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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
The MNRR1 activator nitazoxanide abrogates lipopolysaccharide-induced preterm birth in mice
Neeraja Purandare1, Nardhy Gomez-Lopez2, Marcia Arenas-Hernandez3
1Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD 20892, USA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
Abstract:
Intra-amniotic inflammation leading to preterm birth is one of the leading causes of neonatal morbidity and mortality. We recently reported that the mitochondrial levels of MNRR1 (Mitochondrial Nuclear Retrograde, Regulator 1; also called CHCHD2, AAG10, or PARK22), an important bi-organellar regulator of cellular function, are reduced in the context of inflammation and that genetic and pharmacological increases in MNRR1 levels can counter the inflammatory profile. Herein, we show that nitazoxanide, a clinically approved drug, is an activator of MNRR1 and abrogates preterm birth in a well-characterized murine model caused by intra-amniotic lipopolysaccharide (LPS) injection.
Insights
Nitazoxanide activates MNRR1, a key regulator of cellular function. This drug effectively prevents preterm birth in a mouse model of intra-amniotic inflammation, offering a potential therapeutic strategy.
Area of Science:
- Obstetrics and Gynecology
- Cellular Biology
- Pharmacology
Background:
- Intra-amniotic inflammation is a primary cause of preterm birth, leading to significant neonatal morbidity and mortality.
- Mitochondrial Nuclear Retrograde, Regulator 1 (MNRR1) levels decrease during inflammation, impacting cellular function.
- Previous research indicated that increasing MNRR1 levels can counteract inflammatory responses.
Purpose of the Study:
- To investigate nitazoxanide as a potential therapeutic agent for preterm birth.
- To determine if nitazoxanide activates MNRR1 and mitigates inflammation-induced preterm birth.
Main Methods:
- Utilized a well-established murine model of preterm birth induced by intra-amniotic lipopolysaccharide (LPS) injection.
- Assessed the effect of nitazoxanide on MNRR1 activation and preterm birth rates.
Main Results:
- Nitazoxanide was identified as an activator of MNRR1.
- Administration of nitazoxanide abrogated preterm birth in the LPS-induced murine model.
- The drug's action is linked to its ability to modulate MNRR1 activity.
Conclusions:
- Nitazoxanide demonstrates efficacy in preventing preterm birth in an experimental model.
- Targeting MNRR1 with nitazoxanide represents a promising therapeutic avenue for managing intra-amniotic inflammation and preventing preterm birth.
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