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However, despite increasing knowledge of the physiologic, mechanistic, and imaging characterizations of the ischemic penumbra, no effective neuroprotective therapy has been found.\u00a0This study focuses on the neuroprotective bioactivity of docosanoid mediators: Neuroprotectin D1 (NPD1), Resolvin D1 (RvD1), and their combination in experimental stroke. Molecular targets of NPD1 and RvD1 are defined by following dose\u2013response and therapeutic window. We demonstrated that treatment with NPD1, RvD1, and combination therapy provides high-grade neurobehavioral recovery and decreases ischemic core and penumbra volumes even when administered up to 6\u00a0h after stroke. The expression of the following genes was salient: (a) <jats:italic>Cd163,<\/jats:italic> an anti-inflammatory stroke-associated gene, was the most differentially expressed gene by NPD1+RvD1, displaying more than a 123-fold upregulation in the ipsilesional penumbra (Lisi et al., Neurosci Lett 645:106\u2013112, 2017); (b) 100-fold upregulation takes place in astrocyte gene <jats:italic>PTX3<\/jats:italic>, a key regulator of neurogenesis and angiogenesis after cerebral ischemia (. Rodriguez-Grande et al., J Neuroinflammation 12:15, 2015); and (c) <jats:italic>Tmem119<\/jats:italic> and <jats:italic>P2y12<\/jats:italic>, two markers of homeostatic microglia, were found to be enhanced by ten- and fivefold, respectively (Walker et al. Int J Mol Sci 21:678, 2020). Overall, we uncovered that protection after middle cerebral artery occlusion (MCAo) by the lipid mediators elicits expression of microglia and astrocyte-specific genes (<jats:italic>Tmem119, Fcrls, Osmr, Msr1, Cd68, Cd163, Amigo2, Thbs1,<\/jats:italic> and <jats:italic>Tm4sf1<\/jats:italic>) likely participating in enhancing homeostatic microglia, modulating neuroinflammation, promoting DAMP clearance, activating NPC differentiation and maturation, synapse integrity and contributing to cell survival.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s10571-023-01363-3","type":"journal-article","created":{"date-parts":[[2023,6,4]],"date-time":"2023-06-04T09:01:45Z","timestamp":1685869305000},"page":"3555-3573","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["NPD1 Plus RvD1 Mediated Ischemic Stroke Penumbra Protection Increases Expression of Pro-homeostatic Microglial and Astrocyte Genes"],"prefix":"10.1007","volume":"43","author":[{"given":"Madigan M.","family":"Reid","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Audrey I.","family":"Kautzmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gethein","family":"Andrew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Obenaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranab K.","family":"Mukherjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa","family":"Khoutorova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff X.","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassia R.","family":"Roque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinaldo B.","family":"Oria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bola F.","family":"Habeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8687-9340","authenticated-orcid":false,"given":"Ludmila","family":"Belayev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9243-5444","authenticated-orcid":false,"given":"Nicolas G.","family":"Bazan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,6,4]]},"reference":[{"key":"1363_CR1","doi-asserted-by":"publisher","first-page":"107777","DOI":"10.1016\/j.celrep.2020.107777","volume":"31","author":"P Androvic","year":"2020","unstructured":"Androvic P, Kirdajova D, Tureckova J et al (2020) Decoding the transcriptional response to ischemic stroke in young and aged mouse brain. 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