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

PLoS One. 2017 Aug 11;12(8):e0183090. doi: 10.1371/journal.pone.0183090. eCollection 2017.

Abstract

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.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Animals
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Gene Expression Regulation
  • Male
  • Melatonin / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type I / deficiency
  • Nitric Oxide Synthase Type I / genetics*
  • Nitric Oxide Synthase Type II / deficiency
  • Nitric Oxide Synthase Type II / genetics*
  • Oxygen Consumption / drug effects
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / drug therapy*
  • Parkinson Disease, Secondary / genetics
  • Parkinson Disease, Secondary / pathology
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology

Substances

  • Neuroprotective Agents
  • Nitric Oxide
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • Nos1 protein, mouse
  • Nos2 protein, mouse
  • Melatonin

Grants and funding

This study was partially supported from the Instituto de Salud Carlos III (Ministerio de Economía y Competitividad and Fondos Feder, Spain, http://www.isciii.es) grants no. RD12/0043/0005; PI08-1664; PI13-00981; CB16-10-00238, and from the Consejería de Economía y Conocimiento (Junta de Andalucía, Spain, http://www.juntadeandalucia.es/organismos/economiayconocimiento/areas/investigacion-desarrollo.html) grants no. P07-CTS-03135, P10-CTS-5784, and CTS-101. MED-C is a PhD student supported by the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía, Spain. LCL is supported by the “Ramón y Cajal” National Program (Ministerio de Economía y Competitividad, Spain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.