TY - JOUR
T1 - Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice
AU - Zhao, Xiaochun
AU - Wu, Tao
AU - Chang, Che Feng
AU - Wu, He
AU - Han, Xiaoning
AU - Li, Qian
AU - Gao, Yufeng
AU - Li, Qiang
AU - Hou, Zhipeng
AU - Maruyama, Takayuki
AU - Zhang, Jiangyang
AU - Wang, Jian
N1 - Funding Information:
This work was supported by AHA 13GRNT15730001, NIH K01AG031926, R01NS078026, and R01AT007317 (JW). We thank Suzy Cho, Lingshu Liu, Joy Ziyi Zhou, Weizhu Tang, and Jieru Wan for blind analysis of histology and immunofluorescence and for neuronal culture. We thank Claire Levine, MS, ELS, for assistance with manuscript preparation and Dr. Raymond Koehler, Dr. Zengjin Yang, and the Wang lab team members for insightful input.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - Inflammatory mechanisms mediated by prostaglandins may contribute to the progression of intracerebral hemorrhage (ICH)-induced brain injury, but they are not fully understood. In this study, we examined the effect of prostaglandin E2 receptor EP1 (EP1R) activation and inhibition on brain injury in mouse models of ICH and investigated the underlying mechanism of action. ICH was induced by injecting collagenase, autologous blood, or thrombin into the striatum of middle-aged male and female mice and aged male mice. Effects of selective EP1R agonist ONO-DI-004, antagonist SC51089, and nonspecific Src family kinase inhibitor PP2 were evaluated by a combination of histologic, magnetic resonance imaging (MRI), immunofluorescence, molecular, cellular, and behavioral assessments. EP1R was expressed primarily in neurons and axons but not in astrocytes or microglia after ICH induced by collagenase. In middle-aged male mice subjected to collagenase-induced ICH, EP1R inhibition mitigated brain injury, brain edema, cell death, neuronal degeneration, neuroinflammation, and neurobehavioral deficits, whereas its activation exacerbated these outcomes. EP1R inhibition also was protective in middle-aged female mice and aged male mice after collagenase-induced ICH and in middle-aged male mice after blood- or thrombin-induced ICH. EP1R inhibition also reduced oxidative stress, white matter injury, and brain atrophy and improved functional outcomes. Histologic results were confirmed by MRI. Src kinase phosphorylation and matrix metalloproteinase-9 activity were increased by EP1R activation and decreased by EP1R inhibition. EP1R regulated matrix metalloproteinase-9 activity through Src kinase signaling, which mediated EP1R toxicity after collagenase-induced ICH. We conclude that prostaglandin E2 EP1R activation plays a toxic role after ICH through mechanisms that involve the Src kinases and the matrix metalloproteinase-9 signaling pathway. EP1R inhibition could be a novel therapeutic strategy to improve outcomes after ICH.
AB - Inflammatory mechanisms mediated by prostaglandins may contribute to the progression of intracerebral hemorrhage (ICH)-induced brain injury, but they are not fully understood. In this study, we examined the effect of prostaglandin E2 receptor EP1 (EP1R) activation and inhibition on brain injury in mouse models of ICH and investigated the underlying mechanism of action. ICH was induced by injecting collagenase, autologous blood, or thrombin into the striatum of middle-aged male and female mice and aged male mice. Effects of selective EP1R agonist ONO-DI-004, antagonist SC51089, and nonspecific Src family kinase inhibitor PP2 were evaluated by a combination of histologic, magnetic resonance imaging (MRI), immunofluorescence, molecular, cellular, and behavioral assessments. EP1R was expressed primarily in neurons and axons but not in astrocytes or microglia after ICH induced by collagenase. In middle-aged male mice subjected to collagenase-induced ICH, EP1R inhibition mitigated brain injury, brain edema, cell death, neuronal degeneration, neuroinflammation, and neurobehavioral deficits, whereas its activation exacerbated these outcomes. EP1R inhibition also was protective in middle-aged female mice and aged male mice after collagenase-induced ICH and in middle-aged male mice after blood- or thrombin-induced ICH. EP1R inhibition also reduced oxidative stress, white matter injury, and brain atrophy and improved functional outcomes. Histologic results were confirmed by MRI. Src kinase phosphorylation and matrix metalloproteinase-9 activity were increased by EP1R activation and decreased by EP1R inhibition. EP1R regulated matrix metalloproteinase-9 activity through Src kinase signaling, which mediated EP1R toxicity after collagenase-induced ICH. We conclude that prostaglandin E2 EP1R activation plays a toxic role after ICH through mechanisms that involve the Src kinases and the matrix metalloproteinase-9 signaling pathway. EP1R inhibition could be a novel therapeutic strategy to improve outcomes after ICH.
KW - Diffusion tensor imaging
KW - Hemoglobin
KW - Inflammation
KW - Intracerebral hemorrhage
KW - Magnetic resonance imaging
KW - Matrix metalloproteinase
KW - Prostaglandin EP1 receptor
KW - Src-kinase
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U2 - 10.1016/j.bbi.2015.02.011
DO - 10.1016/j.bbi.2015.02.011
M3 - Article
C2 - 25697396
AN - SCOPUS:84928825586
SN - 0889-1591
VL - 46
SP - 293
EP - 310
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -