{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T18:41:57Z","timestamp":1780339317692,"version":"3.54.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T00:00:00Z","timestamp":1659657600000},"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. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Hyperglycemia is one of the major risk factors for stroke and stroke\u00a0recurrence, leading to aggravated neuronal damage after cerebral ischemia\/reperfusion (I\/R). ERK1\/2 signaling pathway plays a vital role in cerebral ischemic injury. However, the role of the ERK1\/2 pathway in hyperglycemia-aggravated ischemic brain damage is not clear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Streptozotocin (STZ; 50 mg\/kg)-induced diabetes (blood glucose \u226512 mmol\/L) or control groups in adult Sprague-Dawley rats were further subdivided into I\/R (carotid artery\/vein clamping), I\/R + PD98059 (I\/R plus ERK1\/2 inhibitor), and Sham-operated groups (n = 10 each). Neurobehavioral status (Neurological behavior scores) and the volume of the cerebral infarction (TTC staining); brain mitochondrial potential (JCI ratio test) and cell apoptosis (TUNEL assay); RAS protein expression, phosphorylated\/total ERK1\/2 and Drp-1 (Dynamic-related protein 1) protein levels (Western blotting); mitochondrial fusion-related proteins mitofusin-1\/2 (Mfn1\/2), optic atrophy (OPA-1) and mitochondrial fission 1 (Fis1), and autophagy-associated proteins Beclin-1, LC3-I\/II and P62 (Western blotting and immunohistochemistry) were analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The I\/R + PD98059 group demonstrated better neurobehavior on the 1<jats:sup>st<\/jats:sup> (p &amp;lt; 0.05) and the 3<jats:sup>rd<\/jats:sup> day (p &amp;lt; 0.01) than the I\/R group. Compared to the Sham group, cerebral ischemia\/reperfusion brought about neuronal damage in the I\/R group (p &amp;lt;0.01). However, treatment with PD98059 showed an improved situation with faster recovery of mitochondrial potential and less apoptosis of neuronal cells in the I\/R + PD98059 group (p &amp;lt; 0.01). The I\/R group had a higher-level expression of RAS and phosphorylated ERK1\/2 and Drp-1 than the diabetes mellitus (DM) group (p &amp;lt; 0.01). The PD98059 treated group showed decreased expression of p-ERK1\/2, p-Drp-1, Fis1, and Beclin-1, LC3-I\/II and P62, but increased Mfn1\/2 and OPA-1 than the I\/R group (p &amp;lt; 0.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Hyperglycemia worsens cerebral ischemia\/reperfusion-induced neuronal damage <jats:italic>via<\/jats:italic> ERK1\/2 activated cell autophagy and mitochondrial fission.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2022.928591","type":"journal-article","created":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T06:33:03Z","timestamp":1659681183000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Hyperglycemia aggravates ischemic brain damage via ERK1\/2 activated cell autophagy and mitochondrial 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