PMID- 35980566 OWN - NLM STAT- MEDLINE DCOM- 20221004 LR - 20221012 IS - 1559-1182 (Electronic) IS - 0893-7648 (Linking) VI - 59 IP - 11 DP - 2022 Nov TI - Quinolinic Acid Induces Alterations in Neuronal Subcellular Compartments, Blocks Autophagy Flux and Activates Necroptosis and Apoptosis in Rat Striatum. PG - 6632-6651 LID - 10.1007/s12035-022-02986-1 [doi] AB - 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 (TNFalpha) 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. CI - (c) 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Silva-Islas, Carlos Alfredo AU - Silva-Islas CA AUID- ORCID: 0000-0003-1405-7377 AD - Laboratorio de Patologia Vascular Cerebral, Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez, Av. Insurgentes Sur 3877, 14269, Mexico City, Mexico. FAU - Santana-Martinez, Ricardo Alberto AU - Santana-Martinez RA AD - Laboratorio de Patologia Vascular Cerebral, Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez, Av. Insurgentes Sur 3877, 14269, Mexico City, Mexico. FAU - Leon-Contreras, Juan Carlos AU - Leon-Contreras JC AD - Laboratorio de Patologia Experimental, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, 14080, Mexico City, Mexico. FAU - Barrera-Oviedo, Diana AU - Barrera-Oviedo D AD - Departamento de Farmacologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, 04510, Mexico City, Mexico. FAU - Pedraza-Chaverri, Jose AU - Pedraza-Chaverri J AD - Departamento de Biologia, Facultad de Quimica, Universidad Nacional Autonoma de Mexico, 04510, Mexico City, Mexico. FAU - Hernandez-Pando, Rogelio AU - Hernandez-Pando R AD - Laboratorio de Patologia Experimental, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, 14080, Mexico City, Mexico. FAU - Maldonado, Perla D AU - Maldonado PD AD - Laboratorio de Patologia Vascular Cerebral, Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez, Av. Insurgentes Sur 3877, 14269, Mexico City, Mexico. maldonado.perla@quimica.unam.mx. LA - eng GR - A1-S-21433/CONACYT/ PT - Journal Article DEP - 20220818 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (Beclin-1) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Sequestosome-1 Protein) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (bcl-2-Associated X Protein) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 3.4.23.5 (Cathepsin D) RN - F6F0HK1URN (Quinolinic Acid) SB - IM MH - Animals MH - Apoptosis/physiology MH - Autophagy/physiology MH - Beclin-1/metabolism MH - Cathepsin D/metabolism MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Lysosomes/metabolism MH - Microtubule-Associated Proteins/metabolism MH - Necroptosis MH - *Quinolinic Acid/toxicity MH - Rats MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Sequestosome-1 Protein/metabolism MH - *Tumor Necrosis Factor-alpha/metabolism MH - bcl-2-Associated X Protein/metabolism OTO - NOTNLM OT - Apoptosis OT - Autophagy impairment OT - Excitotoxicity OT - Necroptosis OT - Quinolinic acid EDAT- 2022/08/19 06:00 MHDA- 2022/10/05 06:00 CRDT- 2022/08/18 11:21 PHST- 2022/03/18 00:00 [received] PHST- 2022/07/29 00:00 [accepted] PHST- 2022/08/19 06:00 [pubmed] PHST- 2022/10/05 06:00 [medline] PHST- 2022/08/18 11:21 [entrez] AID - 10.1007/s12035-022-02986-1 [pii] AID - 10.1007/s12035-022-02986-1 [doi] PST - ppublish SO - Mol Neurobiol. 2022 Nov;59(11):6632-6651. doi: 10.1007/s12035-022-02986-1. Epub 2022 Aug 18.