{"doi":"10.3390/pharmaceutics14050950","title":"3,6′- and 1,6′-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation","abstract":"(1) Background: An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF-α generation and thus has potent anti-inflammatory actions. Well-tolerated analogs may provide a stroke treatment and allow evaluation of the role of neuroinflammation in the ischemic brain. (2) Methods: Two novel pomalidomide derivatives, 3,6′-dithiopomalidomide (3,6′-DP) and 1,6′-dithiopomalidomide (1,6′-DP), were evaluated alongside pomalidomide in a rat middle cerebral artery occlusion (MCAo) stroke model, and their anti-inflammatory actions were characterized. (3) Results: Post-MCAo administration of all drugs lowered pro-inflammatory TNF-α and IL1-β levels, and reduced stroke-induced postural asymmetry and infarct size. Whereas 3,6′- and 1,6′-DP, like pomalidomide, potently bound to cereblon in cellular studies, 3,6′-DP did not lower Ikaros, Aiolos or SALL4 levels—critical intermediates mediating the anticancer/teratogenic actions of pomalidomide and IMiDs. 3,6′-DP and 1,6′-DP lacked activity in mammalian chromosome aberration, AMES and hERG channel assays –critical FDA regulatory tests. Finally, 3,6′- and 1,6′-DP mitigated inflammation across rat primary dopaminergic neuron and microglia mixed cultures challenged with α-synuclein and mouse LPS-challenged RAW 264.7 cells. (4) Conclusion: Neuroinflammation mediated via TNF-α plays a key role in stroke outcome, and 3,6′-DP and 1,6′-DP may prove valuable as stroke therapies and thus warrant further preclinical development.","journal":"Pharmaceutics","year":2022,"id":276498,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":467942,"name":"Dong Seok Kim","orcid":"0000-0001-5637-2469","position":1,"is_corresponding":false},{"id":715808,"name":"Shih‐Chang Hsueh","orcid":"0009-0002-0838-0223","position":2,"is_corresponding":false},{"id":947054,"name":"Kai‐Yun Chen","orcid":"0000-0002-2941-3197","position":3,"is_corresponding":false},{"id":947055,"name":"John Chung-Che Wu","orcid":"0000-0002-2243-6062","position":4,"is_corresponding":false},{"id":467943,"name":"Jia‐Yi Wang","orcid":"0000-0002-9106-3351","position":5,"is_corresponding":false},{"id":947056,"name":"Yi‐Syue Tsou","orcid":"0000-0001-8982-0440","position":6,"is_corresponding":false},{"id":715810,"name":"Inho Hwang","orcid":"0000-0003-2039-3895","position":7,"is_corresponding":false},{"id":947057,"name":"Yu‐Kyung Kim","orcid":"0000-0001-5682-0241","position":8,"is_corresponding":false},{"id":947058,"name":"Dayeon Gil","orcid":"0009-0008-9282-0300","position":9,"is_corresponding":false},{"id":947059,"name":"Euijung Jo","orcid":"0000-0003-1131-2723","position":10,"is_corresponding":false},{"id":715811,"name":"Baek‐Soo Han","orcid":"0000-0003-3610-7216","position":11,"is_corresponding":false},{"id":305915,"name":"David Tweedie","orcid":"0000-0002-8446-4544","position":12,"is_corresponding":false},{"id":468713,"name":"Daniela Lecca","orcid":null,"position":13,"is_corresponding":false},{"id":468714,"name":"Michael T. Scerba","orcid":null,"position":14,"is_corresponding":false},{"id":716350,"name":"Warren R. Selman","orcid":null,"position":15,"is_corresponding":false},{"id":333743,"name":"Barry J. Hoffer","orcid":"0000-0002-1122-9025","position":16,"is_corresponding":false},{"id":297917,"name":"Nigel H. Greig","orcid":"0000-0002-3032-1468","position":17,"is_corresponding":false},{"id":715812,"name":"Yung‐Hsiao Chiang","orcid":"0000-0002-8426-4016","position":18,"is_corresponding":false},{"id":947053,"name":"Yan-Rou Tsai","orcid":"0000-0002-3879-6177","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T00:28:30.709588Z","pmid":"35631536","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}