Prostaglandin EP4 receptor agonist protects against acute neurotoxicity

Ahmad, Abdullah Shafique; Ahmad, Muzamil; Brum‐Fernandes, Artur J. de; Doré, Sylvain

doi:10.1016/j.brainres.2005.10.068

Cited by 80 publications

(62 citation statements)

References 37 publications

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“…The effect of EP4 on cerebral perfusion via endothelial nitric-oxide synthase function may be involved in such beneficial roles. A neuroprotective effect of EP4 signaling has been reported in various other models, e.g., a mouse multiple sclerosis model (Esaki et al, 2010), a rat spinal cord injury model (Umemura et al, 2010), and a mouse N-methyl-D-aspartate-mediated acute brain damage model (Ahmad et al, 2005). Taken together, these data suggest that EP4 contributes to hyperalgesia and fever production and plays protective roles in neuronal degeneration and regeneration, although its precise downstream signaling pathways have not been reported.…”

Section: +mentioning

confidence: 89%

The Prostanoid EP4 Receptor and Its Signaling Pathway

Yokoyama

Iwatsubo²,

Umemura³

et al. 2013

Pharmacol Rev

223

257

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Section: +mentioning

confidence: 89%

The Prostanoid EP4 Receptor and Its Signaling Pathway

Yokoyama

Iwatsubo²,

Umemura³

et al. 2013

Pharmacol Rev

223

257

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“…We previously reported that in mice, the EP1 receptor plays a toxic role in transient cerebral ischemia and excitotoxicity models (Ahmad et al, 2006a), a finding further substantiated by Kawano et al (2006), and that EP2 and EP4 receptor activation is protective in N-methyl-Daspartic acid (NMDA)-induced excitotoxic lesions (Ahmad et al, 2005;Ahmad et al, 2006b). We also have evaluated the effects of the drug 1-OH-PGE1, which stimulates EP4 and to a lesser extent EP3, and found it to be neuroprotective in transient ischemia (Ahmad et al, 2006c) and oxidative stress after β-amyloid exposure in mouse primary cultured neurons (Echeverria et al, 2005).…”

Section: Introductionmentioning

confidence: 85%

Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury

Ahmad¹,

Ahmad²,

Zhuang³

et al. 2007

Journal of Neuroimmunology

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The effect of PGE 2 EP3 receptors on injury size was investigated following cerebral ischemia and induced excitotoxicity in mice. Treatment with the selective EP3 agonist ONO-AE-248 significantly and dose-dependently increased infarct size in the middle cerebral artery occlusion model. In a separate experiment, pretreatment with ONO-AE-248 exacerbated the lesion caused by N-methyl-D-aspartic acid-induced acute excitotoxicity. Conversely, genetic deletion of EP3 provided protection against N-methyl-D-aspartic acid-induced toxicity. The results suggest that PGE 2 , by stimulating EP3 receptors, can contribute to the toxicity associated with cyclooxygenase and that antagonizing this receptor could be used therapeutically to protect against stroke-and excitotoxicityinduced brain damage.

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“…In view of our aim to identify alternate targets for control of P-glycoprotein expression in the epileptic brain, we considered tolerability issues when selecting a target candidate among these receptors. Because EP2, EP3, and EP4 receptors mediate neuroprotective effects (Bilak et al, 2004;McCullough et al, 2004;Ahmad et al, 2005), antagonism of these receptor subtypes cannot be considered as an applicable therapeutic approach. In apparent contrast, EP1 receptors are critically involved in the neurotoxicity associated with activation of NMDA receptors in the diseased brain (Bilak et al, 2004;McCullough et al, 2004;Ahmad et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Because EP2, EP3, and EP4 receptors mediate neuroprotective effects (Bilak et al, 2004;McCullough et al, 2004;Ahmad et al, 2005), antagonism of these receptor subtypes cannot be considered as an applicable therapeutic approach. In apparent contrast, EP1 receptors are critically involved in the neurotoxicity associated with activation of NMDA receptors in the diseased brain (Bilak et al, 2004;McCullough et al, 2004;Ahmad et al, 2005). In accordance with this role, EP1 receptor antagonism exhibits neuroprotection (Suganami et al, 2003;Kawano et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…It acts on four different G protein-coupled receptors (EP1, EP2, EP3, and EP4), each of which has a very distinct signal transduction profile and often opposing cellular actions (Hata and Breyer, 2004). Whereas blocking EP2, EP3, and EP4 can aggravate neurodegeneration (Bilak et al, 2004;McCullough et al, 2004;Ahmad et al, 2005), blocking EP1 has neuroprotective effects (Suganami et al, 2003;Kawano et al, 2006). Thus, EP1 represents the most interesting target on which we focused our experimental efforts.…”

mentioning

confidence: 99%

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Targeting Prostaglandin E₂ EP1 Receptors Prevents Seizure-Associated P-glycoprotein Up-Regulation

Pekcec¹,

Unkrüer²,

Schlichtiger³

et al. 2009

J Pharmacol Exp Ther

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Up-regulation of the blood-brain barrier efflux transporter Pglycoprotein in central nervous system disorders results in restricted brain access and limited efficacy of therapeutic drugs. In epilepsies, seizure activity strongly triggers expression of P-glycoprotein. Here, we identified the prostaglandin E2 receptor, EP1, as a key factor in the signaling pathway that mediates seizure-induced up-regulation of P-glycoprotein at the bloodbrain barrier. In the rat pilocarpine model, status epilepticus significantly increased P-glycoprotein expression by 92 to 197% in the hippocampal hilus and granule cell layer as well as the piriform cortex. The EP1 receptor antagonist 8-chlorodibenz [b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide hydrochloride (SC-51089) abolished seizure-induced P-glycoprotein up-regulation and retained its expression at the control level. The control of P-glycoprotein expression despite prolonged seizure activity suggests that EP1 receptor antagonism will also improve antiepileptic drug efficacy. Preliminary evidence for this concept has been obtained using a massive kindling paradigm during which animals received a subchronic SC-51089 treatment. After withdrawal of the EP1 receptor antagonist, a low dose of the P-glycoprotein substrate phenobarbital resulted in an anticonvulsant effect in this pretreated group, whereas the same dosage of phenobarbital did not exert a significant effect in the respective control group. In conclusion, our data demonstrate that EP1 is a key signaling factor in the regulatory pathway that drives P-glycoprotein up-regulation during seizures. These findings suggest new intriguing possibilities to prevent and interrupt P-glycoprotein overexpression in epilepsy. Future studies are necessary to further evaluate the appropriateness of the strategy to enhance the efficacy of antiepileptic drugs.

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Prostaglandin EP4 receptor agonist protects against acute neurotoxicity

Cited by 80 publications

References 37 publications

The Prostanoid EP4 Receptor and Its Signaling Pathway

The Prostanoid EP4 Receptor and Its Signaling Pathway

Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury

Targeting Prostaglandin E₂ EP1 Receptors Prevents Seizure-Associated P-glycoprotein Up-Regulation

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Prostaglandin EP4 receptor agonist protects against acute neurotoxicity

Cited by 80 publications

References 37 publications

The Prostanoid EP4 Receptor and Its Signaling Pathway

The Prostanoid EP4 Receptor and Its Signaling Pathway

Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury

Targeting Prostaglandin E2 EP1 Receptors Prevents Seizure-Associated P-glycoprotein Up-Regulation

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Targeting Prostaglandin E₂ EP1 Receptors Prevents Seizure-Associated P-glycoprotein Up-Regulation