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. 2024 Mar 15;25(6):3328.
doi: 10.3390/ijms25063328.

Steroid-Induced Ocular Hypertension in Mice Is Differentially Reduced by Selective EP2, EP3, EP4, and IP Prostanoid Receptor Agonists

Najam A Sharif  1   2   3   4   5   6   7   8 , J Cameron Millar  8 , Gulab Zode  9 , Takashi Ota  10
Affiliations

Steroid-Induced Ocular Hypertension in Mice Is Differentially Reduced by Selective EP2, EP3, EP4, and IP Prostanoid Receptor Agonists

Najam A Sharif et al. Int J Mol Sci. .

Abstract

We tested five chemically and metabolically stable prostaglandin (PG) receptor agonists in a mouse model of dexamethasone-induced ocular hypertension (OHT). Whilst all compounds significantly (p < 0.05, ANOVA) lowered intraocular pressure (IOP) after twice-daily bilateral topical ocular dosing (5 µg/dose) over three weeks, the time course and magnitude of the responses varied. The onset of action of NS-304 (IP-PG receptor agonist) and rivenprost (EP4-PG receptor agonist) was slower than that of misoprostol (mixed EP2/EP3/EP4-PG receptor agonist), PF-04217329 (EP2-PG receptor agonist), and butaprost (EP2-PG receptor agonist). The rank order of IOP-lowering efficacies aligned with the onset of actions of these compounds. Peak IOP reductions relative to vehicle controls were as follows: misoprostol (74.52%) = PF-04217329 (74.32%) > butaprost (65.2%) > rivenprost (58.4%) > NS-304 (55.3%). A literature survey indicated that few previously evaluated compounds (e.g., latanoprost, timolol, pilocarpine, brimonidine, dorzolamide, cromakalim analog (CKLP1), losartan, tissue plasminogen activator, trans-resveratrol, sodium 4-phenyl acetic acid, etc.) in various animal models of steroid-induced OHT were able to match the effectiveness of misoprostol, PF-04217329 or butaprost. Since a common feature of the latter compounds is their relatively high affinity and potency at the EP2-PG receptor sub-type, which activates the production of intracellular cAMP in target cells, our studies suggest that drugs selective for the EP2-PG receptor may be suited to treat corticosteroid-induced OHT.

Keywords: Butaprost; EP2 receptor agonist; IOP; PF-04217329; ocular hypertension; steroid.

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Conflict of interest statement

Author N.A.S. was employed by the company Santen Inc. Author T.O. is employed by the company Santen Pharmaceuticals Co., Ltd. Author N.A.S. is currently employed by Nanoscope Therapeutics Inc., and the affiliation is only provided for current address purposes. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic of multiple mechanisms of glucocorticoid-induced elevation of intraocular pressure (IOP). Vertical arrows indicate the following: ↑ (Increased); ↓ (Decreased).
Figure 2
Figure 2
Chemical structures of the major prostaglandin receptor type agonists used and/or discussed in this article. The blue labels indicate the preference of the compound to primarily interact with the particular prostanoid receptor type or sub-type shown over the other receptors in this family.
Figure 3
Figure 3
The ability of various prostaglandin receptor-type-selective agonist compounds to reduce IOP in DEX-induced OHT in mice is shown. The vertical arrow indicates when twice-daily topical ocular dosing commenced, which then continued for the remainder of the experiment. Data are mean ± SDM from 5 mice/group. In all cases, weekly periocular injections of DEX significantly elevated IOP (p < 0.001). Also, in all cases, subsequent drug treatment significantly reduced IOP in both the DEX OHT eyes and the ocular normotensive control eyes. *** p < 0.001; the significance of difference between PG agonist and corresponding PG Vehi groups in DEX-injected eyes; # p < 0.05; ### p < 0.001; the significance of difference between PG agonist and corresponding PG Vehi groups in DEX Vehi injected eyes, as indicated by 2-Factor ANOVA followed by the Holm-Sidak post-hoc test. Vertical arrow (↓) indicates maximum % reduction in IOP in DEX group following topical ocular drug treatment.
Figure 4
Figure 4
Schematic showing the interconnectivity and the signal transduction mechanisms and pathways within endothelial-like and smooth muscle-like TM cells in the TM tissue. The endothelial nitric oxide (NO) synthase (eNOS), NO, soluble guanylate cyclase, cGMP, PG EP2 receptors, and their signaling components all play a major role in the final IOP-reducing actions of EP2 receptor agonists (A). The cytoplasmic and nuclear components of the TM cells are also involved in terms of amplification of the overall biological response through upregulation of the gene that encodes cyclooxygenase-2, which generates endogenous PGs that cause IOP lowering via their cognate receptors (B). The heterogeneity of cells within the TM tissue (smooth muscle-like; endothelial-like, etc. as in (A)) permits cooperative local signaling to occur that ensures eventual homeostasis in terms of regulation of IOP.
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