The role of the kynurenine pathway in the pathogenesis of pain and affective disorders after traumatic brain injury

Traumatic brain injury (TBI) alters neuroimmune physiology resulting in an imbalance between pro- and anti-inflammatory cascades. Whereas acute inflammation serves as an adaptive defense mechanism of the innate immune system to promote healing and restore homeostasis after injury, unresolved pro-inflammatory cascades have been shown to contribute to long-term sequelae of TBI. An important, yet understudied, neuroimmune signaling pathway affected by TBI is the kynurenine pathway (KP). Kynurenine is a product of tryptophan metabolism by indoleamine 2,3 dioxygenase in the central nervous system, a metabolite downstream of kynurenine, e.g., quinolinic acid and kynurenic acid, as products of kynurenine 3 monooxygenase and kynurenine aminotransferase, respectively. TBI patients exhibit disrupted levels of KP metabolites, including kynurenine and quinolinic acid, in plasma, cerebrospinal fluid, and brain. Alterations in KP metabolite levels have been reported in both Major Depressive Disorder and pain-related conditions, including headaches, fibromyalgia, and neuropathic pain, thereby suggesting a role of the KP in progression of prevalent pathological TBI sequalae, that include depression and chronic pain. This narrative review outlines the KP, evaluates its alterations following TBI in relation to sequelae such as chronic pain and depression, and discusses potential KP directed therapeutic targets within the TBI framework.