…In addition to expansions, the regression of PM alleles to normal alleles has also been reported [Cabanes et al., ; Likhite et al., ; Jin et al., ]. Furthermore, many PM and FM carriers are mosaic, often showing a complex mixture of different PM and FM alleles [Murdoch and Van Kirk, ; Taylor et al., ; Araneda et al., ; Newman et al., ; Berger et al., ; Dietrich et al., ; Tome et al., ]. This mosaicism is thought to arise from a series of expansion and contraction events that occur during the individual's lifetime.…”

Migraine Triggers and Oxidative Stress: A Narrative Review and Synthesis

“…For oxidative damage that has already occurred, the body has a number of compensatory and repair processes. For example, an enzyme, apurinic endonuclease (Ape1), activates the base excision repair pathway, correcting common types of oxidative damage to DNA …”