Muscimol delays lipopolysaccharide-induced preterm delivery in mice: role of GABA(A) receptors and nitric oxide.
OBJECTIVE
Immunologic processes are involved in preterm delivery (PTD). Considering the anti-inflammatory properties of muscimol (GABA(A) agonist), the effect of this drug was evaluated in lipopolysaccharide-induced PTD in mice.


METHODS
PTD was induced by two intraperitoneal injections of lipopolysaccharide (35 µg/kg; n = 11), on gestational day 15 (d15). Muscimol was administered twice on d14 and twice on d15 (1 h prior to each lipopolysaccharide injection; 0.05, 0.1, 0.2 mg/kg; intraperitoneally; n = 8-12). To assess the involved mechanisms, either bicuculline (GABA(A) antagonist; 0.1 and 1 µg/kg; intraperitoneally; n = 6-7) or N(ω)-nitro-l-arginine methyl ester (l-NAME; non-selective inhibitor of nitric oxide (NO) synthase enzymes; 2 mg/kg; intraperitoneally; n = 6) were administered 1 h before each muscimol administration on d14 and the first dose of muscimol on d15. Maternal plasma and amniotic fluid nitrite + nitrate levels, placental histopathologies and uterine contractions were assessed.


RESULTS
Muscimol (0.1 mg/kg) significantly decreased lipopolysaccharide-induced PTD rates from 100 to 50% and delayed delivery time from d16 to d18. Muscimol moderately increased maternal plasma and amniotic fluid nitrite + nitrate concentrations and decreased lipopolysaccharide-induced placental inflammation and surge in nitrite + nitrate levels. Contrary to bicuculline, l-NAME reversed the beneficial effects of muscimol. Muscimol did not affect myometrial contractions.


CONCLUSIONS
Muscimol inhibits lipopolysaccharide-induced PTD through modulating NO release.
Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran.
Mohammad Hadi
MH
Gharedaghi
Mehrak
M
Javadi-Paydar
Yashar
Y
Yousefzadeh-Fard
Mohammad
M
Salehi-Sadaghiani
Pouya
P
Javadian
Nahid
N
Fakhraei
Seyed Mohammad
SM
Tavangar
Ahmad Reza
AR
Dehpour
D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D001640:Bicuculline; D004195:Disease Models, Animal; D005260:Female; D058785:GABA-A Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D058787:GABA-A Receptor Antagonists; D008070:Lipopolysaccharides; D051379:Mice; D009118:Muscimol / Q000494:pharmacology / Q000627:therapeutic use*; D019331:NG-Nitroarginine Methyl Ester; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D010920:Placenta / Q000473:pathology; D011247:Pregnancy; D047928:Premature Birth / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011963:Receptors, GABA-A / Q000378:metabolism*; D014590:Uterine Contraction / Q000187:drug effects
D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D011963:Receptors, GABA-A; D009118:Muscimol; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester; D001640:Bicuculline