{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:48:48Z","timestamp":1791877728257,"version":"4.3.4"},"reference-count":72,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>\n                      Cerebral ischaemia is a leading cause of death in older adults and imposes a substantial global economic burden. Recent studies indicate that inhibiting the G\u03b1\n                      <jats:sub>s<\/jats:sub>\n                      \u2010coupled EP\n                      <jats:sub>2<\/jats:sub>\n                      receptor reduces ischaemic brain injury by modulating neuroinflammation. However, these findings derive from the transient middle cerebral artery occlusion (tMCAO) model, which represents only a small subset of large\u2010vessel occlusion (LVO) cases with successful recanalisation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      We characterised the pharmacokinetic parameters of selective EP\n                      <jats:sub>2<\/jats:sub>\n                      antagonists CJ\u201018, CJ\u201019 and CJ\u201021 that we recently developed. We evaluated their therapeutic efficacy in mice subjected to permanent MCAO (pMCAO), a model that more accurately reflects the majority of LVO cases, and assessed the impact of EP\n                      <jats:sub>2<\/jats:sub>\n                      inhibition on brain injury and inflammation. Finally, we examined the effects of EP\n                      <jats:sub>2<\/jats:sub>\n                      inhibition in neuron\u2013glia mixed cultures exposed to oxygen\u2013glucose deprivation (OGD) without reoxygenation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      After systemic administration in mice, new compounds exhibited favourable plasma half\u2010lives and brain penetration. In the pMCAO model, treatment with EP\n                      <jats:sub>2<\/jats:sub>\n                      antagonists significantly reduced brain infarction in both male and female mice, in a dose\u2010dependent manner, whilst improving sensorimotor performance without affecting muscle strength. These benefits were accompanied by reduced neuronal death, lowered pro\u2010inflammatory cytokines and attenuated reactive gliosis within the ischaemic penumbra. In addition, EP\n                      <jats:sub>2<\/jats:sub>\n                      inhibition by CJ\u201018 conferred marked neuroprotection in neuron\u2013glia co\u2010cultures exposed to prolonged OGD, preserving neurite integrity and postsynaptic density.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>\n                      This proof\u2010of\u2010concept study supports our drug\u2010like EP\n                      <jats:sub>2<\/jats:sub>\n                      receptor antagonists, particularly CJ\u201018, as potential treatments for permanent focal cerebral ischaemia.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70709","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:22:45Z","timestamp":1791876165000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Highly potent, brain\u2010penetrant EP\n                    <sub>2<\/sub>\n                    receptor antagonists for the treatment of permanent focal cerebral ischaemia in male and female mice"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0540-5173","authenticated-orcid":false,"given":"Zhen","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy The University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Neuroscience Institute The University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4507-2593","authenticated-orcid":false,"given":"Chenyao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy The University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3326-9692","authenticated-orcid":false,"given":"Eun Bee","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy The University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Neuroscience Institute The University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2703-4011","authenticated-orcid":false,"given":"M. Dennis","family":"Leo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy The University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4483-183X","authenticated-orcid":false,"given":"Jiukuan","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy The University of Houston  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3264-6271","authenticated-orcid":false,"given":"Jiawang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy The University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3729-8456","authenticated-orcid":false,"given":"Ying","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy The University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3955-8928","authenticated-orcid":false,"given":"Jianxiong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy The University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Neuroscience Institute The University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01495.x"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70230"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70229"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01218"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prostaglandins.2009.04.003"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00018"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.5c00780"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.124.049541"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.125"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-025-08636-1"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1224398"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.17441"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1586\/14737175.2016.1134322"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.3758\/BRM.41.4.1149"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.3758\/bf03193146"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/17474930241308142"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-77678-8"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00567"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1089\/jop.2020.0071"},{"key":"e_1_2_12_21_1","unstructured":"Ganesh T. 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