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We utilize a chick excitotoxic retinal damage model to investigate ibudilast's potential to protect retinal neurons. Using single cell RNA\u2010sequencing (scRNA\u2010seq), we find that MIF, putative MIF receptors CD74 and CD44, and several PDEs are upregulated in different retinal cells during damage. Intravitreal ibudilast is well tolerated in the eye and causes no evidence of toxicity. Ibudilast effectively protects neurons in the inner nuclear layer from NMDA\u2010induced cell death, restores retinal layer thickness on spectral domain optical coherence tomography (SD\u2010OCT), and preserves retinal neuron function, particularly for the ON bipolar cells, as assessed by electroretinography. PDE inhibition seems essential for ibudilast's neuroprotection, as AV1013, the analogue that lacks PDE inhibitor activity, is ineffective. scRNA\u2010seq analysis reveals upregulation of multiple signaling pathways, including mTOR, in damaged M\u00fcller glia (MG) with ibudilast treatment compared to AV1013. Components of mTORC1 and mTORC2 are upregulated in both bipolar cells and MG with ibudilast. The mTOR inhibitor rapamycin blocked accumulation of pS6 but did not reduce TUNEL positive dying cells. Additionally, through ligand\u2010receptor interaction analysis, crosstalk between bipolar cells and MG may be important for neuroprotection. We have identified several paracrine signaling pathways that are known to contribute to cell survival and neuroprotection and might play essential roles in ibudilast function. These findings highlight ibudilast's potential to protect inner retinal neurons during damage and show promise for future clinical translation.<\/jats:p>","DOI":"10.1002\/glia.24657","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T02:05:28Z","timestamp":1738893928000},"page":"905-927","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ibudilast Protects Retinal Bipolar Cells From Excitotoxic Retinal Damage and Activates the\n                    <scp>mTOR<\/scp>\n                    Pathway"],"prefix":"10.1002","volume":"73","author":[{"given":"Sumaya","family":"Hamadmad","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Havener Eye Institute The Ohio State University, Wexner Medical Center  Columbus Ohio 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