title: Blood cells serve as a source of factor-inducing rapid ischemic tolerance in brain.
abstract: Ischemic tolerance (IT) has gained attention as an attractive strategy for improving stroke outcome. Recently, it was shown that signal responsible for rapid IT induction (tolerance induction factor - TIF) is transmitted via circulating blood. In this study, we have hypothesized about the role of the blood cell compartment in TIF production. We used hind-limb ischemia to generate TIF as a rapid preconditioning against transient middle cerebral artery occlusion (MCAO). The essential properties of protein synthesis inhibitors actinomycin D and cycloheximide were utilized to obtain the following results: (i) TIF is proteinaceous. Hind-limb ischemia mediates gene expression followed by translation, resulting in the production of TIF. Blocking of each of these two steps in protein synthesis resulted in rapid infarct evolution (281.5 ± 23.37 and 330.4 ± 71.8 mm3, respectively). (ii) Tourniquet-treated muscle is not a source of TIF. Actinomicine D injected into rat prior to tolerance induction significantly suppressed RNA synthesis in blood cells and muscle tissue. Cross-circulation of those rats (donors) with control animals (recipients) did not mediate significant infarct reduction (272.9 ± 12.45 mm3), even when hind-limb ischemia was performed before MCAO in the recipient (223.2 ± 37.51 mm3). (iii) Blood cells serve as a source of TIF. Preischemic transfusion of plasma-free, protein-synthesis-inactive blood cells, which were obtained from tolerant animals did not reduce infarct volume in recipients (131 ± 16.1 mm3) in a range comparable with their protein-synthesis-active counterparts (17.2 ± 12 mm3). We can conclude that blood cells are associated with the induction of rapid IT via production of a bioactive proteinaceous substance.
authors.affiliation: Institute of Neurobiology, Slovak Academy of Sciences, Soltesovej 4/6, Kosice, SK-040 01, Slovakia.
authors.forename: Petra
authors.initials: P
authors.lastname: Bonova
authors.affiliation: Institute of Neurobiology, Slovak Academy of Sciences, Soltesovej 4/6, Kosice, SK-040 01, Slovakia.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Nemethova
authors.affiliation: Institute of Neurobiology, Slovak Academy of Sciences, Soltesovej 4/6, Kosice, SK-040 01, Slovakia.
authors.forename: Milina
authors.initials: M
authors.lastname: Matiasova
authors.affiliation: Department of Anatomy, Faculty of Medicine, Pavol Jozef Safarik University, Kosice, Slovakia.
authors.forename: Martin
authors.initials: M
authors.lastname: Bona
authors.affiliation: Institute of Neurobiology, Slovak Academy of Sciences, Soltesovej 4/6, Kosice, SK-040 01, Slovakia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Gottlieb
mesh_terms: D000818:Animals; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000098:blood supply; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000097:blood* / Q000628:therapy; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D011500:Protein Synthesis Inhibitors; D003609:Dactinomycin; D003513:Cycloheximide
keywords: actinomycin D; blood cells; cycloheximide; rapid ischemic tolerance; tolerance-inducing factor