Cytoskeleton as a Target of Quinolinic Acid Neurotoxicity: Insight from Animal Models

Pierozan, Paula; Pessoa-Pureur, Regina

doi:10.1007/s12035-017-0654-8

Cited by 9 publications

(20 citation statements)

References 80 publications

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“…damage [39]. Kynurenic acid also interferes with the organization and maintenance of the cytoskeletal intermediate filaments [40]. However, in our case no microtubules or other cytoskeleton components were labeled after 3-HOKA treatment, which indicates that this compound has different binding properties and effects compared with those tryptophan derivatives.…”

Section: Application In Cell Imagingcontrasting

confidence: 50%

3-Hydroxykynurenic acid: Physicochemical properties and fluorescence labeling

et al. 2019

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Quinoline is one of the most important heterocyclic systems in life sciences. Some derivatives are normal metabolites, and others are used as antibacterial, antimalarial, and anticancer agents. In this work, we describe the synthesis, physicochemical properties, and fluorescence features of a new 4-quinolinone fluorophore, 3-hydroxykynurenic acid (3-HOKA). 3-HOKA was obtained by alkoxide-induced rearrangement of ethyl isatinacetate followed by acidification and then alkaline hydrolysis. The fluorescent compound was characterized by NMR, MS, IR, and UV-Vis spectra. 3-HOKA can exist under a keto-enol equilibrium, but the 4-quinolinone form is the predominant tautomer. In PBS (pH = 7.4), the anionic keto form of 3-HOKA showed a maximum absorption at 368 nm, a fluorescence peak at 474 nm, and a fluorescence quantum yield (Φ F): 0.73. 3-HOKA is photostable and is a moderately weak oxygen generator. Viability assays on HeLa cells indicated that 3-HOKA did not induce significative cytotoxic effects. Under UV excitation, a bright blue fluorescence was selectively found in a singular body within the cytoplasm, a labeling pattern that suggests the possible localization of the probe in the centriole or related structures. Therefore, this novel fluorophore represents a promising prototype compound owing to its biocompatibility and potential biological applications.

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Section: Application In Cell Imagingcontrasting

confidence: 50%

3-Hydroxykynurenic acid: Physicochemical properties and fluorescence labeling

et al. 2019

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“…The next step is the longitudinal elongation of the NF by the annealing of ULFs, which is followed by radial compaction to form the final NF structure with the diameter of 10 nm ( Khalil et al, 2018 ). The core of the NF consists of NfL subunits, while the NfM and NfH subunits are arranged peripherally, their tails containing multiple phosphorylation sites projecting out radially from the filament structure ( Pierozan and Pessoa-Pureur, 2018 ). NFs are synthesized in the cell body and they are phosphorylated after being transported to the axon.…”

Section: Neurofilaments As a Target Of Quin Toxicity In Msmentioning

confidence: 99%

“…As mentioned earlier, NFs have multiple phosphorylation sites, with the tail domains of NfH and NfM proteins containing many of these sites protruding from the surface of the filament structure. Phosphorylation-dephosphorylation of proteins are an important regulatory mechanism, where negatively charged phosphate groups are added to or removed from Ser, Thr, and Tyr amino acids, thereby changing the function of the protein ( Pierozan and Pessoa-Pureur, 2018 ). The phosphorylation process is executed by protein kinases, while the dephosphorylation is catalyzed by phosphatases.…”

Section: Neurofilaments As a Target Of Quin Toxicity In Msmentioning

confidence: 99%

“…The phosphorylation process is executed by protein kinases, while the dephosphorylation is catalyzed by phosphatases. The phosphorylation sites of NfM and NfH subunits are found at repeating Lys-Ser-Pro (KSP) regions at their C-termini ( Gentil et al, 2015 ; Pierozan and Pessoa-Pureur, 2018 ). The phosphorylation of NFs is a highly specific process catalyzed by mitogen-activated protein kinases (MAPK), such as ERK1/2, JNK, p38MAPK, and proline-directed kinases (e.g., Cdk5), and glycogen synthase kinase 3 (GSK3).…”

