Background: There currently exist no treatments that can regenerate damaged neurons and therefore reverse neurological disability in MS. The kynurenine pathway (KP) is a major pathway that catabolises the essential amino acid tryptophan1 . Tryptophan metabolism is aberrant in a number of inflammatory conditions, including MS2 . The KP yields several neuroactive downstream metabolites, such as quinolinic acid (QUIN).
Aim: To explore the potential of modulating the KP to optimise stem cell function therefore promoting remyelination of neurons.
Methods: Murine NSC were treated with 100 IU/ml IFN-β alone or in combination with 50 nM QUIN. Levels of tryptophan, kynurenine and QUIN were measured in mice with EAE. Tryptophan and kynurenine were quantified using HPLC. Concentrations of QUIN were assessed using GCMS.
Results: Treatment of NSC with IFN-β significantly attenuated their proliferation. The addition of QUIN, at a basal concentration of 50 nM, recovered NSC proliferation in vitro. We found that mice with EAE had an activated KP, as reflected by an increased K/T ratio of 27.14 + 6.67 in diseased mice compared to 16.6 + 2.12 in control animals. We also observed that in vivo levels of QUIN increased almost two-fold with EAE progression from 129.64 nM + 18.93 to 227.82 nM + 54.06 (n=8).
Conclusions: We have shown that NSC are strongly influenced by KP metabolites. Also, in mice with EAE the KP is significantly activated. Chronic activation of the KP generates neurotoxic levels of QUIN and reduces available tryptophan. This is likely to affect NSC proliferation, differentiation and remyelination3 . Results here provide a vital platform for investigating how manipulation of the KP in stem cells could be crucial for the repair of neurons in MS.