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: Massimo Collino, Christoph Thiemermann, Raffaella Mastrocola, Margherita Gallicchio, Elisa Benetti, Gianluca Miglio, Sara Castiglia, Oliviero Danni, Oliver Murch, Chiara Dianzani, Manuela Aragno, Roberto Fantozzi
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 30 Issue 3 Pg. 299-307 (Sep 2008) ISSN: 1540-0514 [Electronic] United States
• PMID: 18323734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
• Antioxidants
• Nerve Growth Factors
• S100 Calcium Binding Protein beta Subunit
• S100 Proteins
• S100b protein, rat
• Thiadiazoles
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Glycogen Synthase Kinase 3

Topics

• Animals
• Antioxidants (metabolism)
• Brain (pathology)
• Brain Ischemia (drug therapy)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Glycogen Synthase Kinase 3 beta
• Hippocampus (drug effects, metabolism)
• Male
• Mitochondria (metabolism)
• Models, Biological
• Nerve Growth Factors (biosynthesis)
• Phosphorylation
• Rats
• Rats, Wistar
• Reperfusion Injury (drug therapy, pathology)
• S100 Calcium Binding Protein beta Subunit
• S100 Proteins (biosynthesis)
• Thiadiazoles (pharmacology)