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Estradiol Receptor Agonists α and β Protect Against Brain Mitochondrial Dysfunction in a Model of Sleep Apnea
Author(s) -
Laouafa Sofien,
Bairam Aida,
Soliz Jorge,
Roussel Damien,
Joseph Vincent
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.696.6
Subject(s) - ovariectomized rat , endocrinology , medicine , intermittent hypoxia , agonist , chemistry , glutamate receptor , receptor , obstructive sleep apnea , hormone
We tested the hypothesis that intermittent hypoxia (IH) induces a mitochondrial dysfunction in the brain of adult female rats, and that agonists of α and β estradiol receptors (ER) protect against this effect. Female rats were ovariectomized (OVX) and implanted with an osmotic pump continuously delivering vehicle (OVX‐Veh), PPT (OVX‐PPT – ERα agonist ‐ 30μg/kg/day) or DPN (OVX‐DPN ‐ ERβ agonist ‐ 100μg/kg/day). Two weeks later, the animals were exposed to intermittent hypoxia (IH‐21–10% O 2 – 10 cycles/hour – 8 hours/day – 7 days) or room air (RA). We then used fresh brain cortex tissue (~2 mg) permeabilized with saponin to assess mitochondrial functions with high‐resolution respirometry ( O2k‐Oroboros ). With substrates of complex I (Pyruvate/Glutamate/Malate) and in presence of ADP, rats exposed to IH have a reduced O 2 consumption compared to RA rats (55±7 vs 88±4 pmol O 2 /s/mg tissue, p<0.0001). PPT and DPN treatments prevented this alteration (O 2 consumption being respectively 104±6 and 90±6 pmolO 2 /s/mg, p<0.0001 vs OVX‐IH rats). With the substrate of complex II (succinate) and ADP, there was no effect of IH, but O 2 consumption was higher in OVX‐PPT rats compared to OVX‐IH rats. With the substrates of complexes I+II and ADP, O 2 consumption was reduced by IH exposure compared to RA (51±9 vs 87±12 pmol O 2 /s/mg, p<0.0001), and this was partially prevented by DPN (68±10, p<0.03 vs OVX‐IH), while OVX‐PPT rats had the highest O 2 consumption (125±11 pmolO 2 /s/mg, p<0.0001 vs OVX‐IH and OVX‐RA). H 2 O 2 production measured by fluorometry with the substrates of complexes I+II and ADP is increased by exposure to IH compared to RA (3.2 ±0.4 vs 0.9±0.3 pmol H 2 O 2 /min/mg– p=0.002), and this is prevented by DPN and PPT (1.8 ±0.2 vs 1.6±0.2 pmol H 2 O 2 /min/mg). We conclude that in OVX female rats, IH impairs the mitochondrial respiratory chain through the complex I leading to an increase of ROS (H 2 O 2 ) production. Selective agonists of ERα and ERβ prevent the mitochondrial dysfunction. ERα appears more efficient to increase mitochondrial respiratory function in this model. This opens new perspectives for menopausal women suffering of sleep apnea. Support or Funding Information Founded by CIHR, Région Rhône alpes and consulat de France à Québec.