Comprehensive Characterization of Chronic Midazolam Exposure on Neonates and Long-Term Neurodevelopment

Authors

Nghi M. Nguyen, University of Nebraska Medical Center
Pranavi Athota, University of Nebraska Medical Center
Adrian Flores, University of Nebraska Medical CenterFollow
Andrew Trease, University of Nebraska Medical Center
Daniel Meyer, University of Nebraska Medical Center
Vamsi K. Singu, University of Nebraska Medical Center
Chandan Krishnamoorthy, University of Nebraska - Lincoln
Victoria L. Schaal, University of Nebraska Medical CenterFollow
Reeyan Bhakat, University of Nebraska Medical Center
Kunal Sualy, University of Nebraska Medical CenterFollow
Sathish Kumar Natarajan, Child Health Research Institute
Kelly L. Stauch, University of Nebraska Medical CenterFollow
Sowmya V. Yelamanchili, University of Nebraska Medical CenterFollow
Gurudutt Pendyala, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

Molecular Psychiatry

Publication Date

2025

Abstract

Approximately 1 in 10 U.S. newborns are born preterm (< 37 weeks of gestation), facing risks of low birth weight, respiratory and birth deficits often requiring surgery, mechanical ventilation, and prolonged sedation. Such long-term exposure to sedatives in these babies can potentially pose neurodevelopmental risks and can further impact changes later in life. The present study focused on midazolam (MDZ), a benzodiazepine class drug commonly used as sedative in the neonatal intensive care unit (NICU). Using a robust preclinical rodent model mimicking chronic MDZ exposure, we did a comprehensive characterization on the phenotypic, molecular, biochemical, and behavioral outcomes in these exposed neonates across key developmental milestones. Our findings indicate that long-term MDZ exposure during the neonatal period negatively affects physical attributes in early childhood. While adult bodyweights between control and MDZ-exposed rats remain comparable, the MDZ rats exhibit accelerated and robust weight gain, potentially indicating a predisposition for binge eating behavior. Additionally, dopamine release in MDZ-exposed rats is markedly reduced in adulthood. Elevated levels of pro-inflammatory cytokines and growth factors in the brain during adulthood suggest a shift in development due to early MDZ exposure. Further, trends of heightened anxiety-like behavior and reduced social interaction during early adolescence compared to other stages were observed. Collectively, our study provides a comprehensive assessment of how long-term MDZ exposure during neonatal stages impacts outcomes throughout life, laying the foundation for understanding mechanisms that contribute to neurodevelopmental complications associated with long-term MDZ use in neonates.

DOI Link

10.1038/s41380-025-03104-y

ISSN

1476-5578

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Recommended Citation

Nguyen, Nghi M.; Athota, Pranavi; Flores, Adrian; Trease, Andrew; Meyer, Daniel; Singu, Vamsi K.; Krishnamoorthy, Chandan; Schaal, Victoria L.; Bhakat, Reeyan; Sualy, Kunal; Natarajan, Sathish Kumar; Stauch, Kelly L.; Yelamanchili, Sowmya V.; and Pendyala, Gurudutt, "Comprehensive Characterization of Chronic Midazolam Exposure on Neonates and Long-Term Neurodevelopment" (2025). Journal Articles: Anesthesiology. 24.
https://digitalcommons.unmc.edu/com_anesth_articles/24