Oral uridine pro-drug PN401 is neuroprotective in the R6/2 and N171-82Q mouse models of Huntington's disease

Neurobiol Dis. 2006 Dec;24(3):455-65. doi: 10.1016/j.nbd.2006.08.011. Epub 2006 Sep 29.

Abstract

Previously, uridine pro-drug 2',3',5'-tri-O-acetyluridine (PN401) was shown to be protective in the mitochondrial complex II inhibitor 3-nitropropionic acid model of Huntington's disease (HD). In this study, PN401 increased survival and improved motor function on the rotarod in both R6/2 and N171-82Q polyglutamine repeat mouse models of HD. PN401 significantly decreased neurodegeneration in both the piriform cortex and striatum although PN401 decreased huntingtin protein aggregates only in the striatum. Cortical and striatal brain-derived neurotrophic factor (BDNF) protein levels were reduced in the +/- compared to the -/- N171-82Q mice and PN401 treatment significantly increased cortical BDNF in both +/- and -/- mice, but PN401 did not affect striatal BDNF. These results suggest that PN401 may have beneficial effects in the treatment of neurodegenerative diseases such as HD.

Publication types

  • Comparative Study

MeSH terms

  • Acetates
  • Administration, Oral
  • Analysis of Variance
  • Animals
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Disease Models, Animal
  • Female
  • Huntingtin Protein
  • Huntington Disease / drug therapy
  • Huntington Disease / mortality
  • Huntington Disease / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Neurologic Mutants
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Neostriatum / cytology
  • Neostriatum / drug effects
  • Neostriatum / metabolism
  • Nerve Degeneration / drug therapy
  • Nerve Degeneration / prevention & control*
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / metabolism
  • Neuroprotective Agents / pharmacology*
  • Nuclear Proteins / drug effects
  • Nuclear Proteins / metabolism
  • Prodrugs / pharmacology*
  • Rotarod Performance Test
  • Uridine / administration & dosage
  • Uridine / analogs & derivatives*
  • Uridine / pharmacology

Substances

  • Acetates
  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Nuclear Proteins
  • Prodrugs
  • uridine triacetate
  • Uridine