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Mitochondrial‐targeted antioxidant drugsas therapeutically tools for apnea of prematurity: intermittent hypoxia and sex dimorphism
Author(s) -
Soliz Jorge,
Arias Christian,
Marcouiller François,
Laouafa Sofien,
Bairam Aida,
Joseph Vincent
Publication year - 2019
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.2019.33.1_supplement.732.1
Subject(s) - oxidative stress , apnea , intermittent hypoxia , mitochondrion , hypoxia (environmental) , hypoxemia , reactive oxygen species , medicine , endocrinology , respiration , mitochondrial ros , respiratory system , respiratory center , biology , anesthesia , chemistry , oxygen , obstructive sleep apnea , anatomy , biochemistry , organic chemistry
Immaturity of the brainstem network system that controls breathing leads to apnea of prematurity (AoP). While AoP is a developmental (and thus self‐resolving) disorder, it is not the apnea but the associated decrease of arterial oxygen levels (Intermittent Hypoxemia ‐ IH) what is detrimental for neural maturation. IH induces mitochondrial dysfunction, increased production of reactive oxygen species (ROS), and oxidative stress, thus promoting higher breathing instability, delayed neural maturation and prolonged hospitalization. We hypothesized that the mitochondrial‐targeted antioxidant drug MitoTEMPO, by restoring mitochondrial dysfunction, protects newborns against the consequences of IH induced by AoP. Moreover, keeping in mind that male sex is an important risk factor for several respiratory diseases in preterm neonates experiments were performed in male and female newborn rats exposed to IH during postnatal days (P) 3–10. During this time, animals were daily injected (i.p.) with vehicle or MitoTEMPO (10–12 pups/group). At P10 the frequency of apneas at rest were measured (as an index of respiratory dysfunction) by plethysmography. Next, the cortex tissue was collected, and a high‐resolution Oxygraph‐2k was used to evaluate the mitochondrial bioenergetics and ROS (H 2 O 2 ) production using saponin‐permeabilized tissue punches of 1.5–3 mg weight. Our preliminary results obtained in male animals showed that mitoTEMPO: 1) restored the IH‐mediated increase of apneic events, 2) restored the IH‐mediated decrease of mitochondrial respiration of complex I (NADH‐linked respiration), and complex II (FADH2‐linked respiration), and 3) decreased the IH‐mediated increase of mitochondrial H 2 O 2 . Surprisingly, no impact of IH and/or the treatment with mitoTEMPO was observed in female animals. We conclude that neonatal IH leads to respiratory disturbances in male animals only. Moreover, our results suggest that antioxidant drugs may be used as new therapeutical tools for apnea of prematurity in males. Support or Funding Information Jorge Soliz is funded by the Canadian Institutes of Health Research (CIHR – Catalyst grant sex as a variable in biomedical research‐IC118777). The salary of Jorge Soliz is supported by Laval University. The Canadian Foundation for Innovations (FCI – 32986) supported the acquisition of state‐of‐the art equipment in Jorge Soliz lab. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .