Synergistic Efficacy of Lactobacillus plantarum Supernatant-Preconditioned BM-MSCs in Alleviating Depression, Anxiety-Like Behavior, and Memory Impairment in a Rat Stress Model by Suppressing the NF-κB Pathway.

Mesenchymal stem cells (MSCs)-based therapy has received considerable research attention for its anti-inflammatory properties in depressive-like behavior, but poor MSC survival and immunogenicity after transplantation limit their therapeutic effectiveness. This study evaluated pretreated bone marrow-derived MSCs (BM-MSCs) with Lactobacillus plantarum supernatant (L.PS) in an animal model of chronic restraint stress (CRS)-induced depressive-like behavior. BM-MSCs were pretreated with 15 μM of fluoxetine (Flx) or 10 µl/ml of L.PS for 24 h. Thirty-six adult male Wistar rats were divided into six groups: CTRL, CRS, CRS + PBS (Phosphate-Buffered Saline), CRS + MSCs, CRS + MSCs(Flx) (Flx-preconditioned MSCs), and CRS + MSCs(L.PS) groups. The open field test, Morris water maze, forced swimming test, body weight, and blood glucose levels were measured. After sacrifice, the hippocampal tissues underwent histopathological analysis. Additionally, hippocampal mRNA levels of NF-κB and pro-inflammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) were measured using real-time PCR, while ELISA was used to measure protein levels of these cytokines and serum corticosterone. A bioinformatic analysis, including protein-protein interaction network, enrichment, and correlation analysis related to depression, was performed. Pre-treatment of MSCs with L.PS significantly improved depressive-like behavior (p < 0.05) by enhancing MSCs neuroprotection through the downregulation of NF-κB and pro-inflammatory cytokines. An in silico analysis also supported the importance of evaluating and targeting this pathway. In conclusion, we found that L.PS pretreated MSCs significantly improves CRS-induced depressive-like behavior, which can be partly attributed to the inhibition of NLRP3-mediated neuroinflammation.