GPER1/GPR30 Activation Improves Neuronal Survival Following Global Cerebral Ischemia Induced by Cardiac Arrest in Mice

Kosaka, Yasuharu; Quillinan, Nidia; Bond, Chris T.; Traystman, Richard J.; Hurn, Patricia D.; Herson, Paco S.

doi:10.1007/s12975-012-0211-8

Cited by 52 publications

(44 citation statements)

References 29 publications

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“…The neuroprotective effect of G1 agonist in our study agrees well with the results of previous studies by other investigators [34, 42]. However, our study extends these observations by demonstrating the rapid signaling effects of G1 on activation of the prosurvival kinases, Akt and ERK, and upon inhibition of the proapototic signaling kinase, JNK in the hippocampal CA1 region after GCI.…”

Section: Discussionsupporting

confidence: 93%

“…Previous studies had used a GPR30 agonist (G1) to show that activation of GPR30 could be neuroprotective against GCI [34, 42]. While these studies provided important information that exogenous G1 activation of GPR30 is neuroprotective, the studies had a limitation in that they were not designed to address whether endogenous GPR30 actually mediates the neuroprotective effects of E2.…”

Section: Discussionmentioning

confidence: 99%

“…The majority of the studies to date have used a GPR30 agonist, G1, to explore the effect of exogenous activation of GPR30 in the brain. These studies have revealed that G1 can attenuate glutamate-induced cell death in cultured cortical and hippocampal neurons in vitro [33, 41] and attenuate focal and global cerebral ischemia-induced neuronal cell death in vivo [34, 41, 42]. While these studies clearly demonstrate that exogenous activation of GPR30 can exert neuroprotection, they do not prove a role for endogenous GPR30 in mediating E2-induced neuroprotection.…”

Section: Introductionmentioning

confidence: 99%

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GPR30 mediates estrogen rapid signaling and neuroprotection

Tang

Zhang

Yang

et al. 2014

Molecular and Cellular Endocrinology

100

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G-protein-coupled estrogen receptor-30 (GPR30), also known as G-protein estrogen receptor-1 (GPER1), is a putative extranuclear estrogen receptor whose precise functions in the brain are poorly understood. Studies using exogenous administration of the GPR30 agonist, G1 suggests that GPR30 may have a neuroprotective role in cerebral ischemia. However, the physiological role of GPR30 in mediating estrogen (E2)-induced neuroprotection in cerebral ischemia remains unclear. Also unclear is whether GPR30 has a role in mediating rapid signaling by E2 after cerebral ischemia, which is thought to underlie its neuroprotective actions. To address these deficits in our knowledge, the current study examined the effect of antisense oligonucleotide (AS) knockdown of GPR30 in the hippocampal CA1 region upon E2-BSA-induced neuroprotection and rapid kinase signaling in a rat model of global cerebral ischemia (GCI). Immunohistochemistry demonstrated that GPR30 is strongly expressed in the hippocampal CA1 region and dentate gyrus, with less expression in the CA3 region. E2-BSA exerted robust neuroprotection of hippocampal CA1 neurons against GCI, an effect abrogated by AS knockdown of GPR30. Missense control oligonucleotides had no effect upon E2-BSA-induced neuroprotection, indicating specificity of the effect. The GPR30 agonist, G1 also exerted significant neuroprotection against GCI. E2-BSA and G1 also rapidly enhanced activation of the prosurvival kinases, Akt and ERK, while decreasing proapototic JNK activation. Importantly, AS knockdown of GPR30 markedly attenuated these rapid kinase signaling effects of E2-BSA. As a whole, the studies provide evidence of an important role of GPR30 in mediating the rapid signaling and neuroprotective actions of E2 in the hippocampus.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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GPR30 mediates estrogen rapid signaling and neuroprotection

Tang

Zhang

Yang

et al. 2014

Molecular and Cellular Endocrinology

100

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“…GPR30 is involved in protection from ischemia-reperfusion injury in neurons[26], [32] and in cardiomyocytes [33],[34]. Work in chronic kidney disease models has suggested that GPR30 agonists exert protective effects [35].…”

