The inflammatory mediator prostaglandin E₂ (PGE₂) binds to G_s-coupled EP2 and EP4 receptors. These receptors are located in the locus coeruleus (LC), the principal noradrenergic nucleus in the brain, but their functional role remains unknown. In this study, the PGE₂ EP2 and EP4 receptors in LC cells from male rat brain slices were pharmacologically characterized by single-unit extracellular electrophysiology. The EP2 receptor agonists butaprost (0.01-10 μM) and treprostinil (0.03-10 µM) and the EP4 receptor agonists rivenprost (0.01 nM-1 µM) and TCS2510 (0.20 nM-2 µM) increased the firing rate of LC neurons in a concentration-dependent manner. The EP2 receptor antagonist PF-04418948 (10 nM) hindered the excitatory effect of butaprost and treprostinil while the EP4 receptor antagonist L-161,982 (30 and 300 nM) blocked the excitatory effect caused by rivenprost and TCS2510. The effects of butaprost and rivenprost were prevented by extracellular sodium replacement but were not modified by the protein kinase A (PKA) activator 8-Br-cAMP (1 mM) or the inhibitor H-89 (10 μM). However, the G_βγ subunit blocker gallein (20 μM) hindered the stimulatory effect of butaprost while the G_αs subunit inhibitor NF449 (10 µM) prevented that of rivenprost. Finally, rivenprost-induced stimulation (30 nM) was not occluded by butaprost (1 µM). In conclusion, activation of EP2 and EP4 receptors excites LC noradrenergic neurons through sodium-dependent currents via different G protein subunits in male rat brain slices. EP2 and EP4 in the LC may constitute pharmacological targets for the treatment of pain, fever, drug addiction, anxiety and neuroinflammatory diseases.

01 Oct 2023·Journal of Ocular Pharmacology and Therapeutics

Ocular Treatments Targeting Separate Prostaglandin Receptors in Mice Exhibit Alterations in Intraocular Pressure and Optic Nerve Lipidome

Article

Author: Sharif, Najam A ; Arcuri, Jennifer ; Elbaz, Abdelrahman ; Bhattacharya, Sanjoy K

Background: Prostaglandin (PG) receptor agonists are the first-line eyedrop medication treatment for glaucoma. The pathophysiology of this disease is not completely known, and elevated intraocular pressure (IOP) is the key risk factor. The membranes of the axons (of the retinal ganglion cells) passing through the optic nerve (ON) head experience significant damage. Lipids are an essential component of the cell's membranes, and their profile changes owing to neurodegeneration. In this investigation, three agonists for distinct PG receptors were used to lower IOP and to determine their effect on the ON lipids. We utilized DBA/2J mice as a model of progressive IOP increase and C57BL/6J mice as a model of ON crush. Methods: DBA/2J and C57BL/6J mice were treated daily for 2 weeks with Latanoprost, PF-04217329, or Rivenprost. The IOP was measured every 2 days and pattern electroretinogram was conducted for DBA/2J throughout the study. Lipidomics of ONs were performed for each model and treatment group. Results: Of the tested compounds, Latanoprost and Rivenprost were the most effective agents decreasing IOP in DBA/2J mice. Triglyceride levels increased in the ONs of DBA/2J mouse model, but phosphatidylethanolamine levels underwent highest level changes in the C57BL/6J mouse model when treated with Latanoprost. Conclusions: Topical ocular FP- and EP4-receptor agonists appreciably lowered IOP in the DBA/2J mice representing pigmentary glaucoma. The observed changes in ON lipidomics in the different models of neurodegeneration suggest possible use of such measures in the development of more effective medicines for both IOP reduction and ON protection.

01 Jul 2022·NeuroscienceQ3 · MEDICINE

The EP3 and EP4 Receptor Subtypes both Mediate the Fever-producing Effects of Prostaglandin E2 in the Rostral Ventromedial Preoptic Area of the Hypothalamus in Rats

Q3 · MEDICINE

Article

Author: Osaka, Toshimasa

This study aimed to re-examine the receptor subtype that mediates the fever-producing effects of prostaglandin E₂ (PGE₂) in the rostral ventromedial preoptic area (rvmPOA) of the hypothalamus. Among the four subtypes of PGE₂ receptors (EP₁, EP₂, EP₃, and EP₄), EP₃ receptor is crucially involved in the febrile effects of PGE₂. However, it is possible for other subtypes of PGE₂ receptor to contribute in the central mechanism of fever generation. Accordingly, effects of microinjection of PGE₂ receptor subtype-specific agonists or antagonists were examined at the locus where a microinjection of a small amount (420 fmol) of PGE₂ elicited prompt increases in the O₂ consumption rate (VO₂), heart rate, and colonic temperature (T_c) in the rvmPOA of urethane-chloralose-anesthetized rats. The EP₃ agonist sulprostone mimicked, whereas its antagonist L-798,106 reduced, the febrile effects of PGE₂ microinjected into the same site. Similarly, the EP₄ agonist rivenprost mimicked, whereas its antagonist ONO-AE3-208 reduced, the effects of PGE₂ microinjected into the same site. In contrast, microinjection of the EP₁ agonist iloprost induced a very small increase in VO₂ but did not have significant influences on the heart rate and T_c, whereas its antagonist, AH6809, did not affect the PGE₂-induced responses. Microinjection of the EP₂ agonist butaprost had no effects on the VO₂, heart rate, and T_c. The results suggest that the EP₃ and EP₄ receptor subtypes are both involved in the fever generated by PGE₂ in the rvmPOA.

100 Deals associated with Rivenprost

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Indication	Highest Phase	Country/Location	Organization	Date
Fractures, Bone	Phase 2	JP	Ono Pharmaceutical Co., Ltd.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASN2021	Not Applicable	Fibrosis	-	Rivenprost	vszsdasyoz(xomkptyvzr) = hrptzlvwpt csntiqtfzt (bfnitrfhky )	Positive	27 Oct 2021

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