NRSF is an essential mediator for the neuroprotection of trichostatin A in the MPTP mouse model of Parkinson's disease

Neuropharmacology. 2015 Dec;99:67-78. doi: 10.1016/j.neuropharm.2015.07.015. Epub 2015 Jul 15.

Abstract

Neuron-restrictive silencer factor (NRSF) blocks the expression of many neuronal genes in non-neuronal cells and neural stem cells. There is growing body of evidence that NRSF functions in mature neurons and plays critical roles in various neurological disorders. Our previous study demonstrated that the expression of NRSF target genes brain-derived neurotrophic factor (BDNF), and tyrosine hydroxylase (TH) is transiently decreased in 1-methyl-4-phenyl-pyridinium ion (MPP+)-treated SH-SY5Y cells. NRSF neuronal deficient mice are more vulnerable to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here we investigated the effect of epigenetic modulation on the expression of NRSF target genes in in vitro and in vivo models of Parkinson's disease (PD). Trichostatin A (TSA) was further used to study the effects of histone deacetylase inhibition on NRSF-mediated repression. We found that the repression of NRSF target genes was relieved by TSA in vitro. A single dose TSA pretreatment also upregulated the expression of TH and BDNF and protected the nigrostriatal dopaminergic pathway against MPTP-induced degeneration in wild type mice. However, the protective functions of TSA were fully abolished in NRSF neuronal deficient mice. Our results suggest that NRSF serves as an essential mediator for the neuroprotection of TSA in the MPTP model of PD.

Keywords: Epigenetic mechanisms; HDAC inhibitors; NRSF; Parkinson's disease; Target genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Cell Line, Tumor
  • Dopamine / metabolism
  • Drug Evaluation, Preclinical
  • Epigenesis, Genetic / drug effects
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Hydroxyindoleacetic Acid / metabolism
  • MPTP Poisoning / drug therapy*
  • MPTP Poisoning / physiopathology*
  • Male
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Neuroprotective Agents / pharmacology*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Serotonin / metabolism

Substances

  • Histones
  • Hydroxamic Acids
  • Neuroprotective Agents
  • RE1-silencing transcription factor
  • Repressor Proteins
  • 3,4-Dihydroxyphenylacetic Acid
  • Serotonin
  • trichostatin A
  • Hydroxyindoleacetic Acid
  • Dopamine