Effect of Prostaglandin E Receptor Subtype EP4 Selective Agonist on the Secretion of Tumor Necrosis Factor-?? by Macrophages in Acute Ethanol-Loaded Rats

Differential neurological outcomes due to prostaglandin E2 activating G-protein-coupled prostaglandin E (EP) receptors have been observed. Here, we investigated the action of the EP4/EP3 agonist 1-hydroxyPGE1 (1-OHPGE1) in modulating transient ischemic brain damage. C57BL/6 mice were pretreated 50 min before transient occlusion of the middle cerebral artery with an intraventricular injection of 1-OHPGE1 (0.1, 0.2, 2.0 nmol/0.2 microL). Brain damage 4 days after reperfusion, as estimated by infarct volume, was significantly reduced by more than 19% with 1-OHPGE1 in the two higher-dose groups (P < 0.05). To further address whether protection also was extended to neurons, primary mouse cultured neuronal cells were exposed to N-methyl-D-aspartate. Co-treatment with 1-OHPGE1 resulted in significant neuroprotection (P < 0.05). To better understand potential mechanisms of action and to test whether changes in cyclic adenosine monophosphate (cAMP) levels and downstream signaling would be neuroprotective, we measured cAMP levels in primary neuronal cells. Brief exposure to 1-OHPGE1 increased cAMP levels more than twofold and increased the phosphorylation of extracellular-regulated kinases at positions Thr-202/Tyr-204. In a separate cohort of animals, 1-OHPGE1 at all doses tested produced no significant effect on the physiological parameters of core body temperature, mean arterial pressure and relative cerebral blood flow observed following drug treatment. Together, these results suggest that modulation of PGE2 receptors that increase cAMP levels and activate extracellular-regulated kinases 1/2 caused by treatment with 1-OHPGE1 can be protective against neuronal injury induced by focal ischemia.

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The Prostanoid EP4 Receptor and Its Signaling Pathway

Yokoyama

Iwatsubo²,

Umemura³

et al. 2013

Pharmacol Rev

227

257

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Effect of Prostaglandin E Receptor Subtype EP4 Selective Agonist on the Secretion of Tumor Necrosis Factor-?? by Macrophages in Acute Ethanol-Loaded Rats

Abstract: An EP4 agonist ONO-AE1-437 suppresses excess TNF-alpha secretion from macrophages and seems promising for future trial in patients with severe alcoholic hepatitis.

Cited by 3 publications

References 35 publications

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Chronic effects of celecoxib, a cyclooxygenase-2 inhibitor, cause enhanced alcohol-induced liver steatosis in rats

1‐HydroxyPGE₁ reduces infarction volume in mouse transient cerebral ischemia

The Prostanoid EP4 Receptor and Its Signaling Pathway

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Effect of Prostaglandin E Receptor Subtype EP4 Selective Agonist on the Secretion of Tumor Necrosis Factor-?? by Macrophages in Acute Ethanol-Loaded Rats

Abstract: An EP4 agonist ONO-AE1-437 suppresses excess TNF-alpha secretion from macrophages and seems promising for future trial in patients with severe alcoholic hepatitis.

Cited by 3 publications

References 35 publications

Chronic effects of celecoxib, a cyclooxygenase-2 inhibitor, cause enhanced alcohol-induced liver steatosis in rats

Chronic effects of celecoxib, a cyclooxygenase-2 inhibitor, cause enhanced alcohol-induced liver steatosis in rats

1‐HydroxyPGE1 reduces infarction volume in mouse transient cerebral ischemia

The Prostanoid EP4 Receptor and Its Signaling Pathway

Contact Info

Product

Resources

About

1‐HydroxyPGE₁ reduces infarction volume in mouse transient cerebral ischemia