Vázquez-González Daniela, Corona Juan Carlos
Laboratory of Neurosciences, Hospital Infantil de México Federico Gómez, Mexico City, Mexico.
Front Neurosci. 2023 Jul 28;17:1186520. doi: 10.3389/fnins.2023.1186520. eCollection 2023.
The psychostimulant methylphenidate (MPH) is the first-line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), but has numerous adverse side effects. The PPARγ receptor agonist pioglitazone (PIO) is known to improve mitochondrial bioenergetics and antioxidant capacity, both of which may be deficient in ADHD, suggesting utility as an adjunct therapy. Here, we assessed the effects of PIO on ADHD-like symptoms, mitochondrial biogenesis and antioxidant pathways in multiple brain regions of neonate rats with unilateral striatal lesions induced by 6-hydroxydopamine (6-OHDA) as an experimental ADHD model. Unilateral striatal injection of 6-OHDA reduced ipsilateral dopaminergic innervation by 33% and increased locomotor activity. This locomotor hyperactivity was not altered by PIO treatment for 14 days. However, PIO increased the expression of proteins contributing to mitochondrial biogenesis in the striatum, hippocampus, cerebellum and prefrontal cortex of 6-OHDA-lesioned rats. In addition, PIO treatment enhanced the expression of the phase II transcription factor Nrf2 in the striatum, prefrontal cortex and cerebellum. In contrast, no change in the antioxidant enzyme catalase was observed in any of the brain regions analyzed. Thus, PIO may improve mitochondrial biogenesis and phase 2 detoxification in the ADHD brain. Further studies are required to determine if different dose regimens can exert more comprehensive therapeutic effects against ADHD neuropathology and behavior.
精神振奋剂哌醋甲酯（MPH）是治疗注意力缺陷多动障碍（ADHD）的一线药物，但有许多不良副作用。已知过氧化物酶体增殖物激活受体γ（PPARγ）激动剂吡格列酮（PIO）可改善线粒体生物能量学和抗氧化能力，而这两者在ADHD中可能都存在缺陷，提示其作为辅助治疗的效用。在此，我们以6-羟基多巴胺（6-OHDA）诱导单侧纹状体损伤的新生大鼠作为实验性ADHD模型，评估了PIO对其ADHD样症状、线粒体生物发生及抗氧化途径在多个脑区的影响。单侧纹状体注射6-OHDA使同侧多巴胺能神经支配减少33%，并增加了运动活性。这种运动性多动在接受14天PIO治疗后未发生改变。然而，PIO增加了6-OHDA损伤大鼠纹状体、海马体、小脑和前额叶皮质中线粒体生物发生相关蛋白的表达。此外，PIO治疗增强了纹状体、前额叶皮质和小脑中II期转录因子Nrf2的表达。相比之下，在所分析的任何脑区中均未观察到抗氧化酶过氧化氢酶的变化。因此，PIO可能改善ADHD大脑中的线粒体生物发生和II期解毒。需要进一步研究以确定不同剂量方案是否能对ADHD神经病理学和行为产生更全面的治疗效果。
