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We have reported the neuroprotective effect of low dose naltrexone (LDN) in type 2 diabetic (\n                    <jats:italic>db\/db)<\/jats:italic>\n                    mice post\u2010hypoxia\u2010ischemia (HI) injury. In this study, we explored LDN mediated mechanisms of neuroprotection in diabetic mice. Adult male\n                    <jats:italic>db\/db<\/jats:italic>\n                    and non\u2010diabetic (\n                    <jats:italic>db\/+)<\/jats:italic>\n                    mice underwent right common carotid artery occlusion followed by hypoxia (8% O\n                    <jats:sub>2<\/jats:sub>\n                    ) for 20\u2009min. LDN (1\u2009mg\/kg) was administered at 4, 24, and 48\u2009h post\u2010HI, and mice were euthanized at 72\u2009h. Blood and brain tissue were analyzed for cytokines and growth factors by multiplex array, immunofluorescence and western blotting. LDN treatment resulted in an increased number of reactive astrocytes in the motor cortex and caudate and hippocampus of diabetic mice, which was decreased in\n                    <jats:italic>db\/+<\/jats:italic>\n                    mice, except in the CA3 hippocampal region. LDN did not show any significant change in the cytokine response between\n                    <jats:italic>db\/+<\/jats:italic>\n                    and\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice. However, the vascular endothelial growth factor (VEGF) levels in the plasma and brain tissue of LDN\u2010treated\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice that were significantly reduced in the vehicle\u2010treated\n                    <jats:italic>db\/db<\/jats:italic>\n                    group were restored to the level of the\n                    <jats:italic>db\/+<\/jats:italic>\n                    treated group. When infarct size was categorized, LDN increased VEGF+ neurons in the motor cortex and caudate in small infarcts, and in the motor cortex of large infarcts, in\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice. The study suggests that acute LDN increased the number of VEGF+ neurons and prevented astrocytic cell death in\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice, thus enhancing neuroprotection following brain HI injury.\n                  <\/jats:p>","DOI":"10.1002\/jnr.70125","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T02:44:27Z","timestamp":1775184267000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Acute Opioid Receptor Blockade Restores Vascular Endothelial Growth Factor and Astrocyte Response in\n                    <i>db<\/i>\n                    \/\n                    <i>db<\/i>\n                    Mouse Brain Following Hypoxia\u2010Ischemic Injury"],"prefix":"10.1002","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7013-7040","authenticated-orcid":false,"given":"Rashmi","family":"Kumari","sequence":"first","affiliation":[{"name":"Department of Neuroscience and Experimental Therapeutics College of Medicine, Penn State University  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth A.","family":"Proctor","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Experimental Therapeutics College of Medicine, Penn State University  Hershey Pennsylvania USA"},{"name":"Department of Neurosurgery College of Medicine, Penn State University  Hershey Pennsylvania USA"},{"name":"Department of Biomedical Engineering Penn State University  University Park Pennsylvania USA"},{"name":"Department of Engineering Science and Mechanics Penn State Neuroscience Institute  University Park Pennsylvania USA"},{"name":"Huck Institutes for the Life Sciences, Penn State University  University Park Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Experimental Therapeutics College of Medicine, Penn State University  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.164.13.1422"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-023-01282-2"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1537-1891(03)00011-9"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/61.4.339"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clineuro.2020.106061"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.18103\/mra.v8i4.2081"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/10738584221120803"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1006\/scdb.2001.0290"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2000.tb00247.x"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.103348"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19051362"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2015.03.005"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.175067"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.59368\/agingbio.20240032"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00905-6"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc06-2363"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/325253a0"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.106.481390"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.18.10242"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.9346"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23010014"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.npep.2023.102325"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000165925.20413.14"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-023-03938-4"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43440-022-00382-z"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600382"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2009.221"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2011.07487.x"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-020-00221-2"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.330612"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2016.88"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63821-7"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-007-9387-9"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2018.05.020"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apjtm.2016.04.001"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23088"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.26.15809"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.060018"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2015.06.016"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1993.264.4.C995"},{"key":"e_1_2_10_42_1","doi-asserted-by":"crossref","unstructured":"Nilsson 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