Laboratory of Neuroprotection and Neurometabolic Diseases, Department of Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, 90035-003 Porto Alegre, RS, Brazil.
Laboratory of Neuroprotection and Neurometabolic Diseases, Department of Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, 90035-003 Porto Alegre, RS, Brazil.
Prog Neuropsychopharmacol Biol Psychiatry. 2024 Aug 30;134:111057. doi: 10.1016/j.pnpbp.2024.111057. Epub 2024 Jun 14.
Methylphenidate (MPH) is a central nervous system stimulant drug and a first order prescription in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Although MPH biochemistry in neurodevelopment is not completely understood, studies showed it alters energy metabolism in rat brains. ADHD prevalence during neurodevelopment is related to males and the investigation has been mainly done in these subjects, therefore, little is known about MPH action in females and, consequently, about sexual dimorphism. In the present study we evaluated markers of mitochondrial dynamics (DRP1 and MFN2, fission and fusion, respectively), biogenesis (mtTFA) and bioenergetics (respiratory chain complexes) in prefrontal cortex of male and female juvenile rats submitted to exposure to MPH to better understand MPH effect during postnatal neurodevelopment. ATP and oxidative stress levels were also evaluated. Wistar rats received intraperitoneal injection of MPH (2.0 mg/kg) or control (saline), once a day, from 15th to 45th day of age. Results showed that MPH increased DRP1 and decreased MFN2, as well as increased mtTFA in prefrontal cortex of male rats. In female, MPH decreased NRF1 and increased Parkin, which are mitochondrial regulatory proteins. Respiratory chain complexes (complex I, SDH, complexes III and IV), ATP production and oxidative stress parameters were altered and shown to be sex-dependent. Taken together, results suggest that chronic MPH exposure at an early age in healthy animals changes mitochondrial dynamics, biogenesis and bioenergetics differently depending on the sex of the subjects.
哌醋甲酯（MPH）是一种中枢神经系统兴奋剂，是治疗注意力缺陷多动障碍（ADHD）的一线处方药。尽管 MPH 在神经发育中的生物化学作用尚未完全理解，但研究表明它会改变大鼠大脑的能量代谢。神经发育过程中 ADHD 的患病率与男性有关，而且研究主要在这些人群中进行，因此，对于女性中 MPH 的作用知之甚少，因此也不了解性别二态性。在本研究中，我们评估了线粒体动力学（DRP1 和 MFN2，分别代表分裂和融合）、生物发生（mtTFA）和生物能量学（呼吸链复合物）的标志物在雄性和雌性未成年大鼠前额叶皮层中的变化，这些大鼠接受 MPH 暴露，以更好地了解 MPH 在产后神经发育过程中的作用。还评估了 ATP 和氧化应激水平。Wistar 大鼠从第 15 天到第 45 天每天接受腹腔注射 MPH（2.0mg/kg）或对照（生理盐水）。结果表明，MPH 增加了雄性大鼠前额叶皮层中的 DRP1，减少了 MFN2，并增加了 mtTFA。在雌性中，MPH 减少了 NRF1 并增加了 Parkin，这是两种线粒体调节蛋白。呼吸链复合物（复合物 I、SDH、复合物 III 和 IV）、ATP 产生和氧化应激参数发生改变，且表现出性别依赖性。总之，结果表明，在健康动物中，早期慢性 MPH 暴露会根据研究对象的性别不同，改变线粒体动力学、生物发生和生物能量学。
