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Protective Effects of Novel Substituted Triazinoindole Inhibitors of Aldose Reductase and Epalrestat in Neuron-like PC12 Cells and BV2 Rodent Microglial Cells Exposed to Toxic Models of Oxidative Stress: Comparison with the Pyridoindole Antioxidant Stobadine

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Abstract

Aldose reductase (AR) catalyzes the conversion of glucose to sorbitol in a NADPH-dependent reaction, thereby increasing the production of reactive oxygen species (ROS). Since AR activation is linked to redox dysregulation and cell damage in neurodegenerative diseases, AR inhibitors (ARIs) constitute promising therapeutic tools for the treatment of these disorders. Among these compounds, the novel substituted triazinoindole derivatives cemtirestat (CMTI) and COTI, as well as the clinically employed epalrestat (EPA) and the pyridoindole-antioxidant stobadine (STB), were tested in both PC12 cells and BV2 microglia exposed to four different neurotoxic models. These include (1) oxidative stress with hydrogen peroxide (H2O2), (2) mitochondrial complex IV inhibition with NaN3, (3) endoplasmic reticulum-stress and lipotoxicity induced by palmitic acid/bovine serum albumin (PAM/BSA), and (4) advanced carbonyl compound lipotoxicity by 4-hydroxynonenal (4-HNE). All toxic compounds decreased cell viability and increased ROS formation in both PC12 and BV2 cells in a concentration-dependent manner (1–1000 μM; NaN3 < H2O2≈PAM/BSA < 4-HNE). In PC12 cells, EPA increased cell viability in all toxic models only at 1 μM, whereas CMTI restored baseline viability in all toxic models. COTI afforded protection against lipotoxicity, while STB only prevented H2O2-induced toxicity. Except for the 4-HNE model, EPA prevented ROS generation in all other toxic models, whereas CMTI, COTI, and STB prevented ROS production in all toxic models. In BV2 cells, EPA and CMTI restored baseline cell viability in all toxic models tested, while COTI and STB did not prevent the loss of viability in the NaN3 model. All ARIs and STB efficiently prevented ROS formation in all toxic models in a concentration-independent manner. The differential protective effects evoked by the novel ARIs and STB on the toxic models tested herein provide novel and relevant comparative evidence for the design of specific therapeutic strategies against neurodegenerative events associated with neurological disorders.

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Funding

This work was supported by The Scientific and Technological Research Council of Turkey (C.K.; TUBITAK Project No: 215S197; SAS-TUBITAK JRP 2015/7), the Slovak Research and Development Agency (M.S.; Contract No. APVV-15-0455), and the Slovak Grant Agency of the Ministry of Education (M.S.P.; VEGA 2/0005/2018). M.A. was supported by the National Institute of Environmental Health Sciences grants R01ES03771 and R01ES10563.

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Authors and Affiliations

  1. Cellular Stress Response and Signal Transduction Research Laboratory, Faculty of Medicine, Department of Medical Pharmacology, Gazi University, Beşevler, 06500, Ankara, Turkey

    Zubeyir Elmazoglu & Cimen Karasu

  2. Institute of Experimental Pharmacology and Toxicology, CEM, Slovak Academy of Sciences, Dubravska cesta 9, 84104, Bratislava, Slovakia

    Marta Soltesova Prnova & Milan Stefek

  3. Department of Medical Pharmacology, Faculty of Medicine, Ankara Yildirim Beyazit University Bilkent, 06800, Ankara, Turkey

    Asli F. Ceylan

  4. Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, Bronx, NY, 10461, USA

    Michael Aschner

  5. Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología Y Neurocirugía, S.S.A, 14269, Mexico City, Mexico

    Edgar Rangel-López & Abel Santamaria

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  1. Zubeyir Elmazoglu
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  2. Marta Soltesova Prnova
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  3. Milan Stefek
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  8. Cimen Karasu
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Correspondence to Abel Santamaria or Cimen Karasu.

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Elmazoglu, Z., Prnova, M.S., Stefek, M. et al. Protective Effects of Novel Substituted Triazinoindole Inhibitors of Aldose Reductase and Epalrestat in Neuron-like PC12 Cells and BV2 Rodent Microglial Cells Exposed to Toxic Models of Oxidative Stress: Comparison with the Pyridoindole Antioxidant Stobadine. Neurotox Res 39, 588–597 (2021). https://doi.org/10.1007/s12640-021-00349-7

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