TY  - JOUR
AB  - In the pathogenesis of Alzheimer's disease, the overexpression of glycogen synthase kinase-3β (GSK-3β) stands out due to its multifaced nature, as it contributes to the promotion of amyloid β and tau protein accumulation, as well as neuroinflammatory processes. Therefore, in the present study, we have designed, synthesized, and evaluated a new series of GSK-3β inhibitors based on the N-(pyridin-2-yl)cyclopropanecarboxamide scaffold. We identified compound 36, demonstrating an IC50 of 70 nM against GSK-3β. Subsequently, through crystallography studies and quantum mechanical analysis, we elucidated its binding mode and identified the structural features crucial for interactions with the active site of GSK-3β, thereby understanding its inhibitory potency. Compound 36 was effective in the cellular model of hyperphosphorylated tau-induced neurodegeneration, where it restored cell viability after okadaic acid treatment and showed anti-inflammatory activity in the LPS model, significantly reducing NO, IL-6, and TNF-α release. In ADME-tox in vitro studies, we confirmed the beneficial profile of 36, including high permeability in PAMPA (Pe equals 9.4) and high metabolic stability in HLMs as well as lack of significant interactions with isoforms of the CYP enzymes and lack of considerable cytotoxicity on selected cell lines (IC50 > 100 μM on HT-22 cells and 89.3 μM on BV-2 cells). Based on promising pharmacological activities and favorable ADME-tox properties, compound 36 may be considered a promising candidate for in vivo research as well as constitute a reliable starting point for further studies.
AU  - Góral, I.*
AU  - Wichur, T.*
AU  - Sługocka, E.*
AU  - Grygier, P.*
AU  - Głuch-Lutwin, M.*
AU  - Mordyl, B.*
AU  - Honkisz-Orzechowska, E.*
AU  - Szałaj, N.*
AU  - Godyń, J.*
AU  - Panek, D.*
AU  - Zaręba, P.*
AU  - Sarka, A.*
AU  - Żmudzki, P.*
AU  - Latacz, G.*
AU  - Pustelny, K.*
AU  - Bucki, A.*
AU  - Czarna, A.*
AU  - Cardoso Micu Menezes, F.M.
AU  - Więckowska, A.*
C1  - 71498
C2  - 56219
CY  - 1155 16th St, Nw, Washington, Dc 20036 Usa
SP  - 3181-3201
TI  - Exploring novel GSK-3β inhibitors for anti-neuroinflammatory and neuroprotective effects: Synthesis, crystallography, computational analysis, and biological evaluation.
JO  - ACS Chem. Neurosci.
VL  - 15
IS  - 17
PB  - Amer Chemical Soc
PY  - 2024
ER  - 

TY  - JOUR
AB  - Amyotrophic lateral sclerosis (ALS) is a lethal progressive neurodegenerative disease, characterized by a loss of function of upper and lower motor neurons. This study aimed to explore probable pathological alterations occurring in individuals with ALS compared to neurologically healthy controls through the analysis of cerebrospinal fluid (CSF), a medium, which directly interacts with brain parenchyma. A total of 7 ALS patients with disease-associated mutations (ATXN2, C9ORF72, FUS, SOD1, and TARDBP) and 13 controls were included in the study. Multiple analytical approaches were employed, including metabolomic and metallomics profiling, as well as genetic screening, using CSF samples obtained from the brain compartment. Data analysis involved the application of multivariate statistical methods. Advanced hyphenated selenium and redox metal (iron, copper, and manganese) speciation techniques and nontargeted Fourier transform ion cyclotron resonance mass spectrometry-based metabolomics were used for data acquisition. Nontargeted metabolomics showed reduced steroids, including sex hormones; additionally, copper and manganese species were found to be the most relevant features for ALS patients. This indicates a potential alteration of sex hormone pathways in the ALS-affected brain, as reflected in the CSF.
AU  - Solovyev, N.
AU  - Lucio, M.
AU  - Mandrioli, J.*
AU  - Forcisi, S.
AU  - Kanawati, B.
AU  - Uhl, J.
AU  - Vinceti, M.*
AU  - Schmitt-Kopplin, P.
AU  - Michalke, B.
C1  - 67970
C2  - 54448
CY  - 1155 16th St, Nw, Washington, Dc 20036 Usa
SP  - 3035-3046
TI  - Interplay of metallome and metabolome in amyotrophic lateral sclerosis: A study on cerebrospinal fluid of patients carrying disease-related gene mutations.
JO  - ACS Chem. Neurosci.
VL  - 14
IS  - 17
PB  - Amer Chemical Soc
PY  - 2023
ER  - 

