The Phosphodiesterase Inhibitor, Ibudilast, Attenuates Neuroinflammation in the MPTP Model of Parkinson's Disease

PLoS One. 2017 Jul 28;12(7):e0182019. doi: 10.1371/journal.pone.0182019. eCollection 2017.

Abstract

Background/aims: Since the degeneration of the nigrostriatal dopaminergic pathway in Parkinson's disease (PD) is associated with the inflammation process and decreased levels of cyclic nucleotides, inhibition of up-regulated cyclic nucleotide phosphodiesterases (PDEs) appears to be a promising therapeutic strategy. We used ibudilast (IBD), a non-selective PDE3,4,10,11 inhibitor, due to the abundant PDE 4 and 10 expression in the striatum. The present study for the first time examined the efficacy of IBD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.

Methods: IBD [0, 20, 30, 40, or 50 mg/kg] was injected b.i.d. subcutaneously for nine days to three-month-old male C57Bl/10Tar mice, beginning two days prior to MPTP (60 mg/kg) intoxication. High-pressure liquid chromatography, Western blot analysis, and real time RT-PCR methods were applied.

Results: Our study demonstrated that chronic administration of IBD attenuated astroglial reactivity and increased glial cell-derived neurotrophic factor (GDNF) production in the striatum. Moreover, IBD reduced TNF-α, IL-6, and IL-1β expression.

Conclusion: IBD had a well-defined effect on astroglial activation in the mouse model of PD; however, there was no protective effect in the acute phase of injury. Diminished inflammation and an increased level of GDNF may provide a better outcome in the later stages of neurodegeneration.

MeSH terms

  • Animals
  • Astrocytes / drug effects*
  • Astrocytes / metabolism
  • Disease Models, Animal
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • MPTP Poisoning / drug therapy*
  • MPTP Poisoning / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / etiology
  • Parkinson Disease / metabolism
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphodiesterase Inhibitors / therapeutic use
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Glial Cell Line-Derived Neurotrophic Factor
  • Interleukin-1beta
  • Interleukin-6
  • Neuroprotective Agents
  • Phosphodiesterase Inhibitors
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • ibudilast

Grant support

This research subject was supported by the CePT infrastructure, financed by the European Union - the European Regional Development Fund within the Operational Programme “Innovative economy” for 2007-2013. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.