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

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.

Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

“…Moreover, using a mouse model of cerebral ischemia and Alzheimer’s disease, we have shown that EP1 receptor blockade could be beneficial for treatment of both conditions [33]. In addition, recent data from another group indicate that the EP1 receptor antagonist used in our study demonstrated strong a therapeutic effect of repeated treatments with SC-51089 (40 µg/kg) in a murine model of Huntington’s disease and pointed out this compound as a new therapeutic candidate for motor and cognitive deficits characteristic for this and other neurodegenerative disorders [40]. Our previous preclinical data also suggested potential therapeutic applications of the antagonists of prostaglandin F 2α FP receptor, which exerts Ca 2+ -modulating effects similar to the EP1 receptor in ischemic stroke and TBI, and these data indicate that despite considerable differences between the mechanisms of primary injury in these models, beneficial effects were obtained with similar treatment regimens [18], [20], [21].…”

“…To overcome the possibility of nonoptimal timing or low dose due to lack of the pharmacokinetic and bioavailability data, in this study, all TBI outcomes measured in WT mice were compared with those obtained in EP1 −/− mice, and all drug treatment experiments performed in WT mice were replicated in EP −/− mice. The lack of effects of the EP1 receptor pharmacological blockade or knockout on either neurobehavioral and anatomical outcomes or Iba1 and GFAP immunohistochemistry in our in vivo CCI model of TBI, which is in contrast with the neuroprotective effects observed in the related in vitro studies [18], [34] and the in vivo models of ischemia and excitotoxicity [19], [22], [23], [40], suggests that involvement of other cell types expressing the EP1 receptor contribute considerably to the brain pathology following TBI. Our data is consistent in part with a report demonstrating a lack of the protective effects of pretreatment with EP1 receptor inhibition in a model of blade incisions leading to localized surgical brain extraction followed by electrocautery by Dr. J. H. Zhang’s group [25].…”

“…Because of encouraging results from preclinical studies from various teams, including ours, effort have been made to investigate the effects of EP1 receptor inhibitors in preclinical models of several other neurological and neurodegenerative conditions, including epilepsy [38], [39], acute surgical brain injury [25], hemorrhagic stroke [24], and Huntington [40] and Alzheimer’s [33] diseases. However, our recent mouse study indicates that the EP1 receptor would be involved in neuroprotective pathways following ICH [24], suggesting that the role of the EP1 receptor in brain injuries is complex.…”

“…We used the treatment regimen for this compound from an aforementioned study showing beneficial effect, and based on the similarity of the effect of the inhibitor of the related FP receptor in stroke and TBI [17], [20], [21]. The similar relative effect of SC-51089 on behavioral and anatomical outcomes of experimental stroke and excitotoxicity compared to controls [19], [23], [31], [40] was observed in the study with another EP1 receptor antagonist, ONO-8713, in similar experimental conditions [32], and these outcomes were comparable to the outcomes measured in the EP1 −/− mice with and without drug treatment, suggesting appropriate SC-51089 bioavailability with the treatment regimen used in this study. The effective doses of SC-51089 in published studies focusing on ischemia and excitotoxicity are between 5 and 100 µg/kg [19], [23], [31], [40] and the data suggest a wide therapeutic window for application of this compound (up to 12 h after permanent or transient focal ischemia) [31], which would be consistent with temporal profiles of COX-2 activation and progression of secondary injuries following ischemia [56], [57] and TBI [5], [6], [8], [14], [58].…”

Pathogenesis of Huntington’s Disease: How to Fight Excitotoxicity and Transcriptional Dysregulation

“…Presynaptic expression of VGluT1 contributes to the proper expression of other synaptic proteins and reduced levels of this glutamate transporter, as occurs in the striatum of R6 mice [154,155], can disrupt cortico-striatal synaptic transmission [154,156]. The expression of glutamate transporters is also altered in glial cells.…”