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To address this, we tested compounds for neuroprotective effects in multiple zebrafish and mouse RP models, reasoning drugs effective across species and\/or independent of disease mutation may translate better clinically. We first performed a large-scale phenotypic drug screen for compounds promoting rod cell survival in a larval zebrafish model of inducible RP. We tested 2934 compounds, mostly human-approved drugs, across six concentrations, resulting in 113 compounds being identified as hits. Secondary tests of 42 high-priority hits confirmed eleven lead candidates. Leads were then evaluated in a series of mouse RP models in an effort to identify compounds effective across species and RP models, that is, potential pan-disease therapeutics. Nine of 11 leads exhibited neuroprotective effects in mouse primary photoreceptor cultures, and three promoted photoreceptor survival in mouse\n                    <jats:italic>rd1<\/jats:italic>\n                    retinal explants. Both shared and complementary mechanisms of action were implicated across leads. Shared target tests implicated\n                    <jats:italic>parp1<\/jats:italic>\n                    -dependent cell death in our zebrafish RP model. Complementation tests revealed enhanced and additive\/synergistic neuroprotective effects of paired drug combinations in mouse photoreceptor cultures and zebrafish, respectively. These results highlight the value of cross-species\/multi-model phenotypic drug discovery and suggest combinatorial drug therapies may provide enhanced therapeutic benefits for RP patients.\n                  <\/jats:p>","DOI":"10.7554\/elife.57245","type":"journal-article","created":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T08:00:15Z","timestamp":1624953615000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.57245","source":"Crossref","is-referenced-by-count":33,"title":["Large-scale phenotypic drug screen identifies neuroprotectants in zebrafish and mouse models of retinitis pigmentosa"],"prefix":"10.7554","volume":"10","author":[{"given":"Liyun","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, 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