{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:21:11Z","timestamp":1787016071469,"version":"build-2736575974"},"reference-count":65,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2018,7,11]],"date-time":"2018-07-11T00:00:00Z","timestamp":1531267200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000861","name":"Sparks","doi-asserted-by":"publisher","award":["07UCL02"],"award-info":[{"award-number":["07UCL02"]}],"id":[{"id":"10.13039\/501100000861","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>This study identifies phosphorylated extracellular signal\u2010regulated kinase (ERK) to be immediately diminished followed by a rapid if transient increase for up to 4\u00a0h following hypoxic\u2013ischaemic insult (HI) in the neonatal mouse.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Phosphorylated ERK up\u2010regulation was prevented with systemic injection of the mitogen\u2010activated protein kinase kinase (MEK) inhibitor SL327. Treatment with SL327 both pre\u2010 and post\u2010HI gave a strong reduction in the number of dying cells and microgliosis.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>By utilising transgenic mouse mutations, we observe that neuronal ERK2 significantly contributes to tissue damage, while ERK1 and astrocytic ERK2 are neuroprotective.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Compared to global inactivation, selective cell\u2010specific interference with ERK activity could result in stronger neuroprotection.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Hypoxia\u2013ischaemia (HI) is a major cause of neonatal brain injury resulting in cerebral palsy, epilepsy, cognitive impairment and other neurological disabilities. The role of extracellular signal\u2010regulated kinase (ERK) isoforms and their mitogen\u2010activated protein kinase kinase (MEK)\u2010dependent phosphorylation in HI has previously been explored but remains unresolved at cellular level. This is pertinent given the growing awareness of the role of non\u2010neuronal cells in neuroprotection. Using a modified Rice\u2013Vannucci model of HI in the neonatal mouse we observed time\u2010 and cell\u2010dependent ERK phosphorylation (pERK), with strongly up\u2010regulated pERK immunoreactivity first in periventricular white matter axons within 15\u201345\u00a0min of HI, followed by forebrain astrocytes and neurons (1\u20134\u00a0h post\u2010HI), and return to baseline by 16\u00a0h. We explored the effects of pharmacological ERK blockade through the MEK inhibitor SL327 on neonatal HI\u2010brain damage following HI alone (30 or 60\u00a0min) or lipopolysaccharide (LPS)\u2010sensitised HI insult (30\u00a0min). Global inhibition of ERK phosphorylation with systemically applied SL327 abolished forebrain pERK immunoreactivity, and significantly reduced cell death and associated microglial activation at 48\u00a0h post\u2010HI. We then explored the effects of cell\u2010specific ERK2 deletion alone or in combination with global ERK1 knockout under the same conditions of HI insult. Neuronal ERK2 deletion strongly decreased infarct size, neuronal cell death and microglial activation in grey matter following both HI alone or LPS\u2010sensitised HI. ERK1 deletion attenuated the protective effect of neuronal ERK2 deletion. Removal of astroglial ERK2 produced a reverse response, with a 3\u2010 to 4\u2010fold increase in microglial activation and cell death. Our data suggest a cell\u2010specific and time\u2010dependent role of ERK in neonatal HI, with a predominant, neurotoxic effect of neuronal ERK2, which is counteracted by neuroprotection by ERK1 and astrocytic ERK2. Overall, global pharmacological inhibition of ERK phosphorylation is strongly neuroprotective.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp275649","type":"journal-article","created":{"date-parts":[[2018,6,6]],"date-time":"2018-06-06T07:51:29Z","timestamp":1528271489000},"page":"6043-6062","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Extracellular signal\u2010regulated kinase 2 has duality in function between neuronal and astrocyte expression following neonatal hypoxic\u2013ischaemic cerebral injury"],"prefix":"10.1113","volume":"596","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9472-731X","authenticated-orcid":false,"given":"Laura","family":"Thei","sequence":"first","affiliation":[{"name":"UCL Institute for Women's Health Maternal and Fetal Medicine Perinatal Brain Repair Group  London WC1E 6HX UK"},{"name":"School of Pharmacy University of Reading  Reading RG6 6UA 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