Treatment with the glycogen synthase kinase-3beta inhibitor, TDZD-8, affects transient cerebral ischemia/reperfusion injury in the rat hippocampus.
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.
Collino
Massimo
M
Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy. massimo.collino@unito.it
Thiemermann
Christoph
C
Mastrocola
Raffaella
R
Gallicchio
Margherita
M
Benetti
Elisa
E
Miglio
Gianluca
G
Castiglia
Sara
S
Danni
Oliviero
O
Murch
Oliver
O
Dianzani
Chiara
C
Aragno
Manuela
M
Fantozzi
Roberto
R
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*
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