TY  - JOUR
AU  - Anglada-Huguet, Marta
AU  - Vidal-Sancho, Laura
AU  - Giralt, Albert
AU  - García-Díaz Barriga, Gerardo
AU  - Xifró, Xavier
AU  - Alberch, Jordi
TI  - Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington's disease by the induction of BDNF-dependent synaptic plasticity.
JO  - Neurobiology of disease
VL  - 95
SN  - 0969-9961
CY  - Orlando, Fla.
PB  - Academic Press
M1  - DZNE-2020-05091
SP  - 22-34
PY  - 2016
AB  - Huntington's disease (HD) patients and mouse models show learning and memory impairment even before the onset of motor symptoms. Deficits in hippocampal synaptic plasticity have been involved in the HD memory impairment. Several studies show that prostaglandin E2 (PGE2) EP2 receptor stimulates synaptic plasticity and memory formation. However, this role was not explored in neurodegenerative diseases. Here, we investigated the capacity of PGE2 EP2 receptor to promote synaptic plasticity and memory improvements in a model of HD, the R6/1 mice, by administration of the agonist misoprostol. We found that misoprostol increases dendritic branching in cultured hippocampal neurons in a brain-derived neurotrophic factor (BDNF)-dependent manner. Then, we implanted an osmotic mini-pump system to chronically administrate misoprostol to R6/1 mice from 14 to 18weeks of age. We observed that misoprostol treatment ameliorates the R6/1 long-term memory deficits as analyzed by the T-maze spontaneous alternation task and the novel object recognition test. Importantly, administration of misoprostol promoted the expression of hippocampal BDNF. Moreover, the treatment with misoprostol in R6/1 mice blocked the reduction in the number of PSD-95 and VGluT-1 positive particles observed in hippocampus of vehicle-R6/1 mice. In addition, we observed an increase of cAMP levels in the dentate ` of WT and R6/1 mice treated with misoprostol. Accordingly, we showed a reduction in the number of mutant huntingtin nuclear inclusions in the dentate gyrus of R6/1 mice. Altogether, these results suggest a putative therapeutic effect of PGE2 EP2 receptor in reducing cognitive deficits in HD.
KW  - Animals
KW  - Brain-Derived Neurotrophic Factor: metabolism
KW  - Cognition Disorders: metabolism
KW  - Dinoprostone: metabolism
KW  - Disease Models, Animal
KW  - Hippocampus: metabolism
KW  - Huntington Disease: metabolism
KW  - Huntington Disease: physiopathology
KW  - Memory: physiology
KW  - Memory Disorders: drug therapy
KW  - Memory Disorders: physiopathology
KW  - Mice, Transgenic
KW  - Neuronal Plasticity: physiology
KW  - Receptors, Prostaglandin E, EP2 Subtype: metabolism
KW  - Brain-Derived Neurotrophic Factor (NLM Chemicals)
KW  - Receptors, Prostaglandin E, EP2 Subtype (NLM Chemicals)
KW  - Dinoprostone (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26369879
DO  - DOI:10.1016/j.nbd.2015.09.001
UR  - https://pub.dzne.de/record/138769
ER  -