{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T20:55:55Z","timestamp":1792356955585,"version":"4.4.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T00:00:00Z","timestamp":1694131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:sec><jats:title>Background and purpose<\/jats:title><jats:p>Experimental studies suggest that ischemic postconditioning interferes with cell death mechanisms and reduces infarction during the acute phase after focal cerebral ischemia. Postconditioning may be a practically feasible way to promote stroke recovery, but many drawbacks prevent its clinical translation. First, all existing studies are mostly on acute 24\u2009h outcomes. Second, the mechanisms of protection and augmented long-term benefits remain unclear. Our study aims to define some of the mechanisms that explain long-term benefits of improved recovery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male Sprague\u2013Dawley rats were subjected to 100-min transient middle cerebral artery occlusion (MCAO) or postconditioning (100-min middle cerebral artery occlusion plus 10-min reperfusion plus 10-min reocclusion). After 3\u2009days or 2\u2009weeks, infarct volumes, western blot, and immunohistochemical markers of neurogenesis and angiogenesis were quantified. Fluorocitrate (FC) or saline were administrated ICV (intraventricular injection) every other day starting on day 5 after focal cerebral ischemia, animals were recovered for 2\u2009weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After postconditioning BDNF protein expression levels increased compared to animals subjected to MCAO. Immunostaining showed that BDNF increased specifically in astrocytes. Moreover, when astrocytes were metabolically inhibited by fluorocitrate the postconditioning neuroprotective effect together with the postconditioning-dependent new angiogenesis and neurogenesis, were no longer observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results suggest for the first time that therapeutic effects of postconditioning may involve the promotion of neurogenesis and angiogenic remodeling, via BDNF released by astrocytes, during the recovery phase after focal cerebral ischemia.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fncel.2023.1260389","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T12:21:16Z","timestamp":1694175676000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Postconditioning promotes recovery in the neurovascular unit after stroke"],"prefix":"10.3389","volume":"17","author":[{"given":"Elga","family":"Esposito","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Licastro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ornella","family":"Cuomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eng H.","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhide","family":"Hayakawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Pignataro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,8]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1523\/JNEUROSCI.0902-21.2021","article-title":"MMP2 and MMP9 activity is crucial for adult visual cortex plasticity in healthy and stroke-affected mice","volume":"42","author":"Akol","year":"2022","journal-title":"J. Neurosci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1002\/jnr.22256","article-title":"Astrocytes protect oligodendrocyte precursor cells via MEK\/ERK and PI3K\/Akt signaling","volume":"88","author":"Arai","year":"2010","journal-title":"J. Neurosci. Res."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1177\/0883073811408610","article-title":"Cellular mechanisms of neurovascular damage and repair after stroke","volume":"26","author":"Arai","year":"2011","journal-title":"J. Child Neurol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"164","DOI":"10.2174\/187152411796011303","article-title":"Astrocytes: targets for neuroprotection in stroke","volume":"11","author":"Barreto","year":"2011","journal-title":"Cent. Nerv. Syst. Agents Med. Chem."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"e29405","DOI":"10.1371\/journal.pone.0029405","article-title":"Circulating and brain BDNF levels in stroke rats. Relevance to clinical studies","volume":"6","author":"B\u00e9jot","year":"2011","journal-title":"PLoS One"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"2441","DOI":"10.1523\/JNEUROSCI.2121-18.2019","article-title":"Conditional BDNF delivery from astrocytes rescues memory deficits, spine density, and synaptic properties in the 5xFAD mouse model of Alzheimer disease","volume":"39","author":"de Pins","year":"2019","journal-title":"J. Neurosci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"2691","DOI":"10.1161\/STROKEAHA.115.009070","article-title":"Effects of Postconditioning on neurogenesis and angiogenesis during the recovery phase after focal cerebral ischemia","volume":"46","author":"Esposito","year":"2015","journal-title":"Stroke"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/s41586-020-2348-z","article-title":"Potential circadian effects on translational failure for neuroprotection","volume":"582","author":"Esposito","year":"2020","journal-title":"Nature"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.expneurol.2013.08.005","article-title":"Effects of normobaric oxygen on the progression of focal cerebral ischemia in rats","volume":"249","author":"Esposito","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"8186","DOI":"10.1523\/JNEUROSCI.4267-13.2014","article-title":"Astrocyte-derived BDNF supports myelin protein synthesis after cuprizone-induced demyelination","volume":"34","author":"Fulmer","year":"2014","journal-title":"J. Neurosci."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1111\/j.1471-4159.2008.05218.x","article-title":"The Akt signaling pathway contributes to postconditioning's protection against stroke; the protection is associated with the MAPK and PKC pathways","volume":"105","author":"Gao","year":"2008","journal-title":"J. Neurochem."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1038\/gt.2010.71","article-title":"BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease","volume":"17","author":"Giralt","year":"2010","journal-title":"Gene Ther."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"e55039","DOI":"10.1371\/journal.pone.0055039","article-title":"Brain-derived neurotrophic factor promotes vasculature-associated migration of neuronal precursors toward the ischemic striatum","volume":"8","author":"Grade","year":"2013","journal-title":"PLoS One"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1038\/jcbfm.2009.257","article-title":"Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice","volume":"30","author":"Hayakawa","year":"2010","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"8790","DOI":"10.1523\/JNEUROSCI.0168-16.2016","article-title":"Mutant huntingtin impairs BDNF release from astrocytes by disrupting conversion of Rab3a-GTP into Rab3a-GDP","volume":"36","author":"Hong","year":"2016","journal-title":"J. Neurosci."