title: Upregulation of TACE/ADAM17 after ischemic preconditioning is involved in brain tolerance.
abstract: A short ischemic event (ischemic preconditioning [IPC]) can result in a subsequent resistance to severe ischemic injury (ischemic tolerance [IT]). Although tumor necrosis factor-alpha (TNF-alpha) contributes to the brain damage, its expression and neuroprotective role in models of IPC have also been described. However, the role of TNF-alpha convertase (TACE) in IPC and IT is not known. Using in vitro models, the authors previously demonstrated that TACE is upregulated after ischemic brain damage. In the present study, the authors used a rat model of transient middle cerebral artery occlusion as IPC to investigate TACE expression, its involvement in TNF-alpha release, and its role in IT. Western blot analysis showed that TACE expression is increased after IPC. Ischemic preconditioning caused TNF-alpha release, an effect that was blocked by the selective TACE inhibitor BB-1101 (10 mg. kg(-1). day(-1); SHAM, 1,050 +/- 180; IPC, 1,870 +/- 290; IPC + BB, 1,320 +/- 260 ng/mg; n = 4, < 0.05). Finally, IPC produced a reduction in infarct volume, which was inhibited by treatment with BB-1101 and with anti-TNF-alpha (10 microg/5 doses; SHAM + permanent middle cerebral artery occlusion [pMCAO], 335 +/- 20; IPC + pMCAO, 244 +/- 14; IPC + BB + pMCAO, 300 +/- 6; IPC + anti-TNF + pMCAO, 348 +/- 22 mm3; n = 6-10, < 0.05). Taken together, these data demonstrate that TACE is upregulated after IPC, plays a major role in TNF-alpha shedding in IPC, and has a neuroprotective role in IT.
authors.affiliation: Departamento de Farmacología de Medicina, Universidad Complutense de Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cárdenas
authors.forename: María A
authors.initials: MA
authors.lastname: Moro
authors.forename: Juan C
authors.initials: JC
authors.lastname: Leza
authors.forename: Esther
authors.initials: E
authors.lastname: O'Shea
authors.forename: Antoni
authors.initials: A
authors.lastname: Dávalos
authors.forename: José
authors.initials: J
authors.lastname: Castillo
authors.forename: Pedro
authors.initials: P
authors.lastname: Lorenzo
authors.forename: Ignacio
authors.initials: I
authors.lastname: Lizasoain
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000503:physiopathology; D019194:Ischemic Preconditioning; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat