Comprehensive characterization of chronic midazolam exposure on neonates and long-term neurodevelopment

IF 10.1 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nghi M. Nguyen, Pranavi Athota, Adrian Flores, Andrew Trease, Daniel Meyer, Vamsi K. Singu, Chandan Krishnamoorthy, Victoria L. Schaal, Reeyan Bhakat, Kunal Sualy, Sathish Kumar Natarajan, Kelly Stauch, Sowmya V. Yelamanchili, Gurudutt Pendyala
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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.

Abstract Image

慢性咪达唑仑暴露对新生儿和长期神经发育的综合表征
大约十分之一的美国新生儿是早产(妊娠37周),面临低出生体重、呼吸和出生缺陷的风险,通常需要手术、机械通气和长时间镇静。这些婴儿长期接触镇静剂可能会造成神经发育风险,并可能进一步影响以后生活的变化。本研究的重点是咪达唑仑(MDZ),一种苯二氮卓类药物,通常用作新生儿重症监护病房(NICU)的镇静剂。利用模拟慢性MDZ暴露的强大的临床前啮齿动物模型,我们对这些暴露于关键发育里程碑的新生儿的表型,分子,生化和行为结果进行了全面的表征。我们的研究结果表明,在新生儿时期长期暴露于MDZ会对儿童早期的身体特征产生负面影响。虽然对照组和暴露于MDZ的大鼠的成年体重保持相当,但MDZ大鼠表现出加速和强劲的体重增加,这可能表明它们有暴食行为的倾向。此外,暴露于mdz的大鼠在成年期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,由于早期接触MDZ,发育发生了变化。此外,与其他阶段相比,观察到青春期早期的焦虑行为加剧和社会互动减少的趋势。总的来说,我们的研究提供了一个全面的评估,新生儿阶段长期暴露于MDZ如何影响一生的结果,为理解与长期使用MDZ相关的新生儿神经发育并发症的机制奠定了基础。
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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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