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"627325","DOI":"10.1155\/2013\/627325","article-title":"Microglia: an active player in the regulation of synaptic activity","volume":"2013","author":"Ji","year":"2013","journal-title":"Neural Plast."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1161\/01.STR.32.5.1201","article-title":"Cortical neurogenesis in adult rats after transient middle cerebral artery occlusion","volume":"32","author":"Jiang","year":"2001","journal-title":"Stroke"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.neuroscience.2013.03.062","article-title":"Ischemic postconditioning protects against focal cerebral ischemia by inhibiting brain inflammation while attenuating peripheral lymphopenia in mice","volume":"243","author":"Joo","year":"2013","journal-title":"Neuroscience"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.tcm.2007.03.002","article-title":"Brain-derived neurotrophic factor: a newly described mediator of angiogenesis","volume":"17","author":"Kermani","year":"2007","journal-title":"Trends Cardiovasc. Med."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"2149","DOI":"10.1128\/MCB.00008-13","article-title":"Brain-derived neurotrophic factor induces matrix metalloproteinase 9 expression in neurons via the serum response factor\/c-Fos pathway","volume":"33","author":"Kuzniewska","year":"2013","journal-title":"Mol. Cell. Biol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/nrn1106","article-title":"Mechanisms, challenges and opportunities in stroke","volume":"4","author":"Lo","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1161\/STROKEAHA.108.534404","article-title":"The neurovascular unit in health and disease: introduction","volume":"40","author":"Lo","year":"2009","journal-title":"Stroke"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1146\/annurev.neuro.28.051804.101459","article-title":"Adult neurogenesis in the mammalian central nervous system","volume":"28","author":"Ming","year":"2005","journal-title":"Annu. Rev. Neurosci."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"12963","DOI":"10.1523\/JNEUROSCI.3118-11.2011","article-title":"Matrix metalloproteinase-9 contributes to kindled seizure development in pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus","volume":"31","author":"Mizoguchi","year":"2011","journal-title":"J. Neurosci."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1002\/ana.10393","article-title":"Rat forebrain neurogenesis and striatal neuron replacement after focal stroke","volume":"52","author":"Parent","year":"2002","journal-title":"Ann. Neurol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1038\/jcbfm.2010.100","article-title":"The NCX3 isoform of the Na+\/Ca2+ exchanger contributes to neuroprotection elicited by ischemic postconditioning","volume":"31","author":"Pignataro","year":"2011","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/s41392-022-01064-1","article-title":"Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions","volume":"7","author":"Qin","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.1007\/s11064-010-0234-z","article-title":"Galectin-1 enhances astrocytic BDNF production and improves functional outcome in rats following ischemia","volume":"35","author":"Qu","year":"2010","journal-title":"Neurochem. Res."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"e3851","DOI":"10.1371\/journal.pone.0003851","article-title":"Delayed postconditioning protects against focal ischemic brain injury in rats","volume":"3","author":"Ren","year":"2008","journal-title":"PLoS One"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"e73244","DOI":"10.1371\/journal.pone.0073244","article-title":"Factors secreted by endothelial progenitor cells enhance neurorepair responses after cerebral ischemia in mice","volume":"8","author":"Rosell","year":"2013","journal-title":"PLoS One"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1007\/s11481-006-9020-8","article-title":"Up-regulation of BDNF in astrocytes by TNF-alpha: a case for the neuroprotective role of cytokine","volume":"1","author":"Saha","year":"2006","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"2165","DOI":"10.1161\/STROKEAHA.106.477331","article-title":"Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis","volume":"38","author":"Sch\u00e4bitz","year":"2007","journal-title":"Stroke"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/s41582-022-00703-z","article-title":"The neurovascular unit and systemic biology in stroke \u2013 implications for translation and treatment","volume":"18","author":"Tiedt","year":"2022","journal-title":"Nat. Rev. Neurol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/S0169-328X(02)00191-2","article-title":"Effect of ischemic preconditioning on the expression of putative neuroprotective genes in the rat brain","volume":"103","author":"Truettner","year":"2002","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jneumeth.2018.09.029","article-title":"Models and methods for conditioning the ischemic brain","volume":"310","author":"Vinciguerra","year":"2018","journal-title":"J. Neurosci. Methods"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"6427","DOI":"10.3892\/mmr.2015.4327","article-title":"Combination of early and delayed ischemic postconditioning enhances brain-derived neurotrophic factor production by upregulating the ERK-CREB pathway in rats with focal ischemia","volume":"12","author":"Wu","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1179\/1743132812Y.0000000019","article-title":"Injury and repair in the neurovascular unit","volume":"34","author":"Xing","year":"2012","journal-title":"Neurol. Res."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1172\/JCI9369","article-title":"VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain","volume":"106","author":"Zhang","year":"2000","journal-title":"J. Clin. Invest."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"138","DOI":"10.2174\/1877381801002010138","article-title":"The protective effects of ischemic Postconditioning against stroke: from rapid to delayed and remote Postconditioning","volume":"5","author":"Zhao","year":"2011","journal-title":"Open Drug Discov J."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"173","DOI":"10.2174\/138945012799201621","article-title":"From rapid to delayed and remote postconditioning: the evolving concept of ischemic postconditioning in brain ischemia","volume":"13","author":"Zhao","year":"2012","journal-title":"Curr. 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