Prostaglandin E2 EP1 receptor antagonist improves motor deficits and rescues memory decline in R6/1 mouse model of Huntington's disease

Mol Neurobiol. 2014 Apr;49(2):784-95. doi: 10.1007/s12035-013-8556-x. Epub 2013 Nov 7.

Abstract

In this study, we evaluated the potential beneficial effects of antagonizing prostaglandin E2 (PGE2) EP1 receptor on motor and memory deficits in Huntington's disease (HD). To this aim, we implanted an osmotic mini-pump system to chronically administrate an EP1 receptor antagonist (SC-51089) in the R6/1 mouse model of HD, from 13 to 18 weeks of age, and used different paradigms to assess motor and memory function. SC-51089 administration ameliorated motor coordination and balance dysfunction in R6/1 mice as analyzed by rotarod, balance beam, and vertical pole tasks. Long-term memory deficit was also rescued after EP1 receptor antagonism as assessed by the T-maze spontaneous alternation and the novel object recognition tests. Additionally, treatment with SC-51089 improved the expression of specific synaptic markers and reduced the number of huntingtin nuclear inclusions in the striatum and hippocampus of 18-week-old R6/1 mice. Moreover, electrophysiological studies showed that hippocampal long-term potentiation was significantly recovered in R6/1 mice after EP1 receptor antagonism. Altogether, these results show that the antagonism of PGE2 EP1 receptor has a strong therapeutic effect on R6/1 mice and point out a new therapeutic candidate to treat motor and memory deficits in HD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Huntington Disease / drug therapy
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Hydrazines / administration & dosage
  • Male
  • Memory Disorders / drug therapy
  • Memory Disorders / genetics
  • Memory Disorders / metabolism*
  • Mice
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Motor Skills Disorders / drug therapy
  • Motor Skills Disorders / genetics
  • Motor Skills Disorders / metabolism*
  • Oxazepines / administration & dosage
  • Receptors, Prostaglandin E, EP1 Subtype / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP1 Subtype / genetics
  • Receptors, Prostaglandin E, EP1 Subtype / metabolism*

Substances

  • Hydrazines
  • Oxazepines
  • Receptors, Prostaglandin E, EP1 Subtype
  • SC 51089