Kutan Başçı Ayşe Reyyan, Arslan-Ergül Ayça
Bilkent University National Nanotechnology Research Center (UNAM), Ankara, Türkiye; Bilkent University, Materials Science and Nanotechnology, Ankara, Türkiye.
Bilkent University National Nanotechnology Research Center (UNAM), Ankara, Türkiye.
Physiol Behav. 2025 Oct 15;300:115027. doi: 10.1016/j.physbeh.2025.115027. Epub 2025 Jul 8.
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent condition characterized by persistent inattention, hyperactivity, and impulsivity, often leading to significant impairments in daily functioning. Numerous medications have been developed to manage ADHD, with methylphenidate (commonly known as Ritalin or Concerta) being the most widely used active compound. While methylphenidate (MPH) effectively improves attention, focus, and emotional regulation, its long-term use can lead to behavioral issues such as increased vigilance-stress response and anxiety, as well as physical side effects like sleep disturbances and decreased sensitivity to rewards. These side effects are more challenging to compensate for in adults compared to children, which may leave permanent effects. This study aims to investigate the long-term effects of MPH use in adult women, with a focus on its role in sleep disorders, circadian rhythm disruption, and the potential implications for pregnancy, specifically on the susceptibility of offspring to accelerated brain aging. Our hypothesis is that MPH use during pregnancy may contribute to changes in offspring telomere length and gene methylation patterns associated with brain aging, thereby increasing their vulnerability to neurodegeneration. To evaluate this, telomere length and methylation analyses were conducted on genes linked to brain aging in the second-generation offspring. Additionally, our hypothesis is that therapeutic interventions, such as melatonin for regulating sleep disturbances and oxytocin as an alternative to mitigate MPH's side effects, may have protective effects. Zebrafish were used as the model organism in this study due to their high genetic similarity to humans and their ease of egg production, enabling multi-generational studies. As a result of this study, it was determined that neuroinflammation caused by circadian rhythm disruption and maternal stress due to MPH accumulation was reduced through melatonin & MPH and oxytocin & MPH combinational treatments. In the offspring of the next generation, it was observed that the telomere length inherited at birth was shorter when treated with MPH only. Also, methylation in the FOXM1 is observed in MPH-only treatment group, and compensated with combinational treatments for melatonin and oxytocin.
注意力缺陷多动障碍（ADHD）是一种常见病症，其特征为持续的注意力不集中、多动和冲动，常导致日常功能出现显著损害。已研发出多种药物来治疗ADHD，其中哌甲酯（通常称为利他林或康奈达）是使用最广泛的活性化合物。虽然哌甲酯（MPH）能有效改善注意力、专注力和情绪调节，但长期使用会导致行为问题，如警惕性 - 应激反应增加和焦虑，以及身体副作用，如睡眠障碍和对奖励的敏感性降低。与儿童相比，这些副作用在成年人中更难补偿，可能会留下永久性影响。本研究旨在调查成年女性使用MPH的长期影响，重点关注其在睡眠障碍、昼夜节律紊乱中的作用以及对怀孕的潜在影响，特别是对后代加速脑老化易感性的影响。我们的假设是，孕期使用MPH可能会导致后代端粒长度和与脑老化相关的基因甲基化模式发生变化，从而增加其患神经退行性变的易感性。为评估这一点，对第二代后代中与脑老化相关的基因进行了端粒长度和甲基化分析。此外，我们的假设是，治疗干预措施，如用于调节睡眠障碍的褪黑素和作为减轻MPH副作用替代品的催产素，可能具有保护作用。由于斑马鱼与人类具有高度的遗传相似性且易于产卵，能够进行多代研究，因此在本研究中被用作模式生物。这项研究的结果表明，通过褪黑素与MPH以及催产素与MPH的联合治疗，可减少因昼夜节律紊乱和MPH积累导致的母体应激所引起的神经炎症。在下一代后代中，观察到仅用MPH治疗时，出生时遗传的端粒长度较短。此外，在仅用MPH治疗组中观察到FOXM1基因存在甲基化现象，而褪黑素和催产素联合治疗可对此进行补偿。
