Synthesis and evaluation of gallocyanine dyes as potential agents for the treatment of Alzheimer's disease and related neurodegenerative tauopathies

Mpousis, Spyros; Thysiadis, Savvas; Avramidis, Nicolaos; Katsamakas, Sotirios; Efthimiopoulos, Spiros; Sarli, Vasiliki

doi:10.1016/j.ejmech.2015.11.024

Cited by 18 publications

(7 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the application of GSK-3β inhibitors in AD patients during clinical studies is disappointed due to the wide range of GSK-3β substrates and physiological actions. Another study has shown that DKK1 inhibitors can treat AD through inhibiting p-Tau protein caused by prostaglandin J2 (Mpousis et al, 2016). Recent studies have shown that curcumin can potentially activate Wnt/β-catenin signaling by increasing the expression of Wnt proteins and suppressing the expression of DKK1, but its practical application is still limited due to poor bioavailability in brain tissues (Farkhondeh et al, 2019;Sanei and Saberi-Demneh, 2019).…”

Section: Discussionmentioning

confidence: 99%

Exercise Attenuates Brain Aging by Rescuing Down-Regulated Wnt/β-Catenin Signaling in Aged Rats

Chen

Zhang

et al. 2020

Front. Aging Neurosci.

View full text Add to dashboard Cite

Down-regulated Wnt signaling is involved in brain aging with declined cognitive capacity due to its modulation on neuronal function and synaptic plasticity. However, the molecular mechanisms are still unclear. In the present study, the naturally aged rat model was established by feeding rats from 6 months old to 21 months old. The cognitive capacity of aged rats was compared with young rats as the controls and the aged rats upon 12-week exercise interventions including treadmill running, resistance exercise, and alternating exercise with resistance exercise and treadmill running. Wnt signaling was examined in hippocampal tissues of the rats from different groups. Results indicated that the expression of Dickkopf-1 (DKK-1) as an antagonist of Wnt signal pathway, the activation of GSK-3β, and the hyperphosphorylated Tau were markedly increased as the extension of age. Meanwhile, higher p-β-catenin Ser33, 37, Thr41 promoted neuronal degradation of aged rats. In contrast, three kinds of exercise interventions rescued the abnormal expression of DKK-1 and synaptophysin such as PSD-93 and PSD-95 in hippocampal tissues of the aged rats; especially 12-week treadmill running suppressed DKK-1 up-regulation, GSK-3β activation, β-catenin phosphorylation, and hyperphosphorylated Tau. In addition, the down-regulated PI3K/AKT and Wnt signal pathways were observed in aged rats, but could be reversed by resistance exercise and treadmill running. Moreover, the increased Bax and reduced Bcl-2 levels in hippocampal tissues of aged rats were also reversed upon treadmill running intervention. Taken together, down-regulated Wnt signaling suppressed PI3K/Akt signal pathway, aggravated synaptotoxicity, induced neuron apoptosis, and accelerated cognitive impairment of aged rats. However, exercise interventions, especially treadmill running, can attenuate their brain aging process via restoring Wnt signaling and corresponding targets.

show abstract

Section: Discussionmentioning

confidence: 99%

Exercise Attenuates Brain Aging by Rescuing Down-Regulated Wnt/β-Catenin Signaling in Aged Rats

Chen

Zhang

et al. 2020

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…Gallocyanine functionally restored Wnt signaling in a concentration dependent manner in a β-catenin intracellular accumulation and nuclear translocation assay, carried-out in L-cells treated with Wnt3a and DKK1 conditioned media (IC 50 12.6 μM) . Mpousis et al followed-up this work and have reported a series of small molecules, based on the gallocyanine core, that inhibit the LRP6–DKK1 interaction and enhance Wnt signaling with micromolar activities . It was also reported that these gallocyanine derivatives could reduce Tau phosphorylation at serine 396 in a DKK1 induced Tau phosphorylation assay in SH-SY5Y cells …”

Section: Small Molecule Approaches To Modulate Wnt Signalingmentioning

confidence: 96%

Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling

et al. 2021

View full text Add to dashboard Cite

Regulation of the Wnt signaling pathway is critically important for a number of cellular processes in both development and adult mammalian biology. This Perspective will provide a summary of current and emerging therapeutic opportunities in modulating Wnt signaling, especially through inhibition of Notum carboxylesterase activity. Notum was recently shown to act as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group. Inhibition of Notum activity may represent a new approach to treat disease where aberrant Notum activity has been identified as the underlying cause. Reliable screening technologies are available to identify inhibitors of Notum, and structural studies are accelerating the discovery of new inhibitors. A selection of these hits have been optimized to give fit-for-purpose small molecule inhibitors of Notum. Three noteworthy examples are LP-922056 (26), ABC99 (27), and ARUK3001185 (28), which are complementary chemical tools for exploring the role of Notum in Wnt signaling.

show abstract

“…Moreover, IIIC3 can reduce basal blood-glucose concentrations and improve glucose tolerance in mice [143]. Interestingly, IIIC3 and its derivatives can decrease DKK1-induced Tau phosphorylation [145, 146]. However, it is unclear whether these gallocyanine inhibitors of DKK1 can cross the BBB.…”

Section: Targeting Wnt/β-catenin Signaling In Ad Therapymentioning

confidence: 99%

Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

2019

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is an aging-related neurological disorder characterized by synaptic loss and dementia. Wnt/β-catenin signaling is an essential signal transduction pathway that regulates numerous cellular processes including cell survival. In brain, Wnt/β-catenin signaling is not only crucial for neuronal survival and neurogenesis, but it plays important roles in regulating synaptic plasticity and blood-brain barrier integrity and function. Moreover, activation of Wnt/β-catenin signaling inhibits amyloid-β production and tau protein hyperphosphorylation in the brain. Critically, Wnt/β-catenin signaling is greatly suppressed in AD brain via multiple pathogenic mechanisms. As such, restoring Wnt/β-catenin signaling represents a unique opportunity for the rational design of novel AD therapies.

show abstract

Synthesis and evaluation of gallocyanine dyes as potential agents for the treatment of Alzheimer's disease and related neurodegenerative tauopathies

Cited by 18 publications

References 43 publications

Exercise Attenuates Brain Aging by Rescuing Down-Regulated Wnt/β-Catenin Signaling in Aged Rats

Exercise Attenuates Brain Aging by Rescuing Down-Regulated Wnt/β-Catenin Signaling in Aged Rats

Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling

Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

Contact Info

Product

Resources

About