Section: Neurofilaments As a Target Of Quin Toxicity In Msmentioning

confidence: 99%

“…The phosphorylation of NFs is a highly specific process catalyzed by mitogen-activated protein kinases (MAPK), such as ERK1/2, JNK, p38MAPK, and proline-directed kinases (e.g., Cdk5), and glycogen synthase kinase 3 (GSK3). The phosphorylation of the NfH tail domain sites most probably plays a role in the regulation of neurofilament mediated axonal transport ( Pierozan and Pessoa-Pureur, 2018 ), and increases the resistance of these subunits against protease activity ( Khalil et al, 2018 ). The N-terminal of the NfL subunit also contains important phosphorylation sites, as the addition of phosphate molecules on these sites regulates the equilibrium of assembly and disassembly of NfM and NfH subunits.…”

Section: Neurofilaments As a Target Of Quin Toxicity In Msmentioning

confidence: 99%

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Kynurenines and Neurofilament Light Chain in Multiple Sclerosis

et al. 2021

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Multiple sclerosis is an autoimmune, demyelinating, and neurodegenerative disease of the central nervous system. In recent years, it has been proven that the kynurenine system plays a significant role in the development of several nervous system disorders, including multiple sclerosis. Kynurenine pathway metabolites have both neurotoxic and neuroprotective effects. Moreover, the enzymes of the kynurenine pathway play an important role in immunomodulation processes, among others, as well as interacting with neuronal energy balance and various redox reactions. Dysregulation of many of the enzymatic steps in kynurenine pathway and upregulated levels of these metabolites locally in the central nervous system, contribute to the progression of multiple sclerosis pathology. This process can initiate a pathogenic cascade, including microglia activation, glutamate excitotoxicity, chronic oxidative stress or accumulated mitochondrial damage in the axons, that finally disrupt the homeostasis of neurons, leads to destabilization of neuronal cell cytoskeleton, contributes to neuro-axonal damage and neurodegeneration. Neurofilaments are good biomarkers of the neuro-axonal damage and their level reliably indicates the severity of multiple sclerosis and the treatment response. There is increasing evidence that connections exist between the molecules generated in the kynurenine metabolic pathway and the change in neurofilament concentrations. Thus the alterations in the kynurenine pathway may be an important biomarker of the course of multiple sclerosis. In our present review, we report the possible relationship and connection between neurofilaments and the kynurenine system in multiple sclerosis based on the available evidences.

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Osteoprotegerin deficiency causes morphological and quantitative damage in epithelial rests of Malassez

et al. 2018

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Epithelial rests of Malassez (ERM), the only odontogenic epithelial structures in periodontal tissue, are proposed to correlate with root resorption, but the detailed mechanism remains unclear. Osteoprotegerin (OPG), the main inhibitor of osteoclastogenesis, plays a pivotal role in inhibiting root resorption, and ERM cells express OPG mRNA in vitro. Thus, in this study, we aimed to clarify OPG expression in ERM in vivo and to explore the role of OPG in ERM to determine whether ERM are associated with root resorption via OPG. We established Opg-knockout (Opg-KO) mice and detected the OPG expression in ERM by immunohistochemical staining in 4-, 6-, 10-, 26- and 52-week-old mice. The ERM of wild-type (WT) mice and Opg-KO mice were evaluated histologically at 4, 10 and 26 weeks of age. Orthodontic root resorption models were established, maxillae were collected after 4 weeks, and ERM were analysed by histomorphometric analysis. In our study, OPG displayed sustained expression in ERM, and OPG deficiency caused the destruction of ERM, characterized by irregular morphology and reduced numbers. Moreover, after orthodontic treatment, the loss of OPG severely damaged ERM, aggravating root resorption. Together, our results demonstrated that ERM expressed the OPG protein in vivo and that OPG deficiency resulted in morphological and quantitative damage to ERM. Furthermore, ERM may be associated with root resorption via OPG, thus helping to explain the mechanism underlying root resorption.

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Cytoskeleton as a Target of Quinolinic Acid Neurotoxicity: Insight from Animal Models

Cited by 9 publications

References 80 publications

3-Hydroxykynurenic acid: Physicochemical properties and fluorescence labeling

3-Hydroxykynurenic acid: Physicochemical properties and fluorescence labeling

Kynurenines and Neurofilament Light Chain in Multiple Sclerosis

Osteoprotegerin deficiency causes morphological and quantitative damage in epithelial rests of Malassez

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