title: Transgenic mice overexpressing XIAP in neurons show better outcome after transient cerebral ischemia.
abstract: X-chromosome linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis protein (IAP) family and known to inhibit death of various cells under different experimental conditions. Although present in brain tissue, little is known about the physiology of the IAPs in nerve cells. Here we report on the establishment of transgenic mice with overexpression of human XIAP in brain neurons. The mice developed normally, and were more resistant to brain injury caused by transient forebrain ischemia after occlusion of the middle cerebral artery compared to control mice. The XIAP transgenic animals exhibited significantly smaller brain damage, as shown by TUNEL labelling, less reduction in brain protein synthesis, and less active caspase-3 after ischemia compared with controls. Upregulation of RhoB, which is an early indicator of neurological damage, was markedly reduced in the XIAP-overexpressing mice, which had also a better neurological outcome than control animals. This together with the increase in XIAP in normal mouse brain in regions surviving the infarct demonstrates that XIAP is an important factor promoting neuronal survival after ischemia. The results suggest that interference with the levels and the activity of XIAP in neurons may provide targets for the development of drugs limiting neuronal death after ischemia, and possibly in other brain injuries.
authors.affiliation: Department of Experimental Neurology, Max Planck Institute for Neurological Research, Gleueler Strasse 50, 50931, Cologne, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Trapp
authors.forename: Laura
authors.initials: L
authors.lastname: Korhonen
authors.forename: Michael
authors.initials: M
authors.lastname: Besselmann
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Martinez
authors.forename: Eric A
authors.initials: EA
authors.lastname: Mercer
authors.forename: Dan
authors.initials: D
authors.lastname: Lindholm
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics*; D002544:Cerebral Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein; D020743:rhoB GTP-Binding Protein / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D020743:rhoB GTP-Binding Protein