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 Ca 2+ 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 microtubuleassociated 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 ux. 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 ux and activated necroptosis and apoptosis at 7 days.

An integrated cytokine and kynurenine network as the basis of neuroimmune communication

“…High micromolar levels have been recorded in patients with immunodeficiency viruses, possibly contributing to the associated dementia ( Heyes et al, 1992b ; Kandanearatchi and Brew, 2012 ). It is likely that the pro-oxidant activity of quinolinic acid ( Platenik et al, 2001 ; Santamaria et al, 2001 ; Seminotti et al, 2016 ; Hernandez-Martinez et al, 2017 ) and its subcellular targets leading to effects on apoptosis and autophagy ( Silva-Islas et al, 2022 ) may also be relevant.…”

Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process

“…Consequently, dysfunction in mitophagy has been implicated in aging and several age-associated neurodegenerative disorders, including AD [ 22 , 23 ]. Several studies reported the role of QA in the alteration of mitochondrial structure and functions [ 18 , 19 ], but its regulatory role in mitophagy has been unexplored. We observed QA significantly increases the protein level of LC3B-II, an autophagosome marker, compared to the control group after 72 h treatment in BV2 cells by western blot (Additional file 1 : Fig.…”

DADLE promotes motor function recovery by inhibiting cytosolic phospholipase A2 mediated lysosomal membrane permeabilization after spinal cord injury

“…Necroptosis is a regulated form of necrosis mediated by RIPK1 and RIPK3 that is capable of exacerbating cell death and neuroinflammation in the pathogenesis of central nervous system diseases (Fan et al, 2019; Liu et al, 2018). Blocking autophagy further activates neural necroptosis and apoptosis in vitro (Silva‐Islas et al, 2022). The impairment of autophagy and the development of necroptosis after SCI potentiate proinflammatory activation and further contribute to worse functional outcomes (Fan et al, 2019; Li et al, 2022).…”