Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease

Abstract Background Alzheimer’s disease (AD) causes substantial medical and societal burden with no therapies ameliorating cognitive deficits. Centralized pathologies involving amyloids, neurofibrillary tangles, and neuroinflammatory pathways are being investigated to identify disease-modifying targ...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Avijit Banik, Radhika Amaradhi, Daniel Lee, Michael Sau, Wenyi Wang, Raymond Dingledine, Thota Ganesh
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Two-hit 5xFAD EP2 Lipopolysaccharide TG11-77.HCl Neuroinflammation Microgliosis Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/5c1524c61ee446028a162ba57509e1d9
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5c1524c61ee446028a162ba57509e1d9
record_format	dspace
spelling	oai:doaj.org-article:5c1524c61ee446028a162ba57509e1d92021-11-21T12:39:53ZProstaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease10.1186/s12974-021-02297-71742-2094https://doaj.org/article/5c1524c61ee446028a162ba57509e1d92021-11-01T00:00:00Zhttps://doi.org/10.1186/s12974-021-02297-7https://doaj.org/toc/1742-2094Abstract Background Alzheimer’s disease (AD) causes substantial medical and societal burden with no therapies ameliorating cognitive deficits. Centralized pathologies involving amyloids, neurofibrillary tangles, and neuroinflammatory pathways are being investigated to identify disease-modifying targets for AD. Cyclooxygenase-2 (COX-2) is one of the potential neuroinflammatory agents involved in AD progression. However, chronic use of COX-2 inhibitors in patients produced adverse cardiovascular effects. We asked whether inhibition of EP2 receptors, downstream of the COX-2 signaling pathway, can ameliorate neuroinflammation in AD brains in presence or absence of a secondary inflammatory stimuli. Methods We treated 5xFAD mice and their non-transgenic (nTg) littermates in presence or absence of lipopolysaccharide (LPS) with an EP2 antagonist (TG11-77.HCl). In cohort 1, nTg (no-hit) or 5xFAD (single-hit—genetic) mice were treated with vehicle or TG11-77.HCl for 12 weeks. In cohort 2, nTg (single-hit—environmental) and 5xFAD mice (two-hit) were administered LPS (0.5 mg/kg/week) and treated with vehicle or TG11-77.HCl for 8 weeks. Results Complete blood count analysis showed that LPS induced anemia of inflammation in both groups in cohort 2. There was no adverse effect of LPS or EP2 antagonist on body weight throughout the treatment. In the neocortex isolated from the two-hit cohort of females, but not males, the elevated mRNA levels of proinflammatory mediators (IL-1β, TNF, IL-6, CCL2, EP2), glial markers (IBA1, GFAP, CD11b, S110B), and glial proteins were significantly reduced by EP2 antagonist treatment. Intriguingly, the EP2 antagonist had no effect on either of the single-hit cohorts. There was a modest increase in amyloid–plaque deposition upon EP2 antagonist treatment in the two-hit female brains, but not in the single-hit genetic female cohort. Conclusion These results reveal a potential neuroinflammatory role for EP2 in the two-hit 5xFAD mouse model. A selective EP2 antagonist reduces inflammation only in female AD mice subjected to a second inflammatory insult.Avijit BanikRadhika AmaradhiDaniel LeeMichael SauWenyi WangRaymond DingledineThota GaneshBMCarticleTwo-hit 5xFADEP2LipopolysaccharideTG11-77.HClNeuroinflammationMicrogliosisNeurology. Diseases of the nervous systemRC346-429ENJournal of Neuroinflammation, Vol 18, Iss 1, Pp 1-21 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Two-hit 5xFAD EP2 Lipopolysaccharide TG11-77.HCl Neuroinflammation Microgliosis Neurology. Diseases of the nervous system RC346-429
spellingShingle	Two-hit 5xFAD EP2 Lipopolysaccharide TG11-77.HCl Neuroinflammation Microgliosis Neurology. Diseases of the nervous system RC346-429 Avijit Banik Radhika Amaradhi Daniel Lee Michael Sau Wenyi Wang Raymond Dingledine Thota Ganesh Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease
