{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:25:38Z","timestamp":1791419138171,"version":"4.3.3"},"reference-count":87,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[1997,6]]},"abstract":"<jats:p>\n                    <jats:italic>Background and Purpose<\/jats:italic>\n                    Tumor necrosis factor-\u03b1 (TNF-\u03b1) is a pleiotropic cytokine that rapidly upregulates in the brain after injury. The present study was designed to explore the pathophysiological significance of brain TNF-\u03b1 in the ischemic brain by systematically evaluating the effects of lateral cerebroventricular administration of exogenous TNF-\u03b1 and agents that block the effects of TNF-\u03b1 on focal stroke and by examining the potential direct toxic effects of TNF-\u03b1 on cultured neurons to better understand how TNF-\u03b1 might mediate stroke injury.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>Methods<\/jats:italic>\n                    TNF-\u03b1 (2.5 or 25 pmol) was administered intracerebroventricularly to spontaneously hypertensive rats 24 hours before permanent or transient (80 minutes and 160 minutes) middle cerebral artery occlusion (MCAO). Animals were examined 24 hours later for neurological deficits and ischemic hemisphere necrosis and swelling. In some of these studies, neutralizing anti\u2013TNF-\u03b1 monoclonal antibody (mAb) (60 pmol) was injected intracerebroventricularly 30 minutes before exogenous TNF-\u03b1 (25 pmol). In addition, the effects of blocking endogenous TNF-\u03b1 on permanent focal ischemic injury were determined with the use of either mAb (60 pmol) or soluble TNF receptor I (sTNF-RI) (0.3 or 0.7 nmol) administered intracerebroventricularly 30 minutes before and 3 and 6 hours after MCAO. Finally, the direct neurotoxic effects of TNF-\u03b1 were studied in cultured rat cerebellar granule cells exposed to TNF-\u03b1 (10 to 2000 U\/mL for 6 to 24 hours), and neurotransmitter release, glutamate toxicity, and oxygen radical toxicity were studied.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>Results<\/jats:italic>\n                    TNF-\u03b1 increased the percent hemispheric infarct induced by permanent MCAO in a dose-related manner from 13.1\u00b11.3% (vehicle) to 18.9\u00b11.7% at 2.5 pmol (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;.05) and 27.1\u00b11.3% at 25 pmol (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;.0001). The high dose of TNF-\u03b1 increased ischemia-induced forelimb deficits from 1.6\u00b10.2 to 2.3\u00b10.2 (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;.01). TNF-\u03b1 (2.5 pmol) also increased the infarction induced by 80 or 160 minutes of transient MCAO from 1.9\u00b10.9% to 4.3\u00b10.4% (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;.01) and from 14.2\u00b11.3% to 21.6\u00b12.2% (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;.05), respectively. The exacerbation of infarct size, swelling, and neurological deficit after exogenous TNF-\u03b1 was reversed by preinjection of 60 pmol mAb. Blocking endogenous TNF-\u03b1 also significantly reduced focal ischemic brain injury. Treatment with 60 pmol mAb before and after permanent MCAO significantly reduced infarct size compared with control (nonimmune) antibody treatment by 20.2% (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;.05). Reduced brain infarction also was produced by brain administration of 0.3 nmol (decreased 18.2%) or 0.7 nmol (decreased 26.1%;\n                    <jats:italic>P<\/jats:italic>\n                    &lt;.05) sTNF-RI before and after focal stroke. The intracerebroventricular administration of TNF-\u03b1 or sTNF-RI did not alter brain or body temperature, blood gases or pH, blood pressure, blood glucose, or general blood chemistry. In cultured cerebellar granule cells, the application of TNF-\u03b1 did not directly affect neurotransmitter release or glutamate or oxygen free radical toxicity.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>Conclusions<\/jats:italic>\n                    These studies demonstrate that exogenous TNF-\u03b1 exacerbates focal ischemic injury and that blocking endogenous TNF-\u03b1 is neuroprotective. The specificity of the action(s) of TNF-\u03b1 was demonstrated by antagonism of its effects with specific anti\u2013TNF-\u03b1 tools (ie, mAb and sTNF-RI). TNF-\u03b1 toxicity does not appear to be due to a direct effect on neurons or modulation of neuronal sensitivity to glutamate or oxygen radicals and apparently is mediated through nonneuronal cells. These data suggest that inhibiting TNF-\u03b1 may represent a novel pharmacological strategy to treat ischemic stroke.\n                  <\/jats:p>","DOI":"10.1161\/01.str.28.6.1233","type":"journal-article","created":{"date-parts":[[2011,6,17]],"date-time":"2011-06-17T16:08:03Z","timestamp":1308326883000},"page":"1233-1244","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":624,"title":["Tumor Necrosis Factor-\u03b1"],"prefix":"10.1161","volume":"28","author":[{"given":"F. C.","family":"Barone","sequence":"first","affiliation":[{"name":"From the Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa, and Department of Neurology, Carmel Medical Center, Haifa, Israel (A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Arvin","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa, and Department of Neurology, Carmel Medical Center, Haifa, Israel (A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. F.","family":"White","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa, and Department of Neurology, Carmel Medical Center, Haifa, Israel (A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Miller","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa, and Department of Neurology, Carmel Medical Center, Haifa, Israel (A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. L.","family":"Webb","sequence":"additional","affiliation":[{"name":"From the Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa, and Department of Neurology, Carmel Medical Center, Haifa, Israel (A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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