Tideglusib protects neural stem cells against NMDA receptor overactivation

Armağan, Güliz; Keser, Ayşegül; Atalayın, Çiğdem; Dağcı, Taner

doi:10.1016/j.pharep.2015.01.007

Cited by 13 publications

(14 citation statements)

References 33 publications

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“…Interestingly, pretreatment with 2.5μM tideglusib for 1 h significantly reduced LDH leakage due to NMDA. [68]. Moreover, a mechanistic study of tideglusib on Human African trypanosomiasis (HAT) reported a significant non-reversible, time-dependent inhibition of GSK-3 leading to significant inhibition of parasitic growth [69].…”

Section: Tideglusibmentioning

confidence: 99%

GSK-3 Inhibitors: A Double-Edged Sword? – An Update on Tideglusib

2018

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GSK-3 inhibitors are an emerging tool for clinical interventions in human diseases and represent a niche area in combinational therapy. They possess diverse facets in applications of nervous system disorders, Type 2 diabetes, regenerative medicine and cancer. However, conflicting reports suggest the controversial role of GSK-3 inhibitors in cancers. This review aims to highlight the rise of GSK-3 inhibitors as tools for molecular-targeted research and its shift to a promising drug candidate. The review also focuses on key GSK-3 inhibitors and their roles in cancer and regenerative medicine with special emphasis to tideglusib. In addition, the decisive roles of GSK-3 in various molecular pathways will be concisely reviewed. Finally, this review concludes the emergence of GSK-3 inhibitors as a 'double-edged sword' in the treatment against human diseases cautioning researchers about the potential ramifications of off-target pharmacological effects.

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Section: Tideglusibmentioning

confidence: 99%

GSK-3 Inhibitors: A Double-Edged Sword? – An Update on Tideglusib

2018

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“…), two thiadiazolidinones that had been previously reported by the same research team . This compound, later named tideglusib, is an irreversible, non‐ATP‐competitive GSK‐3β inhibitor with IC 50 values in the nanomolar range, and was also found to protect neural stem cells against the overactivation of NMDA receptors that lead to neuronal excitotoxicity . In transgenic mice overexpressing human mutant AβPP and tau protein, tideglusib was able to prevent hippocampal neuronal cell death and associated memory loss, while promoting a decrease in the levels of phosphorylated tau and a reduction in brain beta‐amyloid burden .…”

Section: Rational Design and Synthesis Of Novel Molecular Entities Tamentioning

confidence: 94%

Bridging Type 2 Diabetes and Alzheimer's Disease: Assembling the Puzzle Pieces in the Quest for the Molecules With Therapeutic and Preventive Potential

Matos

Macedo²,

Rauter

2017

Medicinal Research Reviews

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Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two age-related amyloid diseases that affect millions of people worldwide. Broadly supported by epidemiological data, the higher incidence of AD among type 2 diabetic patients led to the recognition of T2D as a tangible risk factor for the development of AD. Indeed, there is now growing evidence on brain structural and functional abnormalities arising from brain insulin resistance and deficiency, ultimately highlighting the need for new approaches capable of preventing the development of AD in type 2 diabetic patients. This review provides an update on overlapping pathophysiological mechanisms and pathways in T2D and AD, such as amyloidogenic events, oxidative stress, endothelial dysfunction, aberrant enzymatic activity, and even shared genetic background. These events will be presented as puzzle pieces put together, thus establishing potential therapeutic targets for drug discovery and development against T2D and diabetes-induced cognitive decline-a heavyweight contributor to the increasing incidence of dementia in developed countries. Hoping to pave the way in this direction, we will present some of the most promising and well-studied drug leads with potential against both pathologies, including their respective bioactivity reports, mechanisms of action, and structure-activity relationships.

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“…Troglitazone was approved in 1997, but it was withdrawn from the market for increased risk of liver failure and extensive hepatotoxicity in 2000 (Kohlroser et al 2000). Tideglusib is a potent, irreversible, non ATP-competitive glycogen synthase kinase-3β (GSK-3β) inhibitor and PPARγ agonist tideglusib seems to be suitable candidate for Alzheimer disease treatment or for a treatment of stroke (Armagan et al 2015), but its application in cardiovascular disease treatment has not been examined yet.…”

Section: Pparγ and The Pi3k/akt/enos Signaling Pathwaymentioning

confidence: 99%

The Role of PPARγ in Cardiovascular Diseases

Kvandová

Majzúnová²,

Dovinová

2016

Physiol Res

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The peroxisome proliferator-activated receptors (PPAR) belong to the nuclear superfamily of ligand-activated transcription factors.PPARγ acts as a nutrient sensor that regulates several homeostatic functions. Its disruption can lead to vascular pathologies, disorders of fatty acid/lipid metabolism and insulin resistance. PPARγ can modulate several signaling pathways connected with blood pressure regulation. Firstly, it affects the insulin signaling pathway and endothelial dysfunction by modulation of expression and/or phosphorylation of signaling molecules through the PI3K/Akt/eNOS or MAPK/ET-1 pathways.Secondly, it can modulate gene expression of the reninangiotensin system -cascade proteins, which potentially slow down the progression of atherosclerosis and hypertension.Thirdly, it can modulate oxidative stress response either directly through PPAR or indirectly through Nrf2 activation. In this context, activation and functioning of PPARγ is very important in the regulation of several disorders such as diabetes mellitus, hypertension and/or metabolic syndrome.

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Tideglusib protects neural stem cells against NMDA receptor overactivation

Abstract: Our study provides the evidence that GSK-3β and PPARγ may be directly involved in pathways leading to NMDA receptor-induced cell death and that the inhibitors including tideglusib may exert neuroprotective effect against these receptor overactivation.

Cited by 13 publications

References 33 publications

GSK-3 Inhibitors: A Double-Edged Sword? – An Update on Tideglusib

GSK-3 Inhibitors: A Double-Edged Sword? – An Update on Tideglusib

Bridging Type 2 Diabetes and Alzheimer's Disease: Assembling the Puzzle Pieces in the Quest for the Molecules With Therapeutic and Preventive Potential

The Role of PPARγ in Cardiovascular Diseases

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