Juba Amber N, Keoseyan Petros P, Hamel Riley P, Margaryan Tigran, Barber Michaela L, Foley Amanda N, Jones T Bucky, Batinic-Haberle Ines, Tovmasyan Artak, Buhlman Lori M
Biomedical Sciences Program, Midwestern University, Glendale, AZ 85308, USA.
Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, USA.
Antioxidants (Basel). 2025 Aug 22;14(9):1031. doi: 10.3390/antiox14091031.
Oxidative stress and mitochondrial dysfunction are heavily implicated in all forms of Parkinson's disease; however, antioxidant administration has largely failed in clinical trials. Among the likely causes of failure are brain bioavailability and cellular redox state. We have administered two manganese porphyrin compounds with different bioavailability, MnTE-2-PyP and MnTnBuOE-2-PyP, to parkin-null food and found that the more bioavailable one, with higher brain and mitochondrial availability, MnTnBuOE-2-PyP, improves developmental deficits and motivated behavior in female flies. Using highly sensitive redox reporters, we further found that MnTnBuOE-2-PyP reduces hydrogen peroxide levels in mitochondria of dopaminergic neurons that are functionally homologous to the mammalian substantia nigra and facilitates motivated behavior in female flies. Interestingly, both compounds reduce an oxidative stress marker at the whole-brain level and extend lifespan in control flies. Neither compound improves lifespan in parkin-null flies. Thus, additional studies, changing the timing and/or dosage of compound administration, are warranted.
氧化应激和线粒体功能障碍与所有形式的帕金森病密切相关；然而，抗氧化剂在临床试验中大多失败了。失败的可能原因包括脑生物利用度和细胞氧化还原状态。我们给缺乏parkin基因的果蝇投喂了两种具有不同生物利用度的锰卟啉化合物，即MnTE-2-PyP和MnTnBuOE-2-PyP，发现生物利用度更高、脑和线粒体可用性更高的MnTnBuOE-2-PyP可改善雌性果蝇的发育缺陷和动机行为。使用高灵敏度的氧化还原报告基因，我们进一步发现MnTnBuOE-2-PyP可降低与哺乳动物黑质功能同源的多巴胺能神经元线粒体中的过氧化氢水平，并促进雌性果蝇的动机行为。有趣的是，这两种化合物都能降低全脑水平的氧化应激标志物，并延长对照果蝇的寿命。这两种化合物都不能提高缺乏parkin基因果蝇的寿命。因此，有必要进行更多研究，改变化合物给药的时间和/或剂量。
