It is becoming appreciated that the kynurenine pathway (KP) plays a role in the pathophysiology and/or progression of numerous neurological diseases. In June 2022 we highlighted a study that demonstrated that KP metabolites may serve as biomarkers of disease progression in Alzheimer’s patients (M. Cespedes et al., 2022). As such, observed KP alterations in Alzheimer’s disease (AD) may serve as a potential therapeutic target.
Dr. Dan Cheng and colleagues published a study on how minocycline affected neuroinflammation and the KP in Brain Behavior and Immunity. The chronic unpredictable mild stress (CUMS) model was used in this study to induce a cognitive decline in mice. This model also leads to anxiety and depression, which are commonly observed in AD patients (R. Botto et al., 2022). Minocycline treatment decreased depression- and anxiety-like behavior as well as improved cognitive ability in CUMS mice. Inflammatory cytokines were significantly elevated in the hippocampus following CUMS and when treated with the high dose of minocycline this increase was significantly reduced. It is well known that inflammatory cytokines can impact KP activation through their interaction with KP enzymes such as indoleamine-2,3-dioxygenase (IDO). Therefore, the authors investigated the KP enzyme expression in the plasma and prefrontal cortex. Indeed, there were reductions observed following minocycline treatment demonstrating an overall reduction in the activation of the KP. Kynurenine, 3-HK, and quinolinic acid levels were significantly decreased in the serum and the prefrontal cortex following treatment. Interestingly, minocycline therapy also induced interleukin 10 (IL-10) and kynurenic acid (KYNA), an anti-inflammatory cytokine and neuroprotective metabolite, while reducing both pro-inflammatory cytokines and neurotoxic KP metabolites. These data demonstrate that minocycline impacts the KP and observed improvements in cognition, depression, and anxiety may be driven by alterations in the KP. Further research is required to understand the impact minocycline would have on psychiatric and neurodegenerative diseases.