Glycogen synthase kinase 3 (GSK‐3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation

Martı́nez, Ana; Castro, Ana; Dorronsoro, Isabel; Alonso, Mercedes

doi:10.1002/med.10011

Cited by 318 publications

(190 citation statements)

References 77 publications

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“…We have previously reported that hypothermia blocks ischemic injury without inhibiting increased-GSK3β activity [14]; this result contradicts with the earlier results showing that GSK3β activity leads to neuronal death [2,6,8]. In our prior study, however, hypothermia blocks nuclear translocation of β-catenin [14], suggesting that hypothermia may block molecular signaling downstream of GSK3β.…”

Section: Discussioncontrasting

confidence: 86%

“…Moderate hypothermia attenuates reductions in Akt activity after stroke [14] but does not attenuate reduction in GSK 3 β phosphorylation, suggesting that it may not inhibit GSK3β activity [14]. Since GSK3β activity is known to exacerbate ischemic injury, and its inhibition reduces infarction [2,6,8], it is puzzling that hypothermia can inhibit ischemic injury without blocking GSK 3 β activity. To address this paradox, we further examined the protective effects of moderate hypothermia on β-catenin phosphorylation and total protein level of β-catenin (molecules downstream of GSK3β), in the same focal ischemia model with rats we used before for studying the Akt/GSK3β pathway.…”

Section: Introductionmentioning

confidence: 99%

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Hypothermia blocks β-catenin degradation after focal ischemia in rats

Zhang¹,

Ren²,

Gao³

et al. 2008

Brain Research

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Dephosphorylated and activated glycogen synthase kinase (GSK) 3β hyperphophorylates β-catenin, leading to its ubiquitin-proteosome-mediated degradation. β-catenin-knockdown increases while β-catenin overexpression prevents neuronal death in vitro; in addition, protein levels of β-catenin are reduced in the brain of Alzheimer's patients. However, whether β-catenin degradation is involved in stroke-induced brain injury is unknown. Here we studied activities of GSK3 β and β-catenin, and the protective effect of moderate hypothermia (30 °C) on these activities after focal ischemia in rats. The results of Western blot showed that GSK3 β was dephosphorylated at 5 and 24 hours after stroke in the normothermic (37 °C) brain; hypothermia augmented GSK3β dephosphorylation. Because hypothermia reduces infarction, these results contradict with previous studies showing that GSK3β dephosphorylation worsens neuronal death. Nevertheless, hypothermia blocked degradation of total GSK3β protein. Corresponding to GSK3β activity in normothermic rats, β-catenin phosphorylation transiently increased at 5 hours in both the ischemic penumbra and core, and the total protein level of β-catenin degraded after normothermic stroke. Hypothermia did not inhibit β-catenin phosphorylation, but it blocked β-catenin degradation in the ischemic penumbra. In conclusion, moderate hypothermia can stabilize β-catenin, which may contribute to the protective effect of moderate hypothermia.

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Section: Discussioncontrasting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Hypothermia blocks β-catenin degradation after focal ischemia in rats

Zhang¹,

Ren²,

Gao³

et al. 2008

Brain Research

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“…Inhibitors of GSK3 have been studied as prospective therapeutic agents for diabetes [9,13,14], and several in vitro and in vivo studies have examined their effects on insulin resistance. A few ATP competitive GSK3 inhibitors have been shown to stimulate glycogen synthase activity and improve glucose tolerance in rodent models of diabetes with mutations in leptin [1,15,16] or the leptin receptor [17].…”

mentioning

confidence: 99%

Glycogen synthase kinase 3 inhibition improves insulin-stimulated glucose metabolism but not hypertension in high-fat-fed C57BL/6J mice

et al. 2006

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Aims/hypothesis In the current study, the effect of a highly specific peptide inhibitor of glycogen synthase kinase 3 (GSK3) (L803-mts) on glucose metabolism and BP was examined in a high-fat (HF) fed mouse model of diabetes. Methods C57/BL6J mice were placed on an HF diet for 3 months and treated with L803-mts for 20 days, following which glucose metabolism was examined by euglycaemichyperinsulinaemic clamp studies. BP and heart rate were measured by radio-telemetry. Results The HF mice were obese, with impaired glucose tolerance and high plasma insulin and leptin levels. L803-mts treatment significantly reduced the insulin levels and doubled the glucose infusion rate required to maintain a euglycaemic condition in the HF+L803-mts group compared with the HF group. Insulin failed to suppress the endogenous glucose production rate in the HF group while decreasing it by 75% in the HF+L803-mts group, accompanied by increased liver glycogen synthase activity and net hepatic glycogen synthesis. GSK3 inhibition also reduced peripheral insulin resistance. Plasma glucose disappearance rate increased by 60% in the HF+L803-mts group compared with the HF group. In addition, glucose uptake in heart and gastrocnemius muscle was markedly improved. Although mean arterial pressure increased following the HF diet, it did not change significantly during the 12 days of L803-mts treatment. Conclusions/interpretation These studies demonstrate that GSK3 inhibition improved hepatic and peripheral insulin resistance in a mouse model of HF-induced diabetes, but it failed to have an effect on BP. GSK3 may represent an important therapeutic target for insulin resistance.

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“…These data, and the findings that both lithium and VPA regulate this pathway, suggest a therapeutic relevance [135]. GSK-3 is also a tau kinase; hence, many pharmaceutical companies are developing CNS-penetrant small molecule GSK-3 inhibitors for the treatment of Alzheimer's and other neurodegenerative diseases [201]. It is anticipated that these will also undergo trials in bipolar disorder.…”

Section: Future Development Of New Agentsmentioning

confidence: 97%

“…This enzyme is involved in a number of neuronal functions including growth, synaptic plasticity and protection from injury [135]. Thus, the finding that GSK-3 is a direct target of lithium is of major interest and GSK-3 inhibitors are actively being developed [201].…”

Section: Direct Targets Of Lithiummentioning

confidence: 99%

Mood stabilizer psychopharmacology

Gould

Chen

Manji

2002

Clinical Neuroscience Research

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Mood stabilizers represent a class of drugs that are efficacious in the treatment of bipolar disorder. The most established medications in this class are lithium, valproic acid, and carbamazepine. In addition to their therapeutic effects for treatment of acute manic episodes, these medications often are useful as prophylaxis against future episodes and as adjunctive antidepressant medications. While important extracellular effects have not been excluded, most available evidence suggests that the therapeutically relevant targets of this class of medications are in the interior of cells. Herein we give a prospective of a rapidly evolving field, discussing common effects of mood stabilizers as well as effects that are unique to individual medications. Mood stabilizers have been shown to modulate the activity of enzymes, ion channels, arachidonic acid turnover, G protein coupled receptors and intracellular pathways involved in synaptic plasticity and neuroprotection. Understanding the therapeutic targets of mood stabilizers will undoubtedly lead to a better understanding of the pathophysiology of bipolar disorder and to the development of improved therapeutics for the treatment of this disease. Furthermore, the involvement of mood stabilizers in pathways operative in neuroprotection suggests that they may have utility in the treatment of classical neurodegenerative disorders.

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Glycogen synthase kinase 3 (GSK‐3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation

Cited by 318 publications

References 77 publications

Hypothermia blocks β-catenin degradation after focal ischemia in rats

Hypothermia blocks β-catenin degradation after focal ischemia in rats

Glycogen synthase kinase 3 inhibition improves insulin-stimulated glucose metabolism but not hypertension in high-fat-fed C57BL/6J mice

Mood stabilizer psychopharmacology

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