Lumbrokinase ameliorates chronic social defeat stress-induced behavioral impairments through modulation of miR-340-5p and SUMO2 signaling.

Chronic social defeat stress (CSDS) is a rodent model used to study mood-related disorders by mimicking social trauma and psychosocial stressors relevant to human society. We recently developed an intranasal lumbrokinase delivery that effectively reaches deeper brain structures, including the hippocampus, and mitigates CSDS-induced cognitive deficits. Here, we further investigated whether intranasal lumbrokinase attenuates CSDS-induced behavioral abnormalities and explored molecular mechanisms underlying synaptic protein modifications in male C57BL/6 mice. Lumbrokinase significantly improved anxiety-like behavior without altering locomotor activity and attenuated chronic stress-associated changes by reducing hippocampal MAO-A and plasma corticosterone levels while restoring hippocampal GR and BDNF expression after 14 days of treatment. In addition, CSDS reduced the expression of multiple synaptic plasticity-related proteins, including synapsin1, NR2B, and PSD95; these deficits were robustly reversed by lumbrokinase. Importantly, CSDS decreased SUMO1 and SUMO2 levels in the hippocampus, whereas lumbrokinase selectively restored SUMO2 expression and enhanced SUMO2-associated SUMOylation activity. Furthermore, SUMO2 knockdown in HT22 hippocampal neurons abolished the protective effects of lumbrokinase on corticosterone-induced reductions in BDNF and synaptic protein expression. Bioinformatic analyses identified miR-340-5p as a candidate regulator of SUMO2, and lumbrokinase normalized the CSDS-induced upregulation of miR-340-5p. Notably, hippocampal delivery of a miR-340-5p agomir negated the behavioral and molecular benefits of lumbrokinase. Collectively, these findings demonstrate that intranasal lumbrokinase effectively alleviates CSDS-induced behavioral impairments and suggest that modulation of the predicted miR-340-5p/SUMO2 signaling pathway contributes to its neuroprotective effects, supporting intranasal lumbrokinase as a promising non-invasive therapeutic strategy for chronic stress-induced behavioral abnormalities.