TREATMENT WITH THE GLYCOGEN SYNTHASE KINASE-3β INHIBITOR, TDZD-8, AFFECTS TRANSIENT CEREBRAL ISCHEMIA/REPERFUSION INJURY IN THE RAT HIPPOCAMPUS

Collino, Massimo; Thiemermann, Christoph; Mastrocola, Raffaella; Gallicchio, Margherita; Benetti, Elisa; Miglio, Gianluca; Castiglia, Sara; Danni, Oliviero; Murch, Oliver; Dianzani, Chiara; Aragno, Manuela; Fantozzi, Roberto

doi:10.1097/shk.0b013e318164e762

Cited by 61 publications

(40 citation statements)

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“…Several studies reported that TDZD-8 as a GSK-3β inhibitor could reduce I/R injury of the intestines and brain due to its anti-inflammatory and anti-apoptosis activities. [19, 27, 28]. It was found in the present study that RI/RI resulted in renal tissue damage accompanied with elevation of serum BUN and Scr levels.…”

Section: Discussionmentioning

confidence: 58%

Activation of Nrf2/HO-1 Pathway by Glycogen Synthase Kinase-3β Inhibition Attenuates Renal Ischemia/Reperfusion Injury in Diabetic Rats

Shen

et al. 2017

Kidney Blood Press Res

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Background/Aims: Diabetes mellitus can exacerbate renal ischemia-reperfusion (I/R) injury (RI/RI). The aim of the present study was to evaluate the protective effect of GSK-3β inhibition (TDZD-8) on I/R-induced renal injury through the Nrf2/HO-1 pathway in a streptozocin (STZ)-induced diabetic rat model. Methods: STZ-induced diabetic rats preconditioned with TDZD-8 and ZnPP were subjected to renal I/R. The extent of renal morphologic lesions. Renal function was assessed from blood urea nitrogen (BUN) and serum creatinine (Scr), as determined utlizing commercial kits. Oxidative stress and inflammatory activity in the kidney tissue was estimated from levels of malondialdehyde (MDA), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), as well as the activities of superoxide dismutase (SOD) and glutathione (GSH) using qRT-PCR and ELISA. The expressions of Nrf2, HO-1, Bcl-2 and NF-κB in the renal tissue were measured by qRT-PCR and western blotting. Results: I/R-induced renal inflammation was reduced significantly by TDZD-8 pretreatment. Preconditioning with TDZD-8 suppressed NF-κB expression and enhanced Bcl-2 expression in the renal tissue. The upregulated level of malondialdehyde (MDA), and reduced activities of superoxide dismutase (SOD) and glutathione (GSH) in I/R-shocked rats were markedly restored by TDZD-8 pretreatment. Furthermore, pretreatment with TDZD-8 enhanced activation of the Nrf2/HO-1 pathway in the renal tissue of diabetic RI/RI rats. Conclusion: These findings suggest that preconditioning with TDZD-8 may protect the kidney from I/R-induced damage via the activation of the Nrf2/HO-1 pathway in STZ-induced diabetic rats. Further detailed studies are needed to further clarify the underlying mechanisms.

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Section: Discussionmentioning

confidence: 58%

Activation of Nrf2/HO-1 Pathway by Glycogen Synthase Kinase-3β Inhibition Attenuates Renal Ischemia/Reperfusion Injury in Diabetic Rats

Shen

et al. 2017

Kidney Blood Press Res

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“…In line with this notion, several other pharmacological GSK-3 inhibitors [125][126][127][128] and HDAC inhibitors [14] have been shown to exert beneficial effects against cerebral ischemia. Bcl-2 is transcriptionally activated by lithium through direct or indirect inhibition of GSK-3, while VPA induces Bcl-2 by direct HDAC inhibition.…”

Section: Discussionmentioning

confidence: 75%

Beneficial effects of mood stabilizers lithium, valproate and lamotrigine in experimental stroke models

2011

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The mood stabilizers lithium, valproate and lamotrigine are traditionally used to treat bipolar disorder. However, accumulating evidence suggests that these drugs have broad neuroprotective properties and may therefore be promising therapeutic agents for the treatment of neurodegenerative diseases, including stroke. Lithium, valproate and lamotrigine exert protective effects in diverse experimental stroke models by acting on their respective primary targets, ie, glycogen synthase kinase-3, histone deacetylases and voltage-gated sodium channels, respectively. This article reviews the most recent findings regarding the underlying mechanisms of these phenomena, which will pave the way for clinical investigations that use mood stabilizers to treat stroke. We also propose several future research avenues that may extend our understanding of the benefits of lithium, valproate and lamotrigine in improving stroke outcomes.

