Universidade Federal de Santa Maria, Centro de Ciências Naturais e Exatas, Departamento de Bioquímica e Biologia Molecular, Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Camobi, 97105-900, Santa Maria, RS, Brazil.
Universidade Federal de Santa Maria, Centro de Ciências Naturais e Exatas, Departamento de Bioquímica e Biologia Molecular, Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Camobi, 97105-900, Santa Maria, RS, Brazil; Universidade Federal do Pampa - Campus Caçapava do Sul, 96570-000, Caçapava do Sul, RS, Brazil.
Neurotoxicology. 2019 Jan;70:1-11. doi: 10.1016/j.neuro.2018.10.005. Epub 2018 Oct 22.
Mitochondrial dysfunction has been demonstrated to have a central role in Parkinson Disease (PD) pathophysiology. Some studies have indicated that PD causes an impairment in mitochondrial bioenergetics; however, the effects of PD on brain-region specific bioenergetics was never investigated before. This study aimed to evaluate mitochondrial bioenergetics in different rat brain structures in an in vitro model of PD using 6-OHDA. Rat brain slices of hippocampus, striatum, and cortex were exposed to 6-OHDA (100 μM) for 1 h and mitochondrial bioenergetic parameters, peroxide production, lactate dehydrogenase (LDH) and citrate synthase (CS) activities were analyzed. Hippocampus slices exposed to 6-OHDA presented increased peroxide production but, no mitochondrial adaptive response against 6-OHDA damage. Cortex slices exposed to 6-OHDA presented increased oxygen flux related to oxidative phosphorylation and energetic pathways exchange demonstrated by the increase in LDH activity, suggesting a mitochondrial compensatory response. Striatum slices exposed to 6-OHDA presented a decrease of oxidative phosphorylation and decrease of oxygen flux related to ATP-synthase indicating an impairment in the respiratory chain. The co-incubation of 6-OHDA with n-acetylcysteine (NAC) abolished the effects of 6-OHDA on mitochondrial function in all brain regions tested, indicating that the increased reactive oxygen species (ROS) production is responsible for the alterations observed in mitochondrial bioenergetics. The present results indicate a brain-region specific response against 6-OHDA, providing new insights into brain mitochondrial bioenergetic function in PD. These findings may contribute to the development of future therapies with a target on energy metabolism.
线粒体功能障碍在帕金森病 (PD) 病理生理学中起着核心作用。一些研究表明 PD 导致线粒体生物能学受损；然而，PD 对大脑区域特定生物能学的影响以前从未被研究过。本研究旨在使用 6-OHDA 在 PD 的体外模型中评估不同大鼠脑结构的线粒体生物能学。将海马、纹状体和皮质的大鼠脑切片暴露于 6-OHDA（100 μM）1 小时，分析线粒体生物能学参数、过氧化物产生、乳酸脱氢酶 (LDH) 和柠檬酸合酶 (CS) 活性。暴露于 6-OHDA 的海马切片过氧化物产生增加，但没有针对 6-OHDA 损伤的线粒体适应性反应。暴露于 6-OHDA 的皮质切片表现出与氧化磷酸化相关的氧通量增加和能量途径交换的增加，这表现为 LDH 活性的增加，表明存在线粒体补偿反应。暴露于 6-OHDA 的纹状体切片表现出氧化磷酸化减少和与 ATP 合酶相关的氧通量减少，表明呼吸链受损。6-OHDA 与 N-乙酰半胱氨酸 (NAC) 共孵育消除了 6-OHDA 对所有测试脑区线粒体功能的影响，表明增加的活性氧 (ROS) 产生是导致线粒体生物能学改变的原因。这些结果表明，大脑区域对 6-OHDA 有特定的反应，为 PD 中大脑线粒体生物能学功能提供了新的见解。这些发现可能有助于开发针对能量代谢的未来治疗方法。
