Melatonin preserves fetal growth in rats by protecting against ischemia/reperfusion-induced oxidative/nitrosative mitochondrial damage in the placenta.
We have previously demonstrated that melatonin protects against ischemia/reperfusion-induced oxidative damage to mitochondria in the fetal rat brain. The purpose of the present study was to evaluate the effects of maternally administered melatonin on ischemia/reperfusion-induced oxidative placental damage and fetal growth restriction in rats. The utero-ovarian arteries were occluded bilaterally for 30 min in rats on day 16 of pregnancy to induce fetal ischemia. Reperfusion was achieved by releasing the occlusion and restoring circulation. Melatonin solution (20 microg/mL) or the vehicle alone was administered orally during pregnancy. A sham operation was performed in control rats, which were treated with vehicle alone. Laparotomy was performed on day 20 of pregnancy and the number and weight of fetal rats and placentas were measured. Placental mitochondrial respiratory control index (RCI), a marker of mitochondrial respiratory activity, was also calculated for each group. Using immunohistochemistry, we investigated the degree of immunostaining of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and redox factor-1(ref-1), which repairs DNA damage and acts as a redox-modifying factor in rat placenta. Predictably, the ischemia/reperfusion operation significantly decreased the weight of fetal rats and placentas and the RCI. Melatonin prevented ischemia/reperfusion-induced changes in RCI (1.55 +/- 0.05 to 1.83 +/- 0.09, P < 0.05) and fetal growth (3.04 +/- 0.17 to 3.90 +/- 0.1, P < 0.0001). Immunohistochemistry revealed significant positive staining for 8-OHdG and ref-1 following ischemia/reperfusion; these effects were also reduced by melatonin treatment. Results indicated that ischemia/reperfusion-induced oxidative placental DNA and mitochondrial damage and fetal growth restriction can be prevented by maternally administered melatonin.
Nagai
Ryuhei
R
Department of Obstetrics and Gynecology, Kochi Medical School, Kochi, Japan.
Watanabe
Kazushi
K
Wakatsuki
Akihiko
A
Hamada
Fumiaki
F
Shinohara
Koichi
K
Hayashi
Yoshihiro
Y
Imamura
Rina
R
Fukaya
Takao
T
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D004249:DNA Damage; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D003849:Deoxyguanosine / Q000031:analogs & derivatives; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005317:Fetal Growth Retardation; D007150:Immunohistochemistry; D008550:Melatonin / Q000627:therapeutic use*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D015538:Nitrosation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011247:Pregnancy; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000517:prevention & control
D000080242:8-Hydroxy-2'-Deoxyguanosine; C470319:Apex1 protein, rat; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D003849:Deoxyguanosine; D008550:Melatonin