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Prostaglandin F(2α) FP receptor antagonist improves outcomes after experimental traumatic brain injury

BACKGROUND: Injuries to the brain promote upregulation of prostaglandins, notably the proinflammatory PGF(2α), and overactivation of their cognate G-protein-coupled FP receptor, which could exacerbate neuronal damage. Our study is focused on investigation of the FP receptor as a target for novel neu...

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Autores principales: Glushakov, Alexander V, Robbins, Sean W, Bracy, Connor L, Narumiya, Shuh, Doré, Sylvain
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907016/
https://www.ncbi.nlm.nih.gov/pubmed/24172576
http://dx.doi.org/10.1186/1742-2094-10-132
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author Glushakov, Alexander V
Robbins, Sean W
Bracy, Connor L
Narumiya, Shuh
Doré, Sylvain
author_facet Glushakov, Alexander V
Robbins, Sean W
Bracy, Connor L
Narumiya, Shuh
Doré, Sylvain
author_sort Glushakov, Alexander V
collection PubMed
description BACKGROUND: Injuries to the brain promote upregulation of prostaglandins, notably the proinflammatory PGF(2α), and overactivation of their cognate G-protein-coupled FP receptor, which could exacerbate neuronal damage. Our study is focused on investigation of the FP receptor as a target for novel neuroprotective drugs in a preclinical animal traumatic brain injury (TBI) model. METHODS: Accordingly, the effects of acute intraperitoneal post-treatment with selective FP antagonist AL-8810 were studied in wildtype (WT) and FP receptor knockout (FP(-/-)) mice after controlled cortical impact (CCI). Neurological impairments were evaluated using neurological deficit scores (NDS) and the grip strength test. Cortical lesions and overall brain pathology were assessed using immunohistochemistry. RESULTS: Morphological analyses of cerebral vasculature and anastomoses revealed no differences between WT and FP(-/-) mice. CCI produced cortical lesions characterized by cavitation, neuronal loss, and hematoma with a volume of 20.0 ± 1.0 mm(3) and significant hippocampal swelling (146.5 ± 7.4% of contralateral) compared with sham (P < 0.05). Post-treatment with AL-8810 (1 to 10 mg/kg) had no significant effect on cortical lesions, which suggests the irreversible effect of primary CCI injury, but significantly reduced hippocampal swelling to a size not significantly different from the sham group. Post-treatment with AL-8810 at a dose of 10 mg/kg significantly improved NDS at 24 and 48 hours after CCI (P < 0.001 and P < 0.01, respectively). In the AL-8810 group, CCI-induced decrease in grip strength was three-fold (2.93 ± 1.71) less and significantly different than in the saline-treated group. The FP(-/-) mice had significantly less hippocampal swelling, but not NDS, compared with WT mice. In addition, immunohistochemistry showed that pharmacologic blockade and genetic deletion of FP receptor led to attenuation of CCI-induced gliosis and microglial activation in selected brain regions. CONCLUSION: This study provides, for the first time, demonstration of the unique role of the FP receptor as a potential target for disease-modifying CNS drugs for treatment of acute traumatic injury.
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spelling pubmed-39070162014-01-31 Prostaglandin F(2α) FP receptor antagonist improves outcomes after experimental traumatic brain injury Glushakov, Alexander V Robbins, Sean W Bracy, Connor L Narumiya, Shuh Doré, Sylvain J Neuroinflammation Research BACKGROUND: Injuries to the brain promote upregulation of prostaglandins, notably the proinflammatory PGF(2α), and overactivation of their cognate G-protein-coupled FP receptor, which could exacerbate neuronal damage. Our study is focused on investigation of the FP receptor as a target for novel neuroprotective drugs in a preclinical animal traumatic brain injury (TBI) model. METHODS: Accordingly, the effects of acute intraperitoneal post-treatment with selective FP antagonist AL-8810 were studied in wildtype (WT) and FP receptor knockout (FP(-/-)) mice after controlled cortical impact (CCI). Neurological impairments were evaluated using neurological deficit scores (NDS) and the grip strength test. Cortical lesions and overall brain pathology were assessed using immunohistochemistry. RESULTS: Morphological analyses of cerebral vasculature and anastomoses revealed no differences between WT and FP(-/-) mice. CCI produced cortical lesions characterized by cavitation, neuronal loss, and hematoma with a volume of 20.0 ± 1.0 mm(3) and significant hippocampal swelling (146.5 ± 7.4% of contralateral) compared with sham (P < 0.05). Post-treatment with AL-8810 (1 to 10 mg/kg) had no significant effect on cortical lesions, which suggests the irreversible effect of primary CCI injury, but significantly reduced hippocampal swelling to a size not significantly different from the sham group. Post-treatment with AL-8810 at a dose of 10 mg/kg significantly improved NDS at 24 and 48 hours after CCI (P < 0.001 and P < 0.01, respectively). In the AL-8810 group, CCI-induced decrease in grip strength was three-fold (2.93 ± 1.71) less and significantly different than in the saline-treated group. The FP(-/-) mice had significantly less hippocampal swelling, but not NDS, compared with WT mice. In addition, immunohistochemistry showed that pharmacologic blockade and genetic deletion of FP receptor led to attenuation of CCI-induced gliosis and microglial activation in selected brain regions. CONCLUSION: This study provides, for the first time, demonstration of the unique role of the FP receptor as a potential target for disease-modifying CNS drugs for treatment of acute traumatic injury. BioMed Central 2013-10-30 /pmc/articles/PMC3907016/ /pubmed/24172576 http://dx.doi.org/10.1186/1742-2094-10-132 Text en Copyright © 2013 Glushakov et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Glushakov, Alexander V
Robbins, Sean W
Bracy, Connor L
Narumiya, Shuh
Doré, Sylvain
Prostaglandin F(2α) FP receptor antagonist improves outcomes after experimental traumatic brain injury
title Prostaglandin F(2α) FP receptor antagonist improves outcomes after experimental traumatic brain injury
title_full Prostaglandin F(2α) FP receptor antagonist improves outcomes after experimental traumatic brain injury
title_fullStr Prostaglandin F(2α) FP receptor antagonist improves outcomes after experimental traumatic brain injury
title_full_unstemmed Prostaglandin F(2α) FP receptor antagonist improves outcomes after experimental traumatic brain injury
title_short Prostaglandin F(2α) FP receptor antagonist improves outcomes after experimental traumatic brain injury
title_sort prostaglandin f(2α) fp receptor antagonist improves outcomes after experimental traumatic brain injury
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907016/
https://www.ncbi.nlm.nih.gov/pubmed/24172576
http://dx.doi.org/10.1186/1742-2094-10-132
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