{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T22:36:24Z","timestamp":1782167784257,"version":"3.54.5"},"reference-count":54,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JNS"],"published-print":{"date-parts":[[2011,4]]},"abstract":"\nObject<\/jats:title>\nDelayed cerebral ischemia after subarachnoid hemorrhage (SAH) remains a major cause of death and disability. It has been hypothesized that cerebrovascular upregulation of vasoconstrictor receptors is a key step in the development of delayed cerebral ischemia. Upregulation of endothelin-B (ETB<\/jats:sub>) and 5-hydroxytryptamine 1B (5-HT1B<\/jats:sub>) receptors has been demonstrated in cerebral artery smooth muscles in the delayed ischemic phase after experimental SAH, and intracellular signaling via the mitogen-activated protein kinase kinase (MEK)\u2013extracellular signal-regulated kinase 1\/2 pathway has been shown to be involved in this upregulation. The aim in the present study was to determine whether treatment with the MEK1\/2 inhibitor U0126 can prevent cerebrovascular receptor upregulation and improve functional outcome after experimental SAH in rats.<\/jats:p><\/jats:sec>\n\nMethods<\/jats:title>\nSubarachnoid hemorrhage was induced in male Sprague-Dawley rats by the injection of 250 \u03bcl of autologous blood into the basal cisterns. Either U0126 or vehicle was intracisternally administered at 6, 12, 24, and 36 hours after SAH. Smooth muscle ETB<\/jats:sub> and 5-HT1B<\/jats:sub> receptor upregulation was studied in isolated cerebral artery segments through immunohistochemical and myographic studies of contractile responses to receptor-specific agonists. Gross sensorimotor function in the rats after SAH was assessed using a rotating pole test.<\/jats:p><\/jats:sec>\n\nResults<\/jats:title>\nContractile concentration-response curves for middle cerebral artery (MCA) and basilar artery (BA) segments to endothelin-1 (ET-1) and 5-carboxamidotryptamine (5-CT) were shifted leftward for SAH-induced compared with shamoperated rats due to enhanced contractile responses to individual doses of the agonists (for example, contractile responses of the BA to 3 \u00d7 10\u221210<\/jats:sup> M of ET-1 and 3 \u00d7 10\u22127<\/jats:sup> M of 5-CT were 9.98 \u00b1 5.01% and 16.75 \u00b1 3.62% of the maximal contractile capacity, respectively, in sham-operated rats and 62.78 \u00b1 9.9% and 45.44 \u00b1 10.62%, respectively, in SAH-induced rats). In vivo treatment with 0.19 \u03bcg\/kg U0126 normalized responses in the SAH-induced rats to levels in the sham-operated rats. Protein expression of ETB<\/jats:sub> and 5-HT1B<\/jats:sub> receptors in cerebrovascular smooth muscles from SAH-induced rats was increased to 175 \u00b1 33.17% and 167.7 \u00b1 24.74%, respectively, of the levels in sham-operated rats. Endothelin-B and 5-HT1B<\/jats:sub> expression levels in U0126-treated SAH-induced rats were at the levels in sham-operated rats (101.9 \u00b1 13.38% and 91.44 \u00b1 16.75%, respectively). In a rotating pole test used to assess gross sensorimotor function on the 2nd day after surgery, sham-operated rats achieved an average score of 5.37 \u00b1 0.23, SAH-induced rats scored 3.35 \u00b1 0.67, and SAH-induced U0126-treated rats scored 5.00 \u00b1 0.4.<\/jats:p><\/jats:sec>\n\nConclusions<\/jats:title>\nThe authors demonstrated that experimental SAH induces upregulation of ETB<\/jats:sub> and 5-HT1B<\/jats:sub> receptors in cerebrovascular smooth muscles and that treatment with the MEK1\/2 inhibitor U0126 abolishes this receptor upregulation. They also demonstrated that experimental SAH results in sensorimotor deficits as assessed by a rotating pole test. These deficits were alleviated by U0126 treatment, suggesting that cerebrovascular receptor upregulation is critical for the functional outcome of delayed cerebral ischemia. The authors suggest that inhibition of MEK1\/2 may be a promising new SAH treatment strategy.<\/jats:p><\/jats:sec>","DOI":"10.3171\/2010.6.jns1018","type":"journal-article","created":{"date-parts":[[2010,7,2]],"date-time":"2010-07-02T15:28:14Z","timestamp":1278084494000},"page":"1143-1153","source":"Crossref","is-referenced-by-count":34,"title":["Improvement in neurological outcome and abolition of cerebrovascular endothelin B and 5-hydroxytryptamine 1B receptor upregulation through mitogen-activated protein kinase kinase 1\/2 inhibition after subarachnoid hemorrhage in rats"],"prefix":"10.3171","volume":"114","author":[{"given":"Carl Christian","family":"Larsen","sequence":"first","affiliation":[{"name":"Departments of Neurosurgery and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gro Klitgaard","family":"Povlsen","sequence":"additional","affiliation":[{"name":"Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne Nelly Paola","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Edvinsson","sequence":"additional","affiliation":[{"name":"Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1754","reference":[{"key":"b1-jns1018","series-title":"J Neurosurg","first-page":"978","article-title":"Equal contribution of increased intracranial pressure and subarachnoid blood to cerebral blood flow reduction and receptor upregulation after subarachnoid hemorrhage. 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