Muscimol delays lipopolysaccharide-induced preterm delivery in mice: role of GABA_A receptors and nitric oxide

Abstract

Objectives: 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.

Keywords::

• Bicuculline
• LPS
• placental inflammation
• uterine contractility
• NOS

Acknowledgements

We wish to thank the reviewer of this article for his/her constructive comments.

Declaration of Interest: This study was supported by grant 9794 from the vice-chancellor for research of Tehran University of Medical Sciences.