Combatting Nitrosative Stress and Inflammation with Novel Substituted Triazinoindole Inhibitors of Aldose Reductase in PC12 Cells Exposed to 6-Hydroxydopamine Plus High Glucose.
Aldose reductase, 2-(3-oxotriazinoindol-5-yl) acetic acid (COTI)
Carboxymethylated thioxotriazinoindoles
Cemtirestat
Epalrestat
Neuroprotection
Parkinson’s disease
Journal
Neurotoxicity research
ISSN: 1476-3524
Titre abrégé: Neurotox Res
Pays: United States
ID NLM: 100929017
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
29
02
2020
accepted:
22
10
2020
revised:
22
09
2020
pubmed:
5
11
2020
medline:
15
12
2021
entrez:
4
11
2020
Statut:
ppublish
Résumé
Cellular redox dysregulation produced by aldose reductase (AR) in the presence of high blood sugar is a mechanism involved in neurodegeneration commonly observed in diabetes mellitus (DM) and Parkinson's disease (PD); therefore, AR is a key target for treatment of both diseases. The substituted triazinoindole derivatives 2-(3-thioxo-2H-[1,2,4]triazino[5,6-b]indol-5(3H)-yl) acetic acid (cemtirestat or CMTI) and 2-(3-oxo-2H-[1,2,4]triazino[5,6-b]indol-5(3H)-yl) acetic acid (COTI) are well-known AR inhibitors (ARIs). The neuroprotective properties of CMTI, COTI, the clinically used epalrestat (EPA), and the pyridoindole antioxidants stobadine and SMe1EC2 were all tested in the neurotoxic models produced by hyperglycemic glucotoxicity (HG, 75 mM D-glucose, 72 h), 6-hydroxydopamine (6-OHDA), and HG+6-OHDA models in PC12 cells. Cell viability decreased in all toxic models, increased by 1-5 μM EPA, and decreased by COTI at ≥ 2.5 μM. In the HG model alone, where compounds were present in the medium for 24 h after a continuous 24-h exposure to HG, cell viability was improved by 100 nM-5 μM EPA, 1-10 μM ARIs, and the antioxidants studied, but decreased by EPA at ≥ 10 μM. In the 6-OHDA model alone, where cells were treated with compounds for 24 h and further exposed to 100 μM 6-OHDA (8 h), only the antioxidants protected cell viability. In the HG+6-OHDA model, where cells were treated with all compounds (1 nM to 50 μM) for 48 h and exposed to 75 mM glucose for 24 h followed by incubation with 6-OHDA for 8 h, cell viability was protected by 100 nM-10 μM ARIs and 100-500 nM EPA, but not by antioxidants. All ARIs inhibited the HG+6-OHDA-induced increase in iNOS, IL-1β, TNF-α, 3-NT, and total oxidant status at 1-50 μM, while increased SOD, CAT, GPx, and total antioxidant status at 1-10 μM. EPA and CMTI also reduced the HG+6-OHDA-induced increase in the cellular levels of nuclear factor kB (NF-KB). The neuroprotective potential of the novel ARIs and the pyridoindole antioxidants studied constitutes a promising tool for the development of therapeutic strategies against DM-induced and PD-related neurodegeneration.
Identifiants
pubmed: 33146867
doi: 10.1007/s12640-020-00305-x
pii: 10.1007/s12640-020-00305-x
doi:
Substances chimiques
Antioxidants
0
Neuroprotective Agents
0
Oxidopamine
8HW4YBZ748
Aldehyde Reductase
EC 1.1.1.21
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
210-226Subventions
Organisme : TUBITAK
ID : 215S197
Organisme : SAS-TUBITAK
ID : JRP 2015/7
Organisme : Slovak Research and Development Agency
ID : APVV-15-0455
Organisme : Slovak Research and Development Agency
ID : VEGA 2/0005/2018
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