Elsevier

Neuropharmacology

Volume 112, Part B, January 2017, Pages 346-364
Neuropharmacology

Invited review
Involvement of quinolinic acid in the neuropathogenesis of amyotrophic lateral sclerosis

https://doi.org/10.1016/j.neuropharm.2016.05.011Get rights and content

Highlights

  • This review describes the mechanisms involving the neurotoxin quinolinic acid in ALS.

  • Highlights the overlap between QUIN toxicity and ALS mechanisms, and provides evidence for a correlation between QUIN and ALS.

  • Summary of pharmacological drugs tested in ALS, and their potential correlation to KP and QUIN.

  • Proposal of using KP modulating agents as potential ALS treatments to alter diseases phenotype.

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease characterized by a progressive degeneration of central and peripheral motor neurons, leading to the atrophy of voluntary muscles. It has been previously demonstrated that the kynurenine pathway (KP), the major biochemical pathway for tryptophan metabolism, is dysregulated in ALS. In particular, the neuroactive intermediate, quinolinic acid (QUIN) has been shown to accumulate with a concomitant decrease in other neuroprotective and immunomodulatory KP metabolites. Furthermore, multiple biochemical phenomena associated with QUIN cytotoxicity are present in ALS, suggesting that QUIN may play a substantial role in the pathogenesis of ALS. This review highlights the potential roles of QUIN in ALS, and explores KP modulation as a therapeutic candidate in ALS.

This article is part of the Special Issue entitled ‘The Kynurenine Pathway in Health and Disease’.

Section snippets

Introduction to ALS

Amyotrophic lateral sclerosis (ALS) is the most common form of Motor Neuron Disease (MND). Also known as Lou Gehrig's disease, it is a fatal neuromuscular disorder characterized by the progressive loss of motor neurons in the spinal cord, brain stem, and cortex, thereby affecting the corticobulbar and corticospinal motor tracts, and nuclei of cranial nerves and ventral horn of the spinal cord (Fig. 1). Clinically, ALS produces progressive weakness, resulting in atrophy of the limb, axial, and

Introduction to the KP

The KP is the primary degradation pathway for the essential amino acid Tryptophan (TRP). TRP is an essential amino acid that cannot be synthesized by the human body, and must be obtained from the diet. Once absorbed by the body, TRP is transported around the periphery either bound to albumin (90%) or in free form, the two states existing in an equilibrium (McMenamy, 1965). Only the free form can be transported across the blood-brain barrier (BBB) by the competitive and non-specific L-type amino

Potential therapeutics for ALS

Several therapeutic agents have been tested in clinical trials in patients with ALS. Among them, riluzole was the first, and remains the only drug approved by the FDA (USA) in 1995 for treatment of ALS. The approval was based on two large placebo controlled clinical studies where riluzole decreased the rate of muscle deterioration and modestly improved the survival rate of ALS patients (Bensimon et al., 1994, Cifra et al., 2013, Lacomblez et al., 1996). Although the specific mechanism of

Hypothetical model of QUIN and KP in ALS, and KP modulators as potential ALS treatments

Based on current literature and our data, we have formulated a hypothetical model (Fig. 3) for the involvement of QUIN in the neuropathogenesis of ALS. It incorporates the ALS mechanisms of excitotoxicity, oxidative stress, mitochondrial dysfunction, inflammatory cascade, apoptosis, and autophagic progress with contributions QUIN and the KP.

We propose that targeting the KP could offer a new therapeutic opportunity in ALS, and QUIN is a forerunner for KP modulation. Elevated concentrations of

Conflict of interest

None.

Acknowledgements

The authors would like to thank Ms Stephanie RAYNER for her assistance with Fig. 3. Ms Vanessa TAN is supported by an international scholarship from Macquarie University. Prof Gilles GUILLEMIN is supported by the National Health and Medical Research Council (NHMRC) and the Australian Research Council (ARC). Prof GUILLEMIN is a recipient of the Australian Research Council Future Fellowship Award (FT120100397). Dr Nady BRAIDY is the recipient of an Alzheimer's Australia Viertel Foundation

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