Fr-HMGB1 and ds-HMGB1 activate the kynurenine pathway via different mechanisms in association with depressive-like behavior

Our previous study reported that fully reduced high mobility group box 1 (fr-HMGB1) and disulfide HMGB1 (ds-HMGB1) induce depressive-like behavior; however, the underlying mechanisms remain unclear. In the present study, the induction of depression via the kynurenine pathway by different redox states of HMGB1 was investigated in vivo and in vitro. To evaluate the expression of enzymes of the kynurenine pathway, reverse transcription-quantitative PCR and western blot analyses were conducted. Additionally, cytokine levels were measured by ELISAs. Following intracerebroventricular injection of ds- and fr-HMGB1, behavioral tests were performed, revealing the presentation of depressive-like behavior, and essential proteins in the kynurenine pathway were demonstrated to be upregulated at the mRNA level, suggesting that ds- and fr-HMGB1 contributed to the development of this behavior via the kynurenine pathway. ds-HMGB1 directly activated the kynurenine pathway and cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the hippocampal tissue. Conversely, fr-HMGB1 upregulated the aforementioned factors only following treatment with H(2)O(2). These findings indicated that ds-HMGB1 induced depression in a manner associated with the kynurenine pathway, whereas oxidation of fr-HMGB1 evoked activation of the kynurenine pathway, resulting in depressive behavior.