Implications for the Kynurenine Pathway and Quinolinic Acid in Amyotrophic Lateral Sclerosis

Abstract

The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of several neurobiologically active molecules. Among them is the excitotoxin quinolinic acid (QUIN) that is known to be involved in the pathogenesis of several major inflammatory neurological diseases. In amyotrophic lateral sclerosis (ALS) degeneration of motor neurons is associated with a chronic and local inflammation (presence of activated microglia and astrocytes). There is emerging evidence that the KP is important in ALS. Recently, we demonstrated that QUIN is significantly increased in serum and CSF of ALS patients. Moreover, most of the factors associated with QUIN toxicity are found in ALS, implying that QUIN may play a substantial role in the neuropathogenesis of ALS. This review details the potential role the KP has in ALS and advances a testable hypothetical model.

Inhibitory effect of some tropical green leafy vegetables on key enzymes linked to Alzheimer’s disease and some pro-oxidant induced lipid peroxidation in rats’ brain

“…The mechanism through which QA induces lipid peroxidation has been linked to free radical generation resulting from overstimulation of NMDA receptors. Increases in QA concentration are known to be associated with several neurodegenerative diseases including Alzheimer's disease (Guillemin et al 2006). Free radical scavengers and antioxidant enzyme inducers can protect neuronal tissue against the oxidotoxicity of QA under in vitro and in vivo conditions (Cabrera et al 2000;Stone 1993;Santamaria et al 1999).…”

“…Quinolinic acid (2,3-pyridine-dicarboxylic acid, QA) is a neuroactive metabolite of the tryptophan-kinurenine pathway produced by macrophages and microglia in human and rat brain; it has been implicated in the pathogenesis of a variety of human neurological diseases (Guillemin and Brew 2002;Guillemin et al 2006;Guillemin et al 2004). There are two main mechanisms by which QA has been implicated in Alzheimer's disease.…”

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

“…Hence, local inflammation may create an environment in the tumor, which results in the attraction and activation of quinolinic acid-producing microglial cells, may enable trpmetabolizing tumor cells to defend themselves from oxidative stress. In this respect, the function of microglial cells may be similar to neurodegenerative diseases where quinolinic aciddegrading microglial cells seem to prevent neurotoxicity (55). In addition to suppressing antitumor immune responses and promoting cell survival and cell motility, trp metabolism may thus also constitute a novel metabolic mechanism to confer resistance of tumor cells to radiochemotherapy.…”

4-pyridone-3-carboxamide ribonucleoside triphosphate accumulating in erythrocytes in end stage renal failure originates from tryptophan metabolism

“…This inverse relationship suggested an alternative explanation for the route of formation of 4PYTP to that previously proposed [4]. Namely, that 4PYTP is not an NAD degradation product, but a tryptophan degradation product formed via the quinolinic acid synthetic route of NAD formation [15,16] (Scheme 1), the last step of which, is catalysed by the enzyme quinolinate phosphorybosyl transferase (QPRTase, enzyme No 7 in Scheme 1). The high 4PYTP concentrations (113 μM and 103 μM respectively) in two patients with severe renal disease due to accumulation of 2.8-dihydroxyadenine, or gross uric acid overproduction in genetic deficiencies of adenine and hypoxanthine phosphoribosyltransferase deficiency respectively, exclude involvement of either purine base salvage enzyme in 4PYTP formation (data not shown), supporting our suggested involvement of QPRTase.…”