description	Abstract Background Alzheimer’s disease (AD) causes substantial medical and societal burden with no therapies ameliorating cognitive deficits. Centralized pathologies involving amyloids, neurofibrillary tangles, and neuroinflammatory pathways are being investigated to identify disease-modifying targets for AD. Cyclooxygenase-2 (COX-2) is one of the potential neuroinflammatory agents involved in AD progression. However, chronic use of COX-2 inhibitors in patients produced adverse cardiovascular effects. We asked whether inhibition of EP2 receptors, downstream of the COX-2 signaling pathway, can ameliorate neuroinflammation in AD brains in presence or absence of a secondary inflammatory stimuli. Methods We treated 5xFAD mice and their non-transgenic (nTg) littermates in presence or absence of lipopolysaccharide (LPS) with an EP2 antagonist (TG11-77.HCl). In cohort 1, nTg (no-hit) or 5xFAD (single-hit—genetic) mice were treated with vehicle or TG11-77.HCl for 12 weeks. In cohort 2, nTg (single-hit—environmental) and 5xFAD mice (two-hit) were administered LPS (0.5 mg/kg/week) and treated with vehicle or TG11-77.HCl for 8 weeks. Results Complete blood count analysis showed that LPS induced anemia of inflammation in both groups in cohort 2. There was no adverse effect of LPS or EP2 antagonist on body weight throughout the treatment. In the neocortex isolated from the two-hit cohort of females, but not males, the elevated mRNA levels of proinflammatory mediators (IL-1β, TNF, IL-6, CCL2, EP2), glial markers (IBA1, GFAP, CD11b, S110B), and glial proteins were significantly reduced by EP2 antagonist treatment. Intriguingly, the EP2 antagonist had no effect on either of the single-hit cohorts. There was a modest increase in amyloid–plaque deposition upon EP2 antagonist treatment in the two-hit female brains, but not in the single-hit genetic female cohort. Conclusion These results reveal a potential neuroinflammatory role for EP2 in the two-hit 5xFAD mouse model. A selective EP2 antagonist reduces inflammation only in female AD mice subjected to a second inflammatory insult.
format	article
author	Avijit Banik Radhika Amaradhi Daniel Lee Michael Sau Wenyi Wang Raymond Dingledine Thota Ganesh
author_facet	Avijit Banik Radhika Amaradhi Daniel Lee Michael Sau Wenyi Wang Raymond Dingledine Thota Ganesh
author_sort	Avijit Banik
title	Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease
title_short	Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease
title_full	Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease
title_fullStr	Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease
title_full_unstemmed	Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease
title_sort	prostaglandin ep2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of alzheimer’s disease
publisher	BMC
publishDate	2021
url	https://doaj.org/article/5c1524c61ee446028a162ba57509e1d9
work_keys_str_mv	AT avijitbanik prostaglandinep2receptorantagonistamelioratesneuroinflammationinatwohitmousemodelofalzheimersdisease AT radhikaamaradhi prostaglandinep2receptorantagonistamelioratesneuroinflammationinatwohitmousemodelofalzheimersdisease AT daniellee prostaglandinep2receptorantagonistamelioratesneuroinflammationinatwohitmousemodelofalzheimersdisease AT michaelsau prostaglandinep2receptorantagonistamelioratesneuroinflammationinatwohitmousemodelofalzheimersdisease AT wenyiwang prostaglandinep2receptorantagonistamelioratesneuroinflammationinatwohitmousemodelofalzheimersdisease AT raymonddingledine prostaglandinep2receptorantagonistamelioratesneuroinflammationinatwohitmousemodelofalzheimersdisease AT thotaganesh prostaglandinep2receptorantagonistamelioratesneuroinflammationinatwohitmousemodelofalzheimersdisease
_version_	1718418885037785088

Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease

Ejemplares similares