TY  - JOUR
AB  - Expanded CAG trinucleotide repeats in Huntington's disease (HD) are causative for neurotoxicity. The mutant CAG repeat RNA encodes neurotoxic polyglutamine proteins and can lead to a toxic gain of function by aberrantly recruiting RNA-binding proteins. One of these is the MID1 protein, which induces aberrant Huntingtin (HTT) protein translation upon binding. Here we have identified a set of CAG repeat binder candidates by in silico methods. One of those, furamidine, reduces the level of binding of HTT mRNA to MID1 and other target proteins in vitro. Metadynamics calculations, fairly consistent with experimental data measured here, provide hints about the binding mode of the ligand. Importantly, furamidine also decreases the protein level of HTT in a HD cell line model. This shows that small molecules masking RNA-MID1 interactions may be active against mutant HTT protein in living cells.
AU  - Matthes, F.*
AU  - Massari, S.*
AU  - Bochicchio, A.*
AU  - Schorpp, K.K.
AU  - Schilling, J.*
AU  - Weber, S.*
AU  - Offermann, N.*
AU  - Desantis, J.*
AU  - Wanker, E.*
AU  - Carloni, P.*
AU  - Hadian, K.
AU  - Tabarrini, O.*
AU  - Rossetti, G.*
AU  - Krauss, S.*
C1  - 53717
C2  - 44980
SP  - 1399-1408
TI  - Reducing mutant huntingtin protein expression in living cells by a newly identified RNA CAG binder.
JO  - ACS Chem. Neurosci.
VL  - 9
IS  - 6
PY  - 2018
ER  - 

TY  - JOUR
AB  - Manganese (Mn) may foster aggregation of alpha-synuclein (αSyn) contributing to the pathogenesis of PD. Here, we examined the influence of αSyn overexpression on distribution and oxidation states of Mn in frozen-hydrated primary midbrain neurons (PMNs) by synchrotron-based X-ray fluorescence (XRF) and X-ray absorption near edge structure spectroscopy (XANES). Overexpression of αSyn increased intracellular Mn levels, whereas levels of Ca, Zn, K, P, and S were significantly decreased. Mn oxidation states were not altered. A strong correlation between Cu-/Mn-levels as well as Fe-/Mn-levels was observed in αSyn-overexpressing cells. Subcellular resolution revealed a punctate or filament-like perinuclear and neuritic distribution of Mn, which resembled the expression of DMT1 and MnSOD. While overexpression of αSyn did not significantly alter the expression patterns of the most-expressed Mn transport proteins (DMT1, VGCC, Fpn1), it attenuated the Mn release from Mn-treated neurons. Thus, these data suggest that αSyn may act as an intracellular Mn store. In total, neurotoxicity in PD could be mediated via regulation of transition metal levels and the metal-binding capacity of αSyn, which could represent a promising therapeutic target for this neurodegenerative disorder.
AU  - Dučić, T.*
AU  - Carboni, E.*
AU  - Lai, B.*
AU  - Chen, S.*
AU  - Michalke, B.
AU  - Lázaro, D.F.*
AU  - Outeiro, T.F.*
AU  - Bähr, M.*
AU  - Barski, E.*
AU  - Lingor, P.*
C1  - 46767
C2  - 37806
SP  - 1769-1779
TI  - Alpha-synuclein regulates neuronal levels of manganese and calcium.
JO  - ACS Chem. Neurosci.
VL  - 6
IS  - 10
PY  - 2015
ER  - 

TY  - JOUR
AB  - A series of bimodal metabotropic glutamate-receptor targeted MRI contrast agents has been developed and evaluated, based on established competitive metabotropic Glu receptor subtype 5 (mGluR5) antagonists. In order to directly visualize mGluR5 binding of these agents on the surface of live astrocytes, variations in the core structure were made. A set of gadolinium conjugates containing either a cyanine dye or a fluorescein moiety was accordingly prepared, to allow visualization by optical microscopy in cellulo. In each case, surface receptor binding was compromised and cell internalization observed. Another approach, examining the location of a terbium analogue via sensitized emission, also exhibited nonspecific cell uptake in neuronal cell line models. Finally, biotin derivatives of two lead compounds were prepared, and the specificity of binding to the mGluR5 cell surface receptors was demonstrated with the aid of their fluorescently labeled avidin conjugates, using both total internal reflection fluorescence (TIRF) and confocal microscopy.
AU  - Mishra, A.
AU  - Mishra, R.*
AU  - Gottschalk, S.
AU  - Pal, R.*
AU  - Sim, N.*
AU  - Engelmann, J.*
AU  - Goldberg, M.*
AU  - Parker, D.*
C1  - 28632
C2  - 33504
SP  - 128-137
TI  - Microscopic visualization of metabotropic glutamate receptors on the surface of living cells using bifunctional magnetic resonance imaging probes.
JO  - ACS Chem. Neurosci.
VL  - 5
IS  - 2
PB  - Amer. Chemical Soc.
PY  - 2014
ER  -