Abstract
The kynurenine pathway (KP) is the major metabolic pathway of the essential amino acid tryptophan (TRP). Stimulation by inflammatory molecules, such as interferon-γ (IFN-γ), is the trigger for induction of the KP, driving a complex cascade of production of both neuroprotective and neurotoxic metabolites, and in turn, regulation of the immune response and responses of brain cells to the KP metabolites. Consequently, substantial evidence has accumulated over the past couple of decades that dysregulation of the KP and the production of neurotoxic metabolites are associated with many neuroinflammatory and neurodegenerative diseases, including Parkinson’s disease, AIDS-related dementia, motor neurone disease, schizophrenia, Huntington’s disease, and brain cancers. In the past decade, evidence of the link between the KP and multiple sclerosis (MS) has rapidly grown and has implicated the KP in MS pathogenesis. KP enzymes, indoleamine 2,3-dioxygenase (IDO-1) and tryptophan dioxygenase (highest expression in hepatic cells), are the principal enzymes triggering activation of the KP to produce kynurenine from TRP. This is in preference to other routes such as serotonin and melatonin production. In neurological disease, degradation of the blood–brain barrier, even if transient, allows the entry of blood monocytes into the brain parenchyma. Similar to microglia and macrophages, these cells are highly responsive to IFN-γ, which upregulates the expression of enzymes, including IDO-1, producing neurotoxic KP metabolites such as quinolinic acid. These metabolites circulate systemically or are released locally in the brain and can contribute to the excitotoxic death of oligodendrocytes and neurons in neurological disease principally by virtue of their agonist activity at N-methyl-d-aspartic acid receptors. The latest evidence is presented and discussed. The enzymes that control the checkpoints in the KP represent an attractive therapeutic target, and consequently several KP inhibitors are currently in clinical trials for other neurological diseases, and hence may make suitable candidates for MS patients. Underpinning these drug discovery endeavors, in recent years, several advances have been made in how KP metabolites are assayed in various biological fluids, and tremendous advancements have been made in how specimens are imaged to determine disease progression and involvement of various cell types and molecules in MS.
Highlights
OF kynurenine pathway (KP) IN multiple sclerosis (MS)Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disorder of the central nervous system (CNS) whose etiology remains multifactorial and the subject of intense debate
We focus on the cells that produce these damaging metabolites (Figure 1); circulating monocytes which enter the brain via a compromised blood–brain barrier (BBB) and to a lesser extent endogenous brain cells; how these metabolites are measured by analytical sampling and the mechanisms of action of these metabolites and how they cause oligodendrocyte death
The importance of this study and of the evidence linking activated mononuclear phagocytes to multiple sclerosis (MS) is highlighted by different lines of evidence about the kynurenine pathway (KP) in these cells: first, the activated monocyte-derived macrophages (MDMs) produce 19 times more quinolinic acid (QUIN) than activated microglia [23]; second, the central nervous system (CNS)-resident cells do not possess the full enzymatic machinery of the KP and are unable to synthesize high quantities of QUIN, but can still produce KYN [14, 22, 62]; third, extra KYN released by astrocytes in the brain can be used by monocytes and MDMs that traffic into the brain to synthesize more QUIN [22]; fourth, the level of QUIN produced by monocytes and MDMs is toxic to neurons and to oligodendrocytes [20, 132]
Summary
Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disorder of the central nervous system (CNS) whose etiology remains multifactorial and the subject of intense debate. Dysregulation of the KP may not be the primary cause of MS; rather the evidence far suggests its involvement is characterized by inflammatory episodes triggering KP activation ( in monocytes), trafficking to the brain, concomitant TRP degradation and production of neurotoxic metabolites. These aspects can contribute to the pathogenesis and the disease course of MS by promoting brain cell dysfunction and death, which in turn prevent the induction of essential brain cell survival and repair mechanisms. Concurrent with this discussion, we consider how advances in microscope imaging and allied techniques (see Microscope Imaging as a Central Tool for Advancing Knowledge of MS Pathology) have made a profound and ongoing contribution to our understanding of MS pathology
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