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S-Allylcysteine Protects Against Excitotoxic Damage in Rat Cortical Slices Via Reduction of Oxidative Damage, Activation of Nrf2/ARE Binding, and BDNF Preservation

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Abstract

Neuroprotective approaches comprising different mechanisms to counteract the noxious effects of excitotoxicity and oxidative stress need validation and detailed characterization. Although S-allylcysteine (SAC) is a natural compound exhibiting a broad spectrum of protective effects characterized by antioxidant, anti-inflammatory, and neuromodulatory actions, the mechanisms underlying its protective role on neuronal cell damage triggered by early excitotoxic insults remain elusive. In this study, we evaluated if the preconditioning or the post-treatment of isolated rat cortical slices with SAC (100 μM) can ameliorate the toxic effects induced by the excitotoxic metabolite quinolinic acid (QUIN, 100 μM), and whether this protective response involves the early display of specific antioxidant and neuroprotective signals. For this purpose, cell viability/mitochondrial reductive capacity, lipid peroxidation, levels of reduced and oxidized glutathione (GSH and GSSG, respectively), the rate of cell damage, the NF-E2-related factor 2/antioxidant response element (Nrf2/ARE) binding activity, heme oxygenase 1 (HO-1) regulation, extracellular signal-regulated kinase (ERK1/2) phosphorylation, and the levels of tumor necrosis factor-alpha (TNF-α) and the neurotrophin brain-derived neurotrophic factor (BDNF) were all estimated in tissue slices exposed to SAC and/or QUIN. The incubation of slices with QUIN augmented all toxic endpoints, whereas the addition of SAC prevented and/or recovered all toxic effects of QUIN, exhibiting better results when administered 60 min before the toxin and demonstrating protective and antioxidant properties. The early stimulation of Nrf2/ARE binding activity, the upregulation of HO-1, the ERK1/2 phosphorylation and the preservation of BDNF tissue levels by SAC demonstrate that this molecule displays a wide range of early protective signals by triggering orchestrated antioxidant responses and neuroprotective strategies. The relevance of the characterization of these mechanisms lies in the confirmation that the protective potential exerted by SAC begins at the early stages of excitotoxicity and neurodegeneration and supports the design of integral prophylactic/therapeutic strategies to reduce the deleterious effects observed in neurodegenerative disorders with inherent excitotoxic events.

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Funding

CYR-S received scholarship 959177 from the Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico. MA was supported in part by grants from the National Institute of Environmental Health Sciences, R01ES03771, R01ES10563, and R01ES020852.

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Authors and Affiliations

  1. Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, Insurgentes Sur 3877, 14269, Mexico City, Mexico

    Carolina Y. Reyes-Soto, Edgar Rangel-López, Ana Laura Colín-González & Abel Santamaría

  2. Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía, 14269, Mexico City, Mexico

    Sonia Galván-Arzate

  3. Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología Ignacio Chávez, 14080, Mexico City, Mexico

    Alejandro Silva-Palacios & Cecilia Zazueta

  4. Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico

    José Pedraza-Chaverri

  5. Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico

    Jair Ramírez & Anahí Chavarria

  6. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina y Enfermería, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004, Córdoba, Spain

    Isaac Túnez

  7. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 11354, USA

    Tao Ke & Michael Aschner

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  1. Carolina Y. Reyes-Soto
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  2. Edgar Rangel-López
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  3. Sonia Galván-Arzate
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  4. Ana Laura Colín-González
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  5. Alejandro Silva-Palacios
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  6. Cecilia Zazueta
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  7. José Pedraza-Chaverri
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  8. Jair Ramírez
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  9. Anahí Chavarria
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  10. Isaac Túnez
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  11. Tao Ke
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  13. Abel Santamaría
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Correspondence to Abel Santamaría.

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Reyes-Soto, C.Y., Rangel-López, E., Galván-Arzate, S. et al. S-Allylcysteine Protects Against Excitotoxic Damage in Rat Cortical Slices Via Reduction of Oxidative Damage, Activation of Nrf2/ARE Binding, and BDNF Preservation. Neurotox Res 38, 929–940 (2020). https://doi.org/10.1007/s12640-020-00260-7

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