Quinolinic acid induces alterations in neuronal subcellular compartments, blocks autophagy flux and activates necroptosis and apoptosis in rat striatum.

Abstract Quinolinic acid (QUIN) is an agonist of N-methyl-D-aspartate receptor (NMDAr) used to study excitotoxicity in animal models. Striatal QUIN administration increases intracellular Ca2+ and oxidative stress, induces cellular damage and activates different mechanisms of cellular death. 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 at 7 days remain unexplored. In this study, the ultrastructural analysis of subcellular compartments and the status of autophagy in the striatum of rats administered with QUIN (120 and 240 nmol) was performed at 7 days. QUIN induced motor behavior impairment, tissue neurodegeneration and cellular damage; moreover, promoted swollen mitochondrial crests, spherical-like morphology and mitochondrial fragmentation. QUIN decreased ribosomal density in the rough endoplasmic reticulum and myelin sheaths discontinuity in axons with separation of the compact lamellae. Furthermore, QUIN induced increase and 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), and decreased 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) as well as decreased B-cell lymphoma 2 (Bcl-2) and increased in 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 indicate that QUIN caused subcellular compartments alteration, a blockage autophagy flux and activated necroptosis and apoptosis at 7 days.