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“…Both TDZD-8 and insulin markedly enhanced the hippocampal Ser9 phosphorylation and hence inhibition of GSK-3␤ activity at both 1 and 24 h of reperfusion. Previous studies in nondiabetic animal models have shown that insulin and TDZD-8 increase GSK-3␤ phosphorylation in the rodent brain (10,25), but this is the first study demonstrating their effects on cerebral GSK-3␤ in the presence of diabetes. Another major observation made in the present study was that both basal GSK-3␤ expression and activity were upregulated in the hippocampus of diabetic animals compared with those in age-matched normal animals.…”

Section: Discussionmentioning

confidence: 77%

Insulin Reduces Cerebral Ischemia/Reperfusion Injury in the Hippocampus of Diabetic Rats

et al. 2009

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OBJECTIVE-There is evidence that insulin reduces brain injury evoked by ischemia/reperfusion (I/R). However, the molecular mechanisms underlying the protective effects of insulin remain unknown. Insulin is a well-known inhibitor of glycogen synthase kinase-3␤ (GSK-3␤). Here, we investigate the role of GSK-3␤ inhibition on I/R-induced cerebral injury in a rat model of insulinopenic diabetes. RESEARCH DESIGN AND METHODS-Ratswith streptozotocin-induced diabetes were subjected to 30-min occlusion of common carotid arteries followed by 1 or 24 h of reperfusion. Insulin (2-12 IU/kg i.v.) or the selective GSK-3␤ inhibitor TDZD-8 (0.2-3 mg/kg i.v.) was administered during reperfusion.RESULTS-Insulin or TDZD-8 dramatically reduced infarct volume and levels of S100B protein, a marker of cerebral injury. Both drugs induced phosphorylation of the Ser9 residue, thereby inactivating GSK-3␤ in the rat hippocampus. Insulin, but not TDZD-8, lowered blood glucose. The hippocampi of the drugtreated animals displayed reduced oxidative stress at 1 h of reperfusion as shown by the decreased generation of reactive oxygen species and lipid peroxidation. I/R-induced activation of nuclear factor-B was attenuated by both drug treatments. At 24 h of reperfusion, TDZD-8 and insulin significantly reduced plasma levels of tumor necrosis factor-␣; neutrophil infiltration, measured as myeloperoxidase activity and intercellular-adhesion-molecule-1 expression; and cyclooxygenase-2 and inducible-NO-synthase expression.CONCLUSIONS-Acute administration of insulin or TDZD-8 reduced cerebral I/R injury in diabetic rats. We propose that the inhibitory effect on the activity of GSK-3␤ contributes to the protective effect of insulin independently of any effects on blood glucose. Diabetes 58:235-242, 2009 E pidemiological studies have shown that diabetes is a leading risk factor for ischemic cerebrovascular diseases (1). Animal and human studies demonstrate that insulin reduces brain damage evoked by ischemia/reperfusion (I/R) injury (2,3). Glycemic control by insulin may be involved in this protective effect, but the molecular mechanisms underlying the protective effects of insulin are debated and still poorly understood (4). One important pharmacological effect of insulin is its ability to inhibit the activity of the glycogen synthase kinase (GSK)-3, a serine/threonine kinase that was originally identified for its key role in glucose metabolism (5). More recently, GSK-3 has emerged as a key regulatory switch in the modulation of neurodegeneration and inflammation (6,7). There are two mammalian isoforms of GSK-3: GSK-3␣ and GSK-3␤. GSK-3␤ is highly expressed in the central nervous system (8). Unlike most kinases, GSK-3␤ is constitutively active in cells and can be inactivated by phosphorylation at Ser9 (9). Binding of insulin to its receptor activates phosphatidylinositol 3-kinase, leading to the subsequent activation of protein kinase B/Akt, and the inactivation of GSK-3␤ by phosphorylation on the regulatory Ser-9. This contributes to the insulin-induce...

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TREATMENT WITH THE GLYCOGEN SYNTHASE KINASE-3β INHIBITOR, TDZD-8, AFFECTS TRANSIENT CEREBRAL ISCHEMIA/REPERFUSION INJURY IN THE RAT HIPPOCAMPUS

Cited by 61 publications

References 31 publications

Activation of Nrf2/HO-1 Pathway by Glycogen Synthase Kinase-3β Inhibition Attenuates Renal Ischemia/Reperfusion Injury in Diabetic Rats

Activation of Nrf2/HO-1 Pathway by Glycogen Synthase Kinase-3β Inhibition Attenuates Renal Ischemia/Reperfusion Injury in Diabetic Rats

Beneficial effects of mood stabilizers lithium, valproate and lamotrigine in experimental stroke models

Insulin Reduces Cerebral Ischemia/Reperfusion Injury in the Hippocampus of Diabetic Rats

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