Lee Yujeong, Heo Gwangbeom, Lee Kyung Moon, Kim Ah Hyun, Chung Ki Wung, Im Eunok, Chung Hae Young, Lee Jaewon
Department of Pharmacy, College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 609-735, Republic of Korea.
Department of Pharmacy, College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 609-735, Republic of Korea.
Brain Res. 2017 May 15;1663:184-193. doi: 10.1016/j.brainres.2017.03.018. Epub 2017 Mar 18.
Neurons depend on mitochondria for homeostasis and survival, and thus, mitochondrial dysfunction has been implicated in neurodegenerative diseases, including Parkinson's disease (PD). Increasing evidence indicates the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), protects neurons against neurodegeneration and enhances neural plasticity. Here, the authors evaluated the protective effects of intraperitoneally (i.p.) administered low dose DNP in an acute mouse model of PD. Mice were administered DNP (1 or 5mg/kg) for 12 consecutive days, and then on day 13, MPTP (20mg/kg, i.p.) was administered four times (with 2h intervals between injections) to induce PD. It was found that MPTP-induced motor dysfunction was ameliorated in the DNP-treated mice versus vehicle-treated controls. Additionally, DNP effectively attenuated dopaminergic neuronal loss observed in MPTP treated mice. Moreover, in primary cultured neurons, DNP at 10μM, but not at 100μM, prevented MPP-induced cell death and mitochondrial membrane potential (MMP) reduction. In addition, DNP was observed to cause the nuclear translocation of Nrf2 in primary neurons. Taken together, these findings of the present study suggest that DNP protects dopaminergic neurons against neurodegeneration and maintains MMP integrity in PD by activating adaptive stress responses.
神经元的稳态和存活依赖于线粒体，因此，线粒体功能障碍与包括帕金森病（PD）在内的神经退行性疾病有关。越来越多的证据表明，线粒体解偶联剂2,4-二硝基苯酚（DNP）可保护神经元免受神经退行性变并增强神经可塑性。在此，作者评估了腹腔注射低剂量DNP在急性PD小鼠模型中的保护作用。小鼠连续12天腹腔注射DNP（1或5mg/kg），然后在第13天，腹腔注射MPTP（20mg/kg）4次（注射间隔2小时）以诱导PD。结果发现，与溶剂处理的对照组相比，DNP处理的小鼠中MPTP诱导的运动功能障碍得到改善。此外，DNP有效减轻了MPTP处理小鼠中观察到的多巴胺能神经元损失。此外，在原代培养的神经元中，10μM的DNP可预防MPP诱导的细胞死亡和线粒体膜电位（MMP）降低，但100μM的DNP则无此作用。另外，观察到DNP可导致原代神经元中Nrf2的核转位。综上所述，本研究的这些发现表明，DNP通过激活适应性应激反应来保护多巴胺能神经元免受神经退行性变，并维持PD中的MMP完整性。
