The localization of PGE2 receptor subtypes in rat retinal cultures and the neuroprotective effect of the EP2 agonist butaprost

Costa, Belmira da Silveira Andrade da Lara; Kang, Kui Dong; Rittenhouse, Kay D.; Osborne, Neville N.

doi:10.1016/j.neuint.2009.02.015

Cited by 22 publications

(8 citation statements)

References 61 publications

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“…In addition, PGE 2 may also reduce microglial activation and secondary neuronal toxicity by decreasing the levels of pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) during brain inflammation (Minghetti et al, 1997; Caggiano et al, 1998; Zhang and Rivest, 2001). Thus, PGE 2 may exert functionally opposing effects; it induces pro- and anti-inflammatory effects, stimulating both toxic and protective effects in a variety of neuronal tissues (Akaike et al, 1994; Takadera et al, 2004; Andreade da Costa et al, 2009), and it elicits both smooth muscle relaxation and constriction (Walch et al, 2001; Davis et al, 2004). These different physiological effects of PGE 2 are mediated by the four PGE 2 receptor subtypes, EP1–4, which are widely expressed and linked to functionally antagonistic second messenger systems.…”

Section: Prostanoids and Their Receptorsmentioning

confidence: 99%

Prostanoid signaling: Dual role for prostaglandin E2 in neurotoxicity

2011

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The prostanoids, a naturally occurring subclass of eicosanoids, are lipid mediators generated through oxidative pathways from arachidonic acid. These cyclooxygenase metabolites, consisting of the prostaglandins (PG), prostacyclin and tromboxane, are released in response to a variety of physiological and pathological stimuli in almost all organs, including the brain. They are produced by various cell types and act upon targeted cells via specific G protein-coupled receptors. The existence of multiple receptors, cross-reactivity and coupling to different signal transduction pathways for each prostanoid, collectively establish their diverse effects. Notably, these effects can occur in functionally opposing directions within the same cell or organ. Prostaglandin E2 (PGE2) is the most versatile prostanoid because of its receptors, E Prostanoid (EP) receptor subtypes 1 through 4, its biological heterogeneity and its differential expression on neuronal and glial cells throughout the central nervous system. Since PGE2 plays an important role in processes associated with various neurological diseases, this review focuses on its dual neuroprotective and neurotoxic role in EP receptor subtype signaling pathways in different models of brain injury.

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Section: Prostanoids and Their Receptorsmentioning

confidence: 99%

Prostanoid signaling: Dual role for prostaglandin E2 in neurotoxicity

2011

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“…We and others have shown that EP1 and EP3 receptor signaling has toxic effects in in vitro and in vivo models of ICH 6,7 and in thrombin-induced brain injury. 8 In contrast, EP2 receptor signaling protects cultured neurons under various conditions through the cAMP/PKA or cAMP/Epac pathway [9][10][11][12] and regulates microglial activation and function in vitro. [13][14][15][16] These findings reflect cell-specific differences in EP2 signaling.…”

Section: Introductionmentioning

confidence: 99%

Cerebroprotection by the neuronal PGE₂ receptor EP2 after intracerebral hemorrhage in middle-aged mice

Han

et al. 2016

J Cereb Blood Flow Metab

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Inflammatory responses mediated by prostaglandins such as PGE 2 may contribute to secondary brain injury after intracerebral hemorrhage (ICH). However, the cell-specific signaling by PGE 2 receptor EP2 differs depending on whether the neuropathic insult is acute or chronic. Using genetic and pharmacologic approaches, we investigated the role of EP2 receptor in two mouse models of ICH induced by intrastriatal injection of collagenase or autologous arterial whole blood. We used middle-aged male mice to enhance the clinical relevance of the study. EP2 receptor was expressed in neurons but not in astrocytes or microglia after collagenase-induced ICH. Brain injury after collagenase-induced ICH was associated with enhanced cellular and molecular inflammatory responses, oxidative stress, and matrix metalloproteinase (MMP)-2/9 activity. EP2 receptor deletion exacerbated brain injury, brain swelling/edema, neuronal death, and neurobehavioral deficits, whereas EP2 receptor activation by the highly selective agonist AE1-259-01 reversed these outcomes. EP2 receptor deletion also exacerbated brain edema and neurologic deficits in the blood ICH model. These findings support the premise that neuronal EP2 receptor activation by PGE 2 protects brain against ICH injury in middle-aged mice through its anti-inflammatory and anti-oxidant effects and anti-MMP-2/9 activity. PGE 2 /EP2 signaling warrants further investigation for potential use in ICH treatment.

