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Quinolinic Acid Induces Alterations in Neuronal Subcellular Compartments, Blocks Autophagy Flux and Activates Necroptosis and Apoptosis in Rat Striatum

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Abstract

Quinolinic acid (QUIN) is an agonist of N-methyl-d-aspartate receptor (NMDAr) used to study the underlying mechanism of excitotoxicity in animal models. There is evidence indicating that impairment in autophagy at early times contributes to cellular damage in excitotoxicity; however, the status of autophagy in QUIN model on day 7 remains unexplored. In this study, the ultrastructural analysis of subcellular compartments and the status of autophagy, necroptosis, and apoptosis in the striatum of rats administered with QUIN (120 nmol and 240 nmol) was performed on day 7. QUIN induced circling behavior, neurodegeneration, and cellular damage; also, it promoted swollen mitochondrial crests, spherical-like morphology, and mitochondrial fragmentation; decreased ribosomal density in the rough endoplasmic reticulum; and altered the continuity of myelin sheaths in axons with separation of the compact lamellae. Furthermore, QUIN induced an increase and a decrease in ULK1 and p-70-S6K phosphorylation, respectively, suggesting autophagy activation; however, the increased microtubule-associated protein 1A/1B-light chain 3-II (LC3-II) and sequestosome-1/p62 (SQSTM1/p62), the coexistence of p62 and LC3 in the same structures, and the decrease in Beclin 1 and mature cathepsin D also indicates a blockage in autophagy flux. Additionally, QUIN administration increased tumor necrosis factor alpha (TNFα) and receptor-interacting protein kinase 3 (RIPK3) levels and its phosphorylation (p-RIPK3), as well as decreased B-cell lymphoma 2 (Bcl-2) and increased Bcl-2-associated X protein (Bax) levels and c-Jun N-terminal kinase (JNK) phosphorylation, suggesting an activation of necroptosis and apoptosis, respectively. These results suggest that QUIN activates the autophagy, but on day 7, it is blocked and organelle and cellular damage, neurodegeneration, and behavior alterations could be caused by necroptosis and apoptosis activation.

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Data Availability

The datasets generated during and/or analyzed though the current study are available as supplementary material.

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Funding

This work was supported by CONACYT (Grant No. A1-S-21433 to PDM).

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Authors and Affiliations

  1. Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Av. Insurgentes Sur 3877, 14269, Mexico City, Mexico

    Carlos Alfredo Silva-Islas, Ricardo Alberto Santana-Martínez & Perla D. Maldonado

  2. Laboratorio de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14080, Mexico City, Mexico

    Juan Carlos León-Contreras & Rogelio Hernández-Pando

  3. Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico

    Diana Barrera-Oviedo

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

    Jose Pedraza-Chaverri

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  1. Carlos Alfredo Silva-Islas
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Contributions

Conceptualization: Perla D. Maldonado and Carlos Alfredo Silva-Islas; methods: Carlos Alfredo Silva-Islas, Ricardo Alberto Santana-Martínez, and Juan Carlos León-Contreras; formal analysis and investigation: Carlos Alfredo Silva-Islas; writing or preparation of the original draft: Carlos Alfredo Silva-Islas and Ricardo Alberto Santana-Martínez; writing which included review and editing: Carlos Alfredo Silva-Islas, Diana Barrera-Oviedo, Jose Pedraza-Chaverri, Rogelio Hernández-Pando, and Perla D. Maldonado; funding acquisition: Perla D. Maldonado; resources: Perla D Maldonado; supervision: Jose Pedraza-Chaverri, Rogelio Hernández-Pando, and Perla D. Maldonado. All authors read and approved the final manuscript.

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Correspondence to Perla D. Maldonado.

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This research only involves animals. All procedures with animals were carried out strictly according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and to the Norma Oficial Mexicana NOM-062-ZOO-1999. The experimental procedures were approved by the Institutional and Local Committee for the Care and Use of Laboratory Animals on the Ethical Use of Animals from Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, INNN project 44/15. During the experiments, all efforts were made to minimize animal suffering. Informed consent is not applicable.

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Silva-Islas, C.A., Santana-Martínez, R.A., León-Contreras, J.C. et al. Quinolinic Acid Induces Alterations in Neuronal Subcellular Compartments, Blocks Autophagy Flux and Activates Necroptosis and Apoptosis in Rat Striatum. Mol Neurobiol 59, 6632–6651 (2022). https://doi.org/10.1007/s12035-022-02986-1

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