Exploration of the Core Pathways and Potential Targets of Luteolin Treatment on Late-Onset Depression Based on Cerebrospinal Fluid Proteomics

Abstract

Cognitive deficiency is one of the fundamental characteristics of late-onset depression (LOD). Luteolin (LUT) possesses antidepressant, anti-aging, and neuroprotective properties, which can dramatically enhance cognition. The altered composition of cerebrospinal fluid (CSF), which is involved in neuronal plasticity and neurogenesis, directly reflects the physio-pathological status of the central nervous system. It is not well known whether the effect of LUT on LOD is in association with a changed CSF composition. Therefore, this study first established a rat model of LOD and then tested the therapeutic effects of LUT using several behavioral approaches. A gene set enrichment analysis (GSEA) was used to evaluate the CSF proteomics data for KEGG pathway enrichment and Gene Ontology annotation. We combined network pharmacology and differentially expressed proteins to screen for key GSEA–KEGG pathways as well as potential targets for LUT therapy for LOD. Molecular docking was adopted to verify the affinity and binding activity of LUT to these potential targets. The outcomes demonstrated that LUT improved the cognitive and depression-like behaviors in LOD rats. LUT may exert therapeutic effects on LOD through the axon guidance pathway. Five axon guidance molecules—EFNA5, EPHB4, EPHA4, SEMA7A, and NTNG—as well as UNC5B, L1CAM, and DCC, may be candidates for the LUT treatment of LOD.

tiRNA‐Gly‐GCC‐001 in major depressive disorder: Promising diagnostic and therapeutic biomarker

“…MDD‐related reductions in vascular endothelial growth factor (VEGF) and BDNF levels have been observed within the CA1/DG areas of the brain (Duric et al, 2010), and both are essential for hippocampal LTP (Costa et al, 2022; Licht et al, 2011). In addition, neural circuit formation relies heavily on axonal guidance, and genes related to this pathway are closely associated with the pathogenesis of depression (Liu et al, 2023). Furthermore, signalling via the oxytocin pathway has also been demonstrated to affect depressive symptoms and suicidality related to MDD (Mori et al, 2022; Warrener et al, 2021), and oxytocin has advanced as a novel therapeutic option for depression (Matsuzaki et al, 2012).…”

Luteolin alleviates depression‐like behavior by modulating glycerophospholipid metabolism in the hippocampus and prefrontal cortex of LOD rats

“…The LOD and LUT groups were subjected to chronic unpredictable mild stress, and the CUMS protocol was based on our previous study 5,18 . Rats were individually housed in Room B during the stress protocol.…”

“…The LOD and LUT groups were subjected to chronic unpredictable mild stress, and the CUMS protocol was based on our previous study. 5 , 18 Rats were individually housed in Room B during the stress protocol. The stress protocol included fasting (12 h), water deprivation (12 h), continuous illumination at night (20:00–8:00 of the next day, 12 h), plantar shock (1 mA, 2 s/time, 10 times/5 min), white noise (85 dB, 5 h), night strobe illumination (300 times/min, 5 h), hot water swimming (45°C, 5 min), restraint (12 h), wet cage (10 h), and fasting and water deprivation (24 h).…”

“…[15][16][17] Our previous studies have suggested that LUT can enhance the brain's transport of folic acid to promote hippocampal neurogenesis and alter the axonal guidance pathway in cerebrospinal fluid to exert its therapeutic effect on LOD. 5,18 Metabolomics technology is considered a valuable tool in the study of central nervous system diseases. Previous metabolomic studies on depression using plasma, 17 brain tissue, 19 and urine 20 have been reported, revealing various metabolic pathways, such as amino acids, 21 lipids, 22 and energy metabolism 23 that are associated with the onset of depression.…”

“… 15 , 16 , 17 Our previous studies have suggested that LUT can enhance the brain's transport of folic acid to promote hippocampal neurogenesis and alter the axonal guidance pathway in cerebrospinal fluid to exert its therapeutic effect on LOD. 5 , 18 …”