Health Rising’s neuroinflammation emphasis continues. The next couple of years may indicate that neuroinflammation and microglial activation play key roles in fibromyalgia and chronic fatigue syndrome. If that turns out to be true, the attention will probably quickly shift to something called the kynurenine pathway.
Kynurenines in CNS disease: regulation by inflammatory cytokines. Brian M. Campbell, Erik Charych, Anna W. Lee and Thomas Möller. Frontiers in Neuroscience. February 2014| Volume 8| Article12 |
The story starts with the metabolism of a single substance – tryptophan (TRP). Tryptophan is an essential amino acid that forms the basis for some central nervous system heavyweights. Serotonin and melatonin are both derived from it and other tryptophan metabolites have significant functions.
Tryptophan is usually metabolized into serotonin and other factors but in the presence of inflammation, whether in the body or the brain, things change. It turns out that immune activation, in particular interferon-y, a key player in the antiviral response causes an enzyme called indole-2,3-dioxygenase (IDO) to transform tryptophan into kynurenine.
That has the unhappy result of depleting the brain of serotonin but that’s just the beginning of the problem.
The Road Not Taken
Kynurenine metabolism is complex but for our purposes the key fact is that at one point kynurenine metabolism splits into the two pathways – a neurotoxic (bad) pathway powered by an enzyme called KMO, and a neuroprotective (good) pathway powered by the KATS enzyme. Inflammation triggered tryptophan metabolism always sends kynurenine metabolism whizzing down the neurotoxic pathway. A recent review of the kynurenine’s pathway effects in HIV/AIDS called it “An Immune Checkpoint at the Crossroads of Metabolism and Inflammation“. (HIV proteins activate the kynurenine pathway)
Activation of this pathway prods the microglia to produce substances like QUIN, an excitatory agent that sends the NMDA-type glutamate receptors into a glutamate producing frenzy. QUIN also teams up with a substance called 3-HK to produce oxidative stress.
The list of central nervous system disorders associated with increased kynurenines is a long one, and includes neurodegenerative disorders like Parkinson’s disease and Alzheimer’s, autoimmune disorders (multiple sclerosis), psychiatric disorders (major depression, ADHD, schizophrenia) and infectious diseases (HIV-associated cognitive disorder). The kynurenine triggered excitatory outburst may get so intense that it actually starts destroying neurons in Parkinson’s and ALS. It may also contribute to the reduced dopamine levels (and reduced reward) present in ME/CFS and fibromyalgia.
Insights into how the kynurenine pathway may figure in chronic fatigue syndrome and fibromyalgia may be seen in interferon-alpha (IFN-a) trials in hepatitis and cancer. Hepatitis C patients getting this intense immune booster experience similar symptoms (fatigue, depression, pain) and central nervous findings as ME/CFS patients.
Studies suggest increased kynurenine levels in hepatitis and breast cancer patients are associated with increased anxiety.
Another link with possible implications for ME/CFS and FM concerns Epstein-barr virus (EBV). Chronic active EBV infection is present when antibody test results indicate an active infection is present. Most people with ME/CFS do not have that kind of EBV infection, but it’s intriguing that chronic EBV activation – which occurs in many cases of mononucleosis – triggers IDO to degrade tryptophan to kynurenine. Given kynurenine’s ability to sensitize the microglia kynurenine pathway upregulation, could be the straw that breaks the camel’s back for many.
Chronic Fatigue Syndrome and Fibromyalgia
Several studies suggest tryptophan levels may be lowered in fibromyalgia and/or ME/CFS. One study suggested an aberrant tryptophan – kynurenine pathway was operating in FM patients. Blankfield asserts the reduced tryptophan levels could reflect malabsorption in the gastrointestinal tract or a chronic infection (or presumably chronic inflammation). The fact that tryptophan degrading bacteria may help produce leaky gut syndrome as well suggests an inflammatory loop beginning at the gut and ending at kynurenine production in the central nervous system could occur. On top of all this kynurenines have profound T-cell depleting properties.
The KP is an important target for the development of new therapies against neurodegenerative disorders, as it is comprised of compounds influencing processes related to excitotoxicity, oxidative damage and inflammation. Bohar et.al 2015
If inflammation either inside or outside the central nervous is triggering the neurotoxic arm of the kynurenine pathway, what can be done about it? Not a lot right now, but the discovery that the kynurenine pathway upregulation is present in virtually every central nervous system disorder is spurring research.
Numerous targets on kynurenine activating enzymes have been identified that could be used to knock the neurotoxic portion of the pathway down. Several compounds have been developed, one of which may be able to stop the production of the neurotoxic metabolite QUIN in its tracks. Other compounds have been developed to turn the neuroprotective side of the kynurenine pathway on.
Miller reports that recent advances provide “great promise” for the development of IDO inhibitors that stop tryptophan from being degraded to kynurenine in the first place. An IDO inhibitor called 1-methyltryptophan (1-MT) is being tested in mice and in human trials of advanced cancer. IDO is a tricky substance: while it’s upregulating tryptophan metabolism it’s also helping to tamp down autoimmune responses and it’s knocking down natural killer cells. IDO inhibitors may not be useful in those with autoimmune disorders.
They may be useful in depression, however. A recent review suggests further research into the intersection between tryptophan degradation, inflammation and depression will likely “provide many targets for novel antidepressant therapies.”
The key factor with the kynurenine pathway is that it’s a growth field. Any disorder from HIV/AIDS, to cancer, to depression, to cardiovascular disease, that is associated with inflammation, has a stake in learning more about the kynurenine pathway. If the trends hold, the number of PubMed studies published on the pathway will almost double from last year. We should learn much more about this intriguing central nervous system pathway in the coming years.