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“…Though we have shown it to have a strong anti-inflammatory effect in our culture models, PGE 2 is a highly pleiotropic molecule known to be both pro- 29,52 and anti-inflammatory, 53,54 as well as having roles in pain, 55–57 cancer, 58,59 neuroprotection, 31–33 and wound repair, 60,61 among others. 62 This diversity of functions is largely attributed to the ability of PGE 2 to bind four receptor subtypes— EP1, EP2, EP3, and EP4 30 —that mediate PGE 2 actions through distinct downstream signaling pathways.…”

Section: Discussionmentioning

confidence: 77%

“…For example, although PGE 2 is best known for its role in the inflammatory response, several studies have demonstrated additional downstream effects in stimulating expression and/or production of neurotrophic factors 17–19 as well as neuroprotective effects. 31–33 Given the potential for broader responses to these two therapies, as well as differences between free and encapsulated MSC, we preliminarily screened gene expression by astrocytes of a number of factors that may play contribute to the neuroprotective and/or regenerative environment following TBI. We were particularly interested in identifying similarities and differences in the expression profiles of astrocytes induced to an inflammatory state with LPS that were treated with PGE 2 or with MSC.…”

Section: Resultsmentioning

confidence: 99%

Prostaglandin E₂Produced by Alginate-Encapsulated Mesenchymal Stromal Cells Modulates the Astrocyte Inflammatory Response

et al. 2017

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Astroglia are well known for their role in propagating secondary injury following brain trauma. Modulation of this injury cascade, including inflammation, is essential to repair and recovery. Mesenchymal stromal cells (MSCs) have been demonstrated as trophic mediators in several models of secondary CNS injury, however, there has been varied success with the use of direct implantation due to a failure to persist at the injury site. To achieve sustained therapeutic benefit, we have encapsulated MSCs in alginate microspheres and evaluated the ability of these encapsulated MSCs to attenuate neuro-inflammation. In this study, astroglial cultures were administered lipopolysaccharide (LPS) to induce inflammation and immediately co-cultured with encapsulated or monolayer human MSCs. Cultures were assayed for the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) produced by astroglia, MSC-produced prostaglandin E2, and expression of neurotrophin-associated genes. We found that encapsulated MSCs significantly reduced TNF-α produced by LPS-stimulated astrocytes, more effectively than monolayer MSCs, and this enhanced benefit commences earlier than that of monolayer MSCs. Furthermore, in support of previous findings, encapsulated MSCs constitutively produced high levels of PGE2, while monolayer MSCs required the presence of inflammatory stimuli to induce PGE2 production. The early, constitutive presence of PGE2 significantly reduced astrocyte-produced TNF-α, while delayed administration had no effect. Finally, MSC-produced PGE2 was not only capable of modulating inflammation, but appears to have an additional role in stimulating astrocyte neurotrophin production. Overall, these results support the enhanced benefit of encapsulated MSC treatment, both in modulating the inflammatory response and providing neuroprotection.

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The localization of PGE2 receptor subtypes in rat retinal cultures and the neuroprotective effect of the EP2 agonist butaprost

Cited by 22 publications

References 61 publications

Prostanoid signaling: Dual role for prostaglandin E2 in neurotoxicity

Prostanoid signaling: Dual role for prostaglandin E2 in neurotoxicity

Cerebroprotection by the neuronal PGE₂ receptor EP2 after intracerebral hemorrhage in middle-aged mice

Prostaglandin E₂Produced by Alginate-Encapsulated Mesenchymal Stromal Cells Modulates the Astrocyte Inflammatory Response

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The localization of PGE2 receptor subtypes in rat retinal cultures and the neuroprotective effect of the EP2 agonist butaprost

Cited by 22 publications

References 61 publications

Prostanoid signaling: Dual role for prostaglandin E2 in neurotoxicity

Prostanoid signaling: Dual role for prostaglandin E2 in neurotoxicity

Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice

Prostaglandin E2Produced by Alginate-Encapsulated Mesenchymal Stromal Cells Modulates the Astrocyte Inflammatory Response

Contact Info

Product

Resources

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Cerebroprotection by the neuronal PGE₂ receptor EP2 after intracerebral hemorrhage in middle-aged mice

Prostaglandin E₂Produced by Alginate-Encapsulated Mesenchymal Stromal Cells Modulates the Astrocyte Inflammatory Response