The Kynurenine Pathway and Inflammation in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease of unknown pathogenesis. The kynurenine pathway (KP), activated during neuroinflammation, is emerging as a possible contributory factor in ALS. The KP is the major route for tryptophan (TRP) catabolism. The intermediates generated can be either neurotoxic, such as quinolinic acid (QUIN), or neuroprotective, such as picolinic acid (PIC), an important endogenous chelator. The first and inducible enzyme of the pathway is indoleamine 2,3-dioxygenase (IDO). The present study aimed to characterize the expression of the KP in cerebrospinal fluid (CSF), serum and central nervous system (CNS) tissue of ALS patients. Using high performance liquid chromatography, we analysed the levels of TRP and kynurenine (KYN), and, with gas chromatography/mass spectrometry, the levels of PIC and QUIN, in the CSF and serum of ALS patients and control subjects. Immunohistochemistry was employed to determine the expression of QUIN, IDO and human leukocyte antigen-DR (HLA-DR) in sections of brain and spinal cord from ALS patients. There were significantly increased levels of CSF and serum TRP (P < 0.0001), KYN (P < 0.0001) and QUIN (P < 0.05) and decreased levels of serum PIC (P < 0.05) in ALS samples. There was a significant increase in activated microglia expressing HLA-DR (P < 0.0001) and increased neuronal and microglial expression of IDO and QUIN in ALS motor cortex and spinal cord. We show the presence of neuroinflammation in ALS and provide the first strong evidence for the involvement of the KP in ALS. These data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which may be amenable to inhibitors of the KP.

Cerebrospinal fluid kynurenines in multiple sclerosis; relation to disease course and neurocognitive symptoms

“…The increased concentration of KYNA is traditionally considered as a neuroprotective response subsequent to an increase in neurotoxic QUIN, and has been shown to convey neuroprotective effects, both experimentally (Andine et al, 1988), and clinically (Atlas et al, 2013). Notably, PPMS therefore displays similarities with ALS, where CSF levels of TRP, KYN and QUIN levels have been reported to be increased (Chen et al, 2010), but also to certain patients of the iOND group, especially SLE, as reported here. This finding may be of therapeutic relevance with regard to laquinimod, an oral disease modulatory treatment in clinical development for MS, since it is a quinoline carboxamid with structural homology to kynurenine metabolites (Chen et al, 2009).…”

“…Conversely, lowered levels of CSF KYNA have been observed in AD and HD (Heyes et al, 1992;Vecsei et al, 2013), which could promote the neurodegenerative processes of these conditions. Moreover, increased expression of indoleamine 2, 3-dioxygenase (IDO) and QUIN has been observed in microglia of ALS patients (Chen et al, 2010). Notably, IDO, which is a rate-limiting enzyme that catalyzes the first step in the pathway, is activated by pro-inflammatory cytokines (Campbell et al, 2014;Mandi and Vecsei, 2012).…”

The Kynurenine Pathway in Brain Tumor Pathogenesis

“…2). This variation in kynurenine pathway activation in neuroblastoma cells may provide a key to understanding tumor persistence and associated neurotoxicity; a weakening in neuroprotection may exacerbate the adverse effects of neurotoxicity (76). The study conducted by Guillemin and colleagues (32) remains the only study to date comprehensively characterizing the KP in tumor cells and exploring the importance of the imbalance between QUIN and PIC production for tumor persistence.…”

An expanding range of targets for kynurenine metabolites of tryptophan

“…The potential value of the kynurenine pathway for the development of new drugs acting in disorders such as these, in which a degree of neuronal damage is involved, has been discussed previously [90] In addition, the identification of a range of molecular targets such as GPR35, Finally, the parallel work that has developed since the early 1980s of the actions of kynurenines in the CNS and their effects in the immune system seem to be moving closer towards an integrated view of their interaction. That may in turn result in the development of compounds that can regulate changes in the processes of CNS neurotransmission directly, but which can also modify the development and progression of inflammatory reactions that increasingly seem to underlie chronic CNS disorders such as AD and HD, but may also be relevant to conditions such as multiple sclerosis (MS) [91] and infection-induced dementias [92]. This is certainly a pathway that is likely to become more intriguing in the future.…”