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, Yelamanchili Sowmya V, Pendyala Gurudutt
Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, NE, USA.
Department of Genetics, Cellular Biology, and Anatomy, UNMC, Omaha, NE, USA.
Mol Psychiatry. 2025 Jul 9. doi: 10.1038/s41380-025-03104-y.
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.
美国约十分之一的新生儿为早产儿(妊娠<37周),面临低出生体重、呼吸和出生缺陷等风险,常需手术、机械通气和长期镇静。这些婴儿长期接触镇静剂可能会带来神经发育风险,并可能进一步影响其日后生活中的变化。本研究聚焦于咪达唑仑(MDZ),这是一种常用于新生儿重症监护病房(NICU)的苯二氮䓬类药物。我们使用了一种强大的临床前啮齿动物模型来模拟慢性MDZ暴露,对这些暴露新生儿在关键发育里程碑中的表型、分子、生化和行为结果进行了全面表征。我们的研究结果表明,新生儿期长期暴露于MDZ会对幼儿期的身体特征产生负面影响。虽然对照组和MDZ暴露组大鼠成年后的体重相当,但MDZ组大鼠体重增加加速且明显,这可能表明存在暴饮暴食行为的倾向。此外,成年期MDZ暴露大鼠的多巴胺释放明显减少。成年期大脑中促炎细胞因子和生长因子水平升高表明,由于早期MDZ暴露,发育发生了改变。此外,与其他阶段相比,在青春期早期观察到焦虑样行为增加和社交互动减少的趋势。总体而言,我们的研究全面评估了新生儿期长期暴露于MDZ如何影响一生的结果,为理解导致新生儿长期使用MDZ相关神经发育并发症的机制奠定了基础。