Mitochondrial impairment and melatonin protection in parkinsonian mice do not depend of inducible or neuronal nitric oxide synthases

MPTP-mouse model constitutes a well-known model of neuroinflammation and mitochondrial failure occurring in Parkinson’s disease (PD). Although it has been extensively reported that nitric oxide (NO●) plays a key role in the pathogenesis of PD, the relative roles of nitric oxide synthase isoforms iNOS and nNOS in the nigrostriatal pathway remains, however, unclear. Here, the participation of iNOS/nNOS isoforms in the mitochondrial dysfunction was analyzed in iNOS and nNOS deficient mice. Our results showed that MPTP increased iNOS activity in substantia nigra and striatum, whereas it sharply reduced complex I activity and mitochondrial bioenergetics in all strains. In the presence of MPTP, mice lacking iNOS showed similar restricted mitochondrial function than wild type or mice lacking nNOS. These results suggest that iNOS-dependent elevated nitric oxide, a major pathological hallmark of neuroinflammation in PD, does not contribute to mitochondrial impairment. Therefore, neuroinflammation and mitochondrial dysregulation seem to act in parallel in the MPTP model of PD. Melatonin administration, with well-reported neuroprotective properties, counteracted these effects, preventing from the drastic changes in mitochondrial oxygen consumption, increased NOS activity and prevented reduced locomotor activity induced by MPTP. The protective effects of melatonin on mitochondria are also independent of its anti-inflammatory properties, but both effects are required for an effective anti-parkinsonian activity of the indoleamine as reported in this study.

MPTP小鼠模型（MPTP-mouse model）是帕金森病（Parkinson’s disease, PD）研究中经典的神经炎症（neuroinflammation）与线粒体功能衰竭（mitochondrial failure）造模体系。尽管已有大量研究证实一氧化氮（nitric oxide, NO·）在PD发病机制中扮演关键角色，但黑质纹状体通路（nigrostriatal pathway）内一氧化氮合酶（nitric oxide synthase, NOS）亚型iNOS与nNOS的相对作用仍未明确。本研究以iNOS与nNOS基因缺陷型小鼠为实验对象，分析了两类一氧化氮合酶亚型在线粒体功能障碍（mitochondrial dysfunction）中的参与情况。结果显示，MPTP可提升黑质（substantia nigra）与纹状体（striatum）中的iNOS活性，同时显著降低所有受试小鼠品系的复合物I（complex I）活性与线粒体生物能学（mitochondrial bioenergetics）水平。在MPTP造模条件下，iNOS基因缺陷小鼠的线粒体功能受限程度与野生型（wild type）小鼠或nNOS基因缺陷小鼠无显著差异。上述结果表明，作为PD神经炎症的核心病理标志，iNOS介导的一氧化氮升高并未参与线粒体损伤过程。因此，在PD的MPTP模型中，神经炎症与线粒体失调似乎以平行通路发挥调控作用。褪黑素（melatonin）已被证实具备明确的神经保护特性（neuroprotective properties），其给药可逆转上述异常效应，阻止MPTP诱导的线粒体耗氧量（mitochondrial oxygen consumption）剧烈变化、NOS活性升高以及运动活性（locomotor activity）下降。本研究同时发现，褪黑素对线粒体的保护作用与其抗炎活性相互独立，但二者均为该吲哚胺类物质（indoleamine）发挥高效抗帕金森活性（anti-parkinsonian activity）所必需。