Section: Discussionmentioning

confidence: 99%

Estrogen-Mediated Renoprotection following Cardiac Arrest and Cardiopulmonary Resuscitation Is Robust to GPR30 Gene Deletion

et al. 2014

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IntroductionAcute kidney injury is a serious,sexually dimorphic perioperative complication, primarily attributed to hypoperfusion. We previously found that estradiol is renoprotective after cardiac arrest and cardiopulmonary resuscitation in ovariectomized female mice. Additionally, we found that neither estrogen receptor alpha nor beta mediated this effect. We hypothesized that the G protein estrogen receptor (GPR30) mediates the renoprotective effect of estrogen.MethodsOvariectomized female and gonadally intact male wild-type and GPR30 gene-deleted mice were treated with either vehicle or 17β-estradiol for 7 days, then subjected to cardiac arrest and cardiopulmonary resuscitation. Twenty four hours later, serum creatinine and urea nitrogen were measured, and histologic renal injury was evaluated by unbiased stereology.ResultsIn both males and females, GPR30 gene deletion was associated with reduced serum creatinine regardless of treatment. Estrogen treatment of GPR30 gene-deleted males and females was associated with increased preprocedural weight. In ovariectomized female mice, estrogen treatment did not alter resuscitation, but was renoprotective regardless of GPR30 gene deletion. In males, estrogen reduced the time-to-resuscitate and epinephrine required. In wild-type male mice, serum creatinine was reduced, but neither serum urea nitrogen nor histologic outcomes were affected by estrogen treatment. In GPR30 gene-deleted males, estrogen did not alter renal outcomes. Similarly, renal injury was not affected by G1 therapy of ovariectomized female wild-type mice.ConclusionTreatment with 17β-estradiol is renoprotective after whole-body ischemia-reperfusion in ovariectomized female mice irrespective of GPR30 gene deletion. Treatment with the GPR30 agonist G1 did not alter renal outcome in females. We conclude GPR30 does not mediate the renoprotective effect of estrogen in ovariectomized female mice. In males, estrogen therapy was not renoprotective. Estrogen treatment of GPR30 gene-deleted mice was associated with increased preprocedural weight in both sexes. Of significance to further investigation, GPR30 gene deletion was associated with reduced serum creatinine, regardless of treatment.

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“…The behaviors assessed included consciousness (0–3), interaction (0–2), ability to grab a wire top (0–2), motor function (0–5), and activity (0–2). Scores in each category were summated to generate an overall health assessment score (Allen et al, 2011, Kosaka et al, 2012). …”

Section: Methodsmentioning

confidence: 99%

Pro-inflammatory T-lymphocytes rapidly infiltrate into the brain and contribute to neuronal injury following cardiac arrest and cardiopulmonary resuscitation

Deng

Carter

Traystman

et al. 2014

Journal of Neuroimmunology

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Although inflammatory mechanisms have been linked to neuronal injury following global cerebral ischemia, the presence of infiltrating peripheral immune cells remains understudied. We performed flow cytometry of single cell suspensions obtained from the brains of mice at varying time points after global cerebral ischemia induced by cardiac arrest and cardiopulmonary resuscitation (CA/CPR) to characterize the influx in lymphocytes into the injured brain. We observed that CA/CPR caused a large influx of lymphocytes within 3 hours of resuscitation that was maintained for the 3 day duration of our experiments. Using cell staining flow cytometry we observed that the large majority of infiltrating lymphocytes were CD4+ T cells. Intracellular stains revealed a large proportion of pro-inflammatory T cells expressing either TNFα or INFγ. Importantly, the lack of functional T cells in TCRα knockout mice reduced neuronal injury following CA/CPR, implicating pro-inflammatory T cells in the progression of ischemic neuronal injury. Finally, we made the remarkable observation that the novel CD4+CD40+ (Th40) population of pro-inflammatory T cells that are strongly associated with autoimmunity are present in large numbers in the injured brain. These data indicate that studies investigating the neuro-immune response after global cerebral ischemia should consider the role of infiltrating T cells in orchestrating the acute and sustained immune response.

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GPER1/GPR30 Activation Improves Neuronal Survival Following Global Cerebral Ischemia Induced by Cardiac Arrest in Mice

Cited by 52 publications

References 29 publications

GPR30 mediates estrogen rapid signaling and neuroprotection

GPR30 mediates estrogen rapid signaling and neuroprotection

Estrogen-Mediated Renoprotection following Cardiac Arrest and Cardiopulmonary Resuscitation Is Robust to GPR30 Gene Deletion

Pro-inflammatory T-lymphocytes rapidly infiltrate into the brain and contribute to neuronal injury following cardiac arrest and cardiopulmonary resuscitation

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