Synthesis of new heterocyclic compounds based on pyrazolopyridine scaffold and evaluation of their neuroprotective potential in MPP + -induced neurodegeneration

Jouha, Jabrane; Loubidi, Mohammed; Bouali, Jamila; Hamri, Salha; Hafid, Abderrafia; Suzenet, Franck; Guillaumet, Gérald; Dağcı, Taner; Khouili, Mostafà; Aydın, Fadime; Saso, Luciano; Armağan, Güliz

doi:10.1016/j.ejmech.2017.02.019

Cited by 27 publications

(11 citation statements)

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“…Recent studies showed that MPP + significantly decreased cell viability in a dose-dependent manner [26,27]. While studying with SH-SY5Y cells, different concentrations suh as 500 μM, 1 mM or 2 mM MPP + were shown to decrease cell viability [27,28]. In our study model, 2.3 mM concentration of MPP + was needed to decrease cell viability to 50% at 24h.…”

Section: Discussionmentioning

confidence: 61%

The comparison of apoptosis-related protein expressions in neurotoxin-based in vitro Parkinson s Disease models

Kaftan¹,

Armağan²,

Dağcı³

2020

jrp

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Programmed cell death (apoptosis) is mainly responsible for neuronal damage in neurodegenerative diseases. Thus, inhibition of apoptosis could represent an effective strategy in the prevention of these diseases. In this study, we aimed to compare the apoptotic responses of neurotoxins that are widely used to induce neuronal damage in cell culture studies and help to decide the most suitable experimental model for drug studies that target apoptosis. Cell viability analyses were performed by MTT assay following 1-methyl-4-phenylpyridinium (MPP +), 6-hydroxydopamine (6-OHDA), rotenone and paraquat treatments at three different time points (12, 24, 48h). Pro-apoptotic (Bax, Bad, Bak), anti-apoptotic (Bcl-2, Bcl-xl) protein levels and total caspase-3 protein levels were determined by Western Blotting technique following treatments. As expected, all neurotoxins managed to trigger cell death and apoptotic pathway. On the other hand, each neurotoxin was found to enhance and/or reduce the levels of different proteins that are associated with apoptosis. Due to different responses of apoptosis related proteins to neurotoxins, it can be concluded that the determination of target proteins with a number of protein-binding assays prior to cell culture studies and then deciding an in vitro model are essential while screening newly synthesized drugs that target apoptosis.

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Section: Discussionmentioning

confidence: 61%

The comparison of apoptosis-related protein expressions in neurotoxin-based in vitro Parkinson s Disease models

Kaftan¹,

Armağan²,

Dağcı³

2020

jrp

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“…MPP + is a widely used toxin for inducing PD-like models in in vitro studies. IC 50 value of MPP + was investigated and found as 2 mM in our previous study and adopted to present study [20]. Firstly, cells were treated with various concentrations of tideglusib or pioglitazone at three different time points (12, 24, 48 h) in order to demonstrate that tested concentrations are not toxic (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Tideglusib (0.1–50 µM) and pioglitazone (0.1–15 µM) in various concentrations dissolved in dimethyl sulfoxide (DMSO) were added and incubated at 37 °C in 5% CO 2 for 3, 6, and 24 h for cell proliferation assay. The concentration used for MPP + was determined in our previous study and adopted to present study [20]. The final concentration of DMSO in cell culture was less than 0.2%.…”

Section: Methodsmentioning

confidence: 99%

Regulation of the Nrf2 Pathway by Glycogen Synthase Kinase-3β in MPP+-Induced Cell Damage

et al. 2019

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Recently, nuclear translocation and stability of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) have gained increasing attention in the prevention of oxidative stress. The present study was aimed to evaluate the regulatory role of glycogen synthase kinase-3β (GSK-3β) inhibition by tideglusib through the Nrf2 pathway in a cellular damage model. Gene silencing (siRNA-mediated) was performed to examine the responses of Nrf2-target genes (i.e., heme oxygenase-1, NAD(P)H:quinone oxidoreductase1) to siRNA depletion of Nrf2 in MPP+-induced dopaminergic cell death. Nrf2 and its downstream regulated genes/proteins were analyzed using Real-time PCR and Western Blotting techniques, respectively. Moreover, free radical production, the changes in mitochondrial membrane potential, total glutathione, and glutathione-S-transferase were examined. The possible contribution of peroxisome proliferator-activated receptor gamma (PPARγ) to tideglusib-mediated neuroprotection was evaluated. The number of viable cells and mitochondrial membrane potential were increased following GSK-3β enzyme inhibition against MPP+. HO-1, NQO1 mRNA/protein expressions and Nrf2 nuclear translocation significantly triggered by tideglusib. Moreover, the neuroprotection by tideglusib was not observed in the presence of siRNA Nrf2. Our study supports the idea that GSK-3β enzyme inhibition may modulate the Nrf2/ARE pathway in cellular damage and the inhibitory role of tideglusib on GSK-3β along with PPARγ activation may be responsible for neuroprotection.

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“…They are also active anti-proliferative and anti-coagulant agents (Goda et al, 2004;Kundariya et al, 2011). This work is part of our continuing efforts to develop new pyrazolo [3,4-b]pyridine derivatives (Jouha et al, 2017).…”

Section: Structure Descriptionmentioning

confidence: 99%

3,4,6-Trimethyl-1-phenyl-5-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine

Loubidi¹,

Jouha²,

Tber³

et al. 2018

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In the title compound, C 19 H 17 N 3 S, the pyrazolo [3,4-b]pyridine unit is slightly bowed across the C-C bond common to the two rings. In the crystal, ribbons extending along the a-axis direction are formed by C-HÁ Á Á(ring) interactions. The ribbons are packed into corrugated layers inclined to the ac plane by approximately 22 . The thiophenyl group is rotationally disordered over two sites 180 apart in a 0.606 (2)/0.394 (2) ratio. Structure descriptionBi-heterocyclic systems have received considerable attention due to their biologically interesting properties that are often exploited in drug manufacture. The pyrazolo[3,4-b]pyridines are bi-heterocyclic systems that are included in many drugs targeting bacterial diseases and malaria. They are also active anti-proliferative and anti-coagulant agents (Goda et al., 2004;Kundariya et al., 2011). This work is part of our continuing efforts to develop new pyrazolo [3,4-b]pyridine derivatives (Jouha et al., 2017).In the title compound (Fig. 1), the pyrazolo[3,4-b]pyridine unit is slightly bowed about the C1Á Á ÁC5 axis with an angle of 2.2 (1) between the two constituent rings. The thiophenyl ring (major orientation) is almost orthogonal to the mean plane of the pyridine ring with an angle of 89.8 (2) between them. In contrast, the C14-C19 phenyl ring is almost coplanar with the pyrazole ring with an interplanar angle of 22.3 (1) . This conformation is aided by the formation of an intramolecular C15-H15Á Á ÁN1 hydrogen bond (Table 1).

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Synthesis of new heterocyclic compounds based on pyrazolopyridine scaffold and evaluation of their neuroprotective potential in MPP + -induced neurodegeneration

Cited by 27 publications

References 31 publications

The comparison of apoptosis-related protein expressions in neurotoxin-based in vitro Parkinson s Disease models

The comparison of apoptosis-related protein expressions in neurotoxin-based in vitro Parkinson s Disease models

Regulation of the Nrf2 Pathway by Glycogen Synthase Kinase-3β in MPP+-Induced Cell Damage

3,4,6-Trimethyl-1-phenyl-5-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine

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