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Prostaglandin E2 EP1 Receptor Antagonist Improves Motor Deficits and Rescues Memory Decline in R6/1 Mouse Model of Huntington's Disease

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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.

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Acknowledgments

We are very grateful to Ana Lopez and Maria Teresa Muñoz for technical assistance and to Dr Teresa Rodrigo, Amèrica Jiménez, and the staff of the animal care facility (Facultat de Psicologia and Facultat de Medicina, Universitat de Barcelona) for their help. We thank members of our laboratory for helpful discussion. Financial support was obtained from Ministerio de Economía y Competitividad (SAF2011-29507 and BFU2011-26339), Instituto de Salud Carlos III (PI10/01072), RETICS (CIBERNED, R006/0010/0006), Junta de Comunidades de Castilla-La Mancha, JCCM (PEII10-0095-8727), Generalitat de Catalunya (2009SGR-00326), and INCRECyT project from European Social Fund and JCCM to E.D.M.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, C/ Casanova, 143, 08036, Barcelona, Spain

    Marta Anglada-Huguet, Xavier Xifró, Albert Giralt & Jordi Alberch

  2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

    Marta Anglada-Huguet, Xavier Xifró, Albert Giralt & Jordi Alberch

  3. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Marta Anglada-Huguet, Xavier Xifró, Albert Giralt & Jordi Alberch

  4. Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, Girona, Spain

    Xavier Xifró

  5. Laboratory of Neurophysiology and Synaptic Plasticity, Albacete Science and Technology Park (PCYTA). Institute for Research in Neurological Disabilities (IDINE), University of Castilla-La Mancha, Albacete, Spain

    Alfonsa Zamora-Moratalla & Eduardo D Martín

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  1. Marta Anglada-Huguet
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  2. Xavier Xifró
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  5. Eduardo D Martín
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  6. Jordi Alberch
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Corresponding author

Correspondence to Jordi Alberch.

Electronic supplementary material

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Online Resource 1

Chronic treatment with SC-51089 in R6/1 mice decreases deficits in motor coordination and balance. At 13 weeks of age, WT and R6/1 mice were treated with SC-51089 (SC; 40 μg/kg/day) or vehicle (discontinuous vertical line). The balance beam task was performed weekly from 13 to 18 weeks of age. The following measurements were recorded: a the mean speed; b the time taken to cross the beam; and c the number of slips. Values are expressed as a mean ± SEM (n = 13 for vehicle and SC-51089-treated WT mice; n = 11 for vehicle-treated R6/1 mice; n = 10 for SC-51089-treated R6/1 mice). Data were analyzed by two-way ANOVA. ***p < 0.001 as compared to WT vehicle-treated mice; $$$ p < 0.001, $$ p < 0.01, and $ p < 0.05, as compared to R6/1 vehicle-treated mice (PDF 85 kb)

Online Resource 2

No changes in anxiety or motivation in R6/1 SC-51089-treated mice. Table showing the covered distance expressed in centimeters (in centimeter) and the percentage of time spent in the center of the open field arena in R6/1 treated with vehicle or SC-51089. Results are expressed as mean ± SEM (n = 13 for vehicle and SC-51089-treated WT mice; n = 11 for vehicle-treated R6/1 mice; n = 10 for SC-51089-treated R6/1 mice) and were analyzed by Student's t test. No significant differences were observed between groups (PDF 63 kb)

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Anglada-Huguet, M., Xifró, X., Giralt, A. et al. Prostaglandin E2 EP1 Receptor Antagonist Improves Motor Deficits and Rescues Memory Decline in R6/1 Mouse Model of Huntington's Disease. Mol Neurobiol 49, 784–795 (2014). https://doi.org/10.1007/s12035-013-8556-x

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