The pan-salt-inducible kinase inhibitor YKL-06-061 exerts antidepressant-like effects via hippocampal CRTC1-CREB-BDNF pathway activation in chronic stress models.

BACKGROUND: Current monoaminergic antidepressants demonstrate limited efficacy and delayed onset, necessitating novel treatment strategies. We previously identified hippocampal salt-inducible kinase 2 (SIK2) as an important regulator of depression pathogenesis through modulation of the cAMP response element-binding protein (CREB)-regulated transcription coactivator 1 (CRTC1)-CREB-brain derived neurotrophic factor (BDNF) pathway. The current study investigated the antidepressant-like efficacy of YKL-06-061, a newly developed potent pan-SIK inhibitor, in male C57BL/6J mice.

METHODS: We established two well-validated depression models, chronic social defeat stress and chronic unpredictable mild stress, to examine the efficacy of daily intraperitoneal YKL-06-061 injection against behavioral despair as measured by forced swim and tail suspension tests, anhedonia as measured by sucrose preference, and social withdrawal as measured by the social interaction test. Western blotting, immunofluorescence, and co-immunoprecipitation were then conducted to evaluate the changes in hippocampal SIK2-CRTC1 signaling, BDNF-TrkB signaling, and adult neurogenesis among all groups. To further determine the antidepressant mechanism of YKL-06-061, model mice were re-examined following adeno-associated virus (AAV)-mediated overexpression of hippocampal SIK2 or knockdown of hippocampal CRTC1/CREB/BDNF.

RESULTS: YKL-06-061 administration suppressed depression-like behaviors in both models, normalized chronic stress-induced alteration in hippocampal SIK2-CRTC1 signaling, and rescued chronic stress-induced impairments in hippocampal BDNF signaling and adult neurogenesis. Both genetic overexpression of hippocampal SIK2 and knockdown of hippocampal CRTC1/CREB/BDNF expression attenuated the antidepressant-like actions of YKL-06-061 in mice.

CONCLUSION: Our findings further establish hippocampal SIK2-CRTC1-CREB-BDNF signaling as an antidepressant target and support YKL-06-061 as a potential antidepressant candidate.