Exploring the roles of tryptophan metabolism in MS beyond neuroinflammation and neurodegeneration: a paradigm shift to neuropsychiatric symptoms

The metabolism of tryptophan through the kynurenine pathway (KP) has been increasingly recognised in contributing to disease progression in the autoimmune and inflammatory disease multiple sclerosis (MS). In this review, the roles of inflammation and the KP are recontextualised to better understand the aetiology of the neuropsychiatric symptoms (depression, postpartum depression, suicidality, fatigue and cognitive dysfunction) in MS. These symptoms will be discussed in the context of cytokine induced sickness behaviours, KP activation and levels of neurotoxicity and neuroprotection in MS. In particular, there will be emphasis on how neuropsychiatric symptoms in MS occur against the shared background of inflammation and KP dysregulation. The discourse of this review aims to promote future research in elucidating KP mechanisms in MS that would inevitably lead to more targeted treatment options for neuropsychiatric symptoms and disease progression.