title: Treatment with the glycogen synthase kinase-3beta inhibitor, TDZD-8, affects transient cerebral ischemia/reperfusion injury in the rat hippocampus.
abstract: The serine/threonine glycogen synthase kinase 3beta (GSK-3beta) is abundant in the central nervous system, particularly in the hippocampus, and plays a pivotal role in the pathophysiology of a number of diseases, including neurodegeneration. This study was designed to investigate the effects of GSK-3beta inhibition against I/R injury in the rat hippocampus. Transient cerebral ischemia (30 min) followed by 1 h of reperfusion significantly increased generation of reactive oxygen species and modulated superoxide dismutase activity; 24 h of reperfusion evoked apoptosis (determined as mitochondrial cytochrome c release and Bcl-2 and caspase-9 expression), resulted in high plasma levels of TNF-alpha and increased expression of cyclooxygenase-2, inducible nitric oxide synthase, and intercellular adhesion molecule-1. The selective GSK-3beta inhibitor, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), was administered before and after ischemia or during reperfusion alone to assess its potential as prophylactic or therapeutic strategy. Prophylactic or therapeutic administration of TDZD-8 caused the phosphorylation (Ser(9)) and hence inactivation of GSK-3beta. Infarct volume and levels of S100B protein, a marker of cerebral injury, were reduced by TDZD-8. This was associated with a significant reduction in markers of oxidative stress, apoptosis, and the inflammatory response resulting from cerebral I/R. These beneficial effects were associated with a reduction of I/R-induced activation of the mitogen-activated protein kinases JNK1/2 and p38 and nuclear factor-kappaB. The present study demonstrates that TDZD-8 protects the brain against I/R injury by inhibiting GSK-3beta activity. Collectively, our data may contribute to focus the role of GSK-3beta in cerebral I/R.
authors.affiliation: Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy. massimo.collino@unito.it
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mastrocola
authors.forename: Margherita
authors.initials: M
authors.lastname: Gallicchio
authors.forename: Elisa
authors.initials: E
authors.lastname: Benetti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Miglio
authors.forename: Sara
authors.initials: S
authors.lastname: Castiglia
authors.forename: Oliviero
authors.initials: O
authors.lastname: Danni
authors.forename: Oliver
authors.initials: O
authors.lastname: Murch
authors.forename: Chiara
authors.initials: C
authors.lastname: Dianzani
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009414:Nerve Growth Factors / Q000096:biosynthesis; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000096:biosynthesis; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D000975:Antioxidants; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579158:S100b protein, rat; D013830:Thiadiazoles; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3