It has been known for some time that chronic neuroinflammation is a primary driver of disease in ALS and its “cousins” Alzheimers, Parkinsons, etc. Many attempts have been made to address it by using anti-inflammation drugs without success. Recently a study was published using a “prodrug” in animal models of Alzheimer’s and Huntington’s diseases. In this study, the drug 2-(3,4-dimethoxybenzenesulfonylamino)-4-(3-nitrophenyl)-5-(piperidin-1-yl)methylthiazole (JM6) inhibited the action of KMO, which is involved in the metabolism of tryptophan. This causes tryptophan to metabolize into kynurenic acid (KYNA), a neuroprotective substance, instead of quinolinic acid (QUIN), a neurotoxic substance. This degradation of tryptophan is called the kynurenine pathway (KP). It is one of the major regulatory pathways of the immune response and is known to be active in neuroinflammation. In HD, AD, and PD (Parkinson) there is decreased KYNA and increased QUIN. In multiple studies, changing the KYNA/QUIN balance in favor of KYNA is neuroprotective via a variety of methods.
Of interest to the ALS Community is that the same imbalances are seen in ALS. Strong evidence suggests that dysregulation of the KP leads to the type of neuronal damage from chronic neuroinflammation seen in many neurodegenerative diseases. In vitro testing with rodent motor neuron cells revealed a functional KP, that degeneration increased with duration and magnitude of exposure of QUIN, and that KYNA was protective against damage to neurons. It is known that QUIN is an NMDA receptor agonist (activator) and that KYNA is an antagonist (inhibitor). NMDA receptor-mediated excitotoxicity via calcium (Ca+) influx is a known cause of motor neuron death in ALS. This means that inhibition of KMO (aka kynurenine 3-hydroxylase) should be beneficial in ALS as well. Fortunately, K3H/KMO has been characterized for some time. In a study done in 2000, KMO (referred to as K3H) was found to be inhibited by Cl- (chloride). Luckily for PALS, there is already a chlorine drug in trial. This drug creates Taurine Chloramine (TauCl) which modulates the pro-inflammatory response seen in ALS, and also appears capable of rerouting KP to a beneficial product rather than harmful.
From the above it appears that previous attempts at modulating neuroinflammation failed because they were targeting symptoms rather than underlying cause (like treating a headache with aspirin when the cause is a tumor). By boosting the body’s endogenous TauCl production a clearly malfunctioning immune response can be guided to its secondary, nurturing, state. At the same time, multiple targets identified in ALS can be struck with a single weapon: Excitotoxic calcium influx from glutamate receptors (currently treated with little effect by Riluzole), mitochondrial distress (currently the target of other drugs in trial), and the neuroinflammation which is one of the main drivers of disease progression in ALS.
While all roads may lead to Rome, it appears that in neurodegenerative disease they may lead to KP moderation by chloramines.