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PGE2 EP1 receptor exacerbated neurotoxicity in a mouse model of cerebral ischemia and Alzheimer's disease.

ABSTRACT: Stroke and Alzheimer's disease (AD) are major age-related neurodegenerative diseases that may worsen the prognosis of each other. Our study was designed to delineate the prostaglandin E(2) EP1 receptor role in AD and in the setting of cerebral ischemia. Genetic deletion of the prostaglandin EP1 receptor significantly attenuated the more severe neuronal damage (38.5 ± 10.6%) and memory loss induced by ischemic insult observed in AD transgenic mice (percentage of viable hippocampal CA1 neurons: 11.2 ± 2.9%) when compared with wild type mice (45.1 ± 9.1%). In addition, we found that the amyloid plaques were reduced in EP1 deleted AD mice. ?-amyloid-induced toxicity (18.0 ± 7.1%) and Ca(2+) response (91.8 ± 12.9%) were also reduced in EP1(-/-) neurons compared with control neurons in in vitro. Hence, EP1 might mediate most of the toxicity associated with cyclooxygenase-2 and contribute substantially to the cell death pathways in AD and stroke. Exploring potential therapeutic agent targeting EP1 receptor could potentially benefit treatments for stroke and AD patients.

SUBMITTER: Zhen G

PROVIDER: S-EPMC3299840 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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PGE2 EP1 receptor exacerbated neurotoxicity in a mouse model of cerebral ischemia and Alzheimer's disease.

Zhen Gehua G Kim Yun Tai YT Li Rung-chi RC Yocum Jennifer J Kapoor Nidhi N Langer John J Dobrowolski Peter P Maruyama Takayuki T Narumiya Shuh S Doré Sylvain S

Neurobiology of aging 20111019 9

Stroke and Alzheimer's disease (AD) are major age-related neurodegenerative diseases that may worsen the prognosis of each other. Our study was designed to delineate the prostaglandin E(2) EP1 receptor role in AD and in the setting of cerebral ischemia. Genetic deletion of the prostaglandin EP1 receptor significantly attenuated the more severe neuronal damage (38.5 ± 10.6%) and memory loss induced by ischemic insult observed in AD transgenic mice (percentage of viable hippocampal CA1 neurons: 11 ...[more]

PMID: 22015313

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Project description:Prostaglandin E2 (PGE2) is involved in numerous physiological and pathological processes of the kidney via its four receptors. A previous study has suggested that a defect in the PGE2 receptor 1 (EP1) gene markedly suppressed the transforming growth factor??1 (TGF??1)?induced mesangial cell (MC) proliferation and extracellular matrix aggregation. Therefore, the present study aimed to adopt a pharmacological method of specifically suppressing or activating the EP1 receptor to further verify and demonstrate these results. The EP1 receptor antagonist SC?19220 and EP1 receptor agonist 17?phenyl?trinor?PGE2 ethyl amide (17?pt?PGE2) were selectively used to treat five?sixths nephrectomy renal fibrosis model mice and TGF??1?stimulated MCs. An Alpha screen PGE2 assay kit, flow cytometry, western blotting and immunohistochemical techniques were adopted to perform in vivo and in vitro experiments. The present results suggested that compared with the control group, the selective EP1 receptor antagonist SC?19220 improved renal function, markedly reduced the plasma blood urea nitrogen and creatinine levels (P<0.05) and alleviated glomerulosclerosis (P<0.05). By contrast, the EP1 receptor agonist 17?pt?PGE2 aggravated renal dysfunction and glomerulosclerosis (P<0.05). To verify the renal protection mechanisms mediated by suppression of the EP1 receptor, the expression levels of endoplasmic reticulum stress (ERS)?related proteins, including chaperone glucose?regulated protein 78 (GRP78), transient receptor potential channel 1 (TRPC1) and protein kinase R?like endoplasmic reticulum kinase (PERK), were further evaluated histologically. The expression of GRP78, TRPC1 and PERK in the antagonist treatment group were markedly downregulated (P<0.05), whereas those in the agonist treatment group were upregulated (P<0.05). The present in vitro experiments demonstrated that, compared with the control group, the EP1 receptor antagonist suppressed the expression of GRP78, TRPC1 and PERK (P<0.05), reduced the production of PGE2 (P<0.05) and decreased the MC apoptosis rate (P<0.05), thus alleviating TGF??1?stimulated MC injury. Consequently, consistent with previous results, selectively antagonizing the EP1 receptor improved renal function and mitigated glomerulosclerosis, and its potential mechanism might be associated with the suppression of ERS.

Dataset Information

PGE2 EP1 receptor exacerbated neurotoxicity in a mouse model of cerebral ischemia and Alzheimer's disease.

Publications

PGE2 EP1 receptor exacerbated neurotoxicity in a mouse model of cerebral ischemia and Alzheimer's disease.

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