Neuroprotective effect of omidenepag on excitotoxic retinal ganglion cell death regulating COX-2–EP2–cAMP–PKA/Epac pathway via Neuron–Glia interaction

• DOI: 10.1016/j.neuroscience.2024.07.006
• Publication Date: 2024-07-09T23:26:43Z
• Authors: Natsuko Nakamura; Megumi Honjo; Reiko Yamagishi-K...; Rei Sakata; Sumiko Watanabe; Makoto Aihara
• Keywords: Retinal Ganglion Cells; Male; Neurons; N-Methylaspartate; Cell Death; Glutamic Acid; Receptors, Prostaglandin E, EP2 Subtype; Cyclic AMP-Dependent Protein Kinases; Rats; Rats, Sprague-Dawley; Mice, Inbred C57BL; Mice; Neuroprotective Agents; Cyclooxygenase 2; Cyclic AMP; Animals; Guanine Nucleotide Exchange Factors; Neuroglia; Signal Transduction

Glutamate excitotoxicity is involved in retinal ganglion cell (RGC) death various degenerative diseases, including ischemia-reperfusion injury and glaucoma. Excitotoxic RGC caused by both direct damage to RGCs indirect through neuroinflammation of glial cells. Omidenepag (OMD), a novel E prostanoid receptor 2 (EP2) agonist, recently approved intraocular pressure-lowering drug. The second messenger EP2 cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA) exchange directly activated cAMP (Epac). In this study, we investigated the neuroprotective effects OMD on excitotoxic focusing differences downstream signaling from perspective glia-neuron interactions. We established glutamate model vitro NMDA intravitreal injection vivo. vitro, rat primary were used an survival rate assay. MG5 cells (mouse microglial line) A1 (astrocyte for immunocytochemistry Western blotting evaluate expressions COX-1/2, PKA, Epac1/2, pCREB, cleaved caspase-3, inflammatory cytokines, neurotrophic factors. Mouse specimens underwent hematoxylin eosin staining, flat-mounted retina examination, immunohistochemistry. significantly suppressed death, caspase-3 expression, glia Moreover, it inhibited Epac1 cytokine expression promoted COX-2, factor expression. may have inhibition Epac pathway promotion COX-2-EP2-cAMP-PKA modulating interaction.