Quinolinic acid and glutamatergic neurodegeneration in Caenorhabditis elegans

Abstract

Quinolinic acid (QUIN) is an endogenous neurotoxin that acts as an N-methyl-D-aspartate receptor (NMDAR) agonist generating a toxic cascade, which can lead to neurodegeneration. The action of QUIN in Caenorhabditis elegans and the neurotoxins that allow the study of glutamatergic system disorders have not been carefully addressed. The effects of QUIN on toxicological and behavioral parameters in VM487 and VC2623 transgenic, as well as wild-type (WT) animals were performed to evaluate whether QUIN could be used as a neurotoxin in C. elegans. QUIN reduced survival of WT worms in a dose-dependent manner. A sublethal dose of QUIN (20 mM) increased reactive oxygen species (ROS) levels in an nmr-1/NMDAR-dependent manner, activated the DAF-16/FOXO transcription factor, and increased expression of the antioxidant enzymes, superoxide dismutase-3, glutathione S-transferase-4, and heat shock protein-16.2. QUIN did not change motor behavioral parameters, but altered the sensory behavior in N2 and VM487 worms. Notably, the effect of QUIN on the sensory behavioral parameters might occur, at least in part, secondary to increased ROS. However, the touch response behavior indicates a mechanism of action that is independent of ROS generation. In addition, non-lethal doses of QUIN triggered neurodegeneration in glutamatergic neurons. Our findings indicate that C. elegans might be useful as a model for studies of QUIN as a glutamatergic neurotoxin in rodent models.

Modeling neurodegeneration in Caenorhabditis elegans

“…As previously described, this assay was used as a readout to examine phenotypic rescue of Aβ-induced degeneration of glutamatergic neurons in the presence of different isoforms of human APOE ( Griffin et al, 2019 ). As another example, animals treated with quinolinic acid exhibited neurodegeneration due to glutamatergic neurotransmission defects ( da Silveira et al, 2018 ). Similarly, in single-copy knock-in SOD1 models of ALS, loss of sod-1 function produced defects in light touch response indicative of a disruption in glutamate signaling ( Baskoylu et al, 2018 ).…”

Effects of Sleep Deprivation on the Tryptophan Metabolism

“… 64 - 66 Imbalance between neurotoxic and neuroprotective and immune-modulator kynurenine pathway metabolites have been reported in many neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), Huntington disease (HD). 43 , 67 - 71 Increased kynurenine levels or catabolic enzyme activity are not the only mechanisms that determine the formation of KYNA in the brain. Accumulation of pro-oxidant factors after sleep deprivation also promotes non-enzymatic degradation of kynurenine to KYNA, which is a stable metabolite, and the enzymes responsible for its breakdown are absent in human.…”

Molecular Mechanisms of Glial Cells Related Signaling Pathways Involved in the Neuroinflammatory Response of Depression

“…KYN can also be transformed into 3-hydroxykynurenine (3-HK) with the kynurenine monooxygenase (KMO). Then, 3-HK is transformed to quinolinic acid (QUIN), which is an agonist of the NMDA receptor [ 24 ]. Since literatures have shown kynurenine signaling could significantly impact glutamate, acetylcholine, and serotonin pathways, the above KYN pathways of tryptophan are considered to play important roles in the pathophysiology of inflammation and depression [ 25 ].…”