RESUMO
ObjectiveTo observe the effect of Liuwei Dihuangtang （LWDHT） on depression-like behaviors of rats with diabetes mellitus and depression （DD） and explore its mechanism. MethodThe diabetes mellitus （DM） model was induced by the high-fat diet and tail vein injection of low-dose streptozotocin （STZ） in 50 male Sprague-Dawley rats of SPF grade. Then the DD model was induced by chronic unpredictable mild stress （CUMS） for 28 days in DM rats. Fifty DD rats were randomly divided into model group， fluoxetine group （10 mg·kg-1·d-1）， and low-， medium-， and high-dose LWDHT groups （3.375， 6.75， 13.5 g·kg-1·d-1）， with 10 rats in each group. Another 10 healthy rats were assigned into a control group and received normal saline by gavage. After four weeks of drug intervention， the forced swimming assay was carried out to assess the depression-like behaviors of rats. The expression levels of tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， interleukin-4 （IL-4）， and interleukin-10 （IL-10） in the anterior cingulate cortex （ACC） were detected by enzyme-linked immunosorbent assay （ELISA）. Immunofluorescence was used to detect the expression of myelin basic protein （MBP） in ACC and the co-localization of ionized calcium-binding adapter molecule 1 （Iba1） with intracellular microtubule-associated protein 1 light chain 3 （LC3）. The protein expression levels of MBP， myelin proteolipid protein （PLP）， myelin oligodendrocyte glycoprotein （MOG）， Beclin-1， LC3， p62， and microglia （MG） phenotypic protein-related inducible nitric oxide synthase （iNOS）， and arginase 1 （Arg1） were detected by Western blot. ResultCompared with the control group， the model group showed shortened swimming time and prolonged immobility time （P<0.01）. Compared with the model group， the medium- and high-dose LWDHT groups showed reduced immobility time （P<0.05， P<0.01）. Compared with the control group， the model group showed decreased protein expression of MBP， PLP， and MOG in the ACC region （P<0.01）. Compared with the model group， the fluoxetine group and the medium- and high-dose LWDHT groups showed up-regulated protein expression of MBP， PLP， and MOG （P<0.05， P<0.01）. Compared with the control group， the model group showed decreased MBP fluorescence intensity in the ACC region （P<0.01）. Compared with the model group， the fluoxetine group and the medium- and high-dose LWDHT groups showed increased MBP fluorescence intensity in the ACC region （P<0.05， P<0.01）. Compared with the control group， the model group showed increased expression of iNOS （P<0.01） and slightly increased Arg1 protein expression. Compared with the model group， the medium- and high-dose LWDHT groups and the fluoxetine group showed down-regulated iNOS expression and up-regulated Arg1 protein expression （P<0.05， P<0.01）， but there was no significant difference between the fluoxetine group and the medium-，high-dose LWDHT groups. Compared with the control group， the model group showed increased expression levels of proinflammatory factors IL-1β and TNF-α in the ACC region （P<0.01） and slightly increased expression levels of anti-inflammatory factors IL-4 and IL-10. Compared with the model group， the fluoxetine group， and the medium- and high-dose LWDHT groups showed down-regulated expression of IL-1β and TNF-α （P<0.05， P<0.01） and up-regulated expression of IL-4 and IL-10 （P<0.05， P<0.01）. Compared with the control group， the model group showed reduced expression levels of Beclin-1 and LC3Ⅱ （P<0.01） and increased expression level of p62 （P<0.01）. Compared with the model group， the fluoxetine group and the medium- and high-dose LWDHT groups showed up-regulated Beclin-1 and LC3Ⅱ expression （P<0.01） and down-regulated p62 expression （P<0.01）. Compared with the control group， the model group showed decreased LC3+Iba1+ cells in the ACC region （P<0.01）. Compared with the model group， the fluoxetine group and the medium- and high-dose LWDHT groups showed increased LC3+Iba1+ cells （P<0.05， P<0.01）. ConclusionLWDHT can alleviate the depression-like behaviors in DD rats presumedly by promoting MG autophagy， regulating MG phenotypic changes， and increasing MG clearance of myelin sheath fragments. Meanwhile， MG phenotypic transformation also inhibits ACC inflammation in DD rats， improves the local microenvironment of oligodendrocyte proliferation and differentiation， and ultimately promotes the repair and remyelination of damaged myelin sheath.
RESUMO
Silibinin, a natural flavonoid antioxidant isolated from extracts of the milk thistle herb, has recently been identified as having anti-hepatotoxic and anticancer properties. In this paper, we investigated the effects of silibinin on behavior and neuroplasticity in mice subjected to chronic unpredictable mild stress (CUMS). After 5 consecutive weeks of CUMS, the mice were treated with silibinin (100 mg/kg, 200 mg/kg and 400 mg/kg by oral gavage) for 3 consecutive weeks. The results showed that silibinin administration significantly alleviated the CUMS-induced depressive-like behavior, including the total number of squares crossed and the frequency of rearing in the open field test, the immobility time in the tail suspension test and the forced swimming test. Furthermore, silibinin treatment increased the levels of brain-derived neurotrophic factor (BDNF), serotonin (5-HT) and norepinephrine (NE) in the prefrontal cortex and hippocampus. Our study provides new insight into the protective effects of silibinin on the depressive status of CUMS mice, specifically by improving neuroplasticity and neurotransmission.