Title:The Many Neuroprogressive Actions of Tryptophan Catabolites (TRYCATs) that may be Associated with the Pathophysiology of Neuro-Immune Disorders
Volume: 22
Issue: 8
Author(s): Gerwyn Morris, André F. Carvalho, George Anderson, Piotr Galecki and Michael Maes
Affiliation:
Keywords:
Schizophrenia, chronic fatigue, inflammation, immune, oxidative and nitrosative stress, leaky gut.
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, -
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.
