The Many Neuroprogressive Actions of Tryptophan Catabolites (TRYCATs) that may be Associated with the Pathophysiology of Neuro-Immune Disorders

Abstract

Many, if not all, chronic medical, neurodegenerative and neuroprogressive illnesses are characterised by chronic immune activation, oxidative and nitrosative stress (O&NS) and systemic inflammation. These factors, notably elevated pro-inflammatory cytokines, activate indoleamine 2,3-dioxygenase (IDO) leading to an upregulated tryptophan catabolite (TRYCAT) pathway of tryptophan degradation in the periphery and in the brain. In such conditions the TRYCAT pathway becomes the predominant system for tryptophan degradation in all body compartments. In this paper we review the pathways whereby TRYCATs may play a role in neuro-inflammatory and neuroprogressive disease. Thus chronic activation of the TRYCAT pathway leads to the production of a range of neuroactive, neuroprotective and neurotoxic TRYCATs. Some TRYCATs such as quinolinic acid act as potent neurotoxins which inhibit ATP production by mitochondria, provoke increases in O&NS, disrupt neuron glial communication and blood brain barrier integrity, induce apoptosis of glial cells, directly damage neurons and function as a N-methyl D-aspartate (NMDA) receptor agonist. Other TRYCATs such as kynurenic acid function as antagonists of NMDA, α- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors and act to regulate levels of glutamate and dopamine. The neuroprotective functions of this TRYCAT are likely exercised via engagement with alpha7 nicotinic acetylcholine and aryl hydrocarbon receptors but the neuroprotective effects stemming from elevated kynurenic acid levels come at the price of severely compromised neurocognitive function and emotional processing. Other TRYCATS also possess neurotoxic or neuroprotective properties via pro-oxidant and antioxidant effects. Here we discuss the involvement of the abovementioned TRYCAT pathways in schizophrenia, Alzheimer's disease and chronic fatigue syndrome.

Metabolomic Differentials in Women With and Without Fibromyalgia

“…Similarly, elevated levels of methionine sulfoxide and anthranilate have been reported . Methionine sulfoxide is a primary oxidation product of methionine (Met) via its nucleophilic oxidation and is sometimes considered a biomarker of oxidative stress, whereas anthranilate is a tryptophan metabolite that has been implicated in brain/immune communication . In addition to higher levels of the metabolites described above, we found lower levels of alpha‐ketoglutaric acid and metabolites associated with cellular metabolism in individuals with FM.…”

“…8,30 Methionine sulfoxide is a primary oxidation product of methionine (Met) via its nucleophilic oxidation and is sometimes considered a biomarker of oxidative stress, 33 whereas anthranilate is a tryptophan metabolite that has been implicated in brain/immune communication. 34 In addition to higher levels of the metabolites described above, we found lower levels of alpha-ketoglutaric acid and metabolites associated with cellular metabolism in individuals with FM. Alpha-ketoglutarate is a crucial intermediate of the Krebs cycle and plays a critical role in multiple metabolic processes and acts as an antioxidant agent.…”

Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?

“…Elevated CNS PIC levels, and subsequent activation of the p38 mitogen-activated protein kinase (MAPK) signalling system, can also adversely affect the synthesis, reuptake and release of serotonin (Miller et al 2013). Elevated PICs in the CNS also provoke the activation of the tryptophan catabolite pathway, depleting levels of tryptophan, which is the precursor of 5-HT, as well as creating another dimension of neuropathology via the synthesis of several neurotoxic tryptophan catabolites including the potentially neurotoxic quinolinic acid (Miller et al 2013) (reviewed (Morris et al 2016e)).…”

Putative neuroprotective pharmacotherapies to target the staged progression of mental illness

“…Tryptophan is the essential pre-cursor for serotonin. Intermediates in the tryptophan pathway known as tryptophan catabolites (TRYCATs) are either pro-inflammatory and neurotoxic or anti-inflammatory and neuroprotective (Morris, Carvalho, Anderson, Galecki, & Maes, 2016). Proinflammatory and neurotoxic TRYCATs include quinolinic acid (QA) and 3OH-kynurenine which are over-produced in an inflammatory milieu such as is seen in depression and schizophrenia, correlating with worsening of negative symptoms including cognition (Kanchanatawan et al, 2018).…”