Post-
stroke depression (PSD) is a common and serious complication that is affecting one thirds of
stroke patients which leaves them with a poor quality of life, high mortality rate, high recurrent rate, and slow recovery. Recent studies showed that serum
interleukin-18 (IL-18) level is a
biomarker for patients with PSD. However, the role of
IL-18 in the pathology of PSD is still unclear. In this study, we demonstrated that the
IL-18 level in the ischemic brain significantly increased in mice with depression-like behaviors that were caused by the combined use of chronic spatial restraint stress and
middle cerebral artery occlusion. Interestingly,
IL-18 expression was mainly found in neurons at early phase and in microglia at a later phase. Injection of the exogenous
IL-18 into the amygdala, but not the hippocampus or the striatum caused severe depression-like behaviors. On the contrary, the blockage of endogenous
IL-18 by
IL-18 binding protein, a specific antagonist of
IL-18, repressed depressive phenotypes in SIR mice.
IL-18 KO mice exhibited the resistance to spatial restraint stress and
cerebral ischemia injury. Finally, we found that
IL-18 mediated depressive behaviors by the interaction of
IL-18 receptor and NKCC1, a
sodium-
potassium chloride co-transporter that is related to GABAergic inhibition. Administration of NKCC1 antagonist
bumetanide exerted a
therapeutic effect on the in IL-18-induced depressive mice. In conclusion, we demonstrated that increased
IL-18 in the brain causes depression-like behaviors by promoting the
IL-18 receptor/NKCC1 signaling pathway. Targeting
IL-18 and its downstream pathway is a promising strategy for the prevention and treatment of PSD.