Background: The comorbidity between diabetes mellitus and depression was revealed, and diabetes mellitus increased the prevalence of depressive disorder, which ranked 13th in the leading causes of disability‐adjusted life‐years. Insulin resistance, which is common in diabetes mellitus, has increased the risk of depressive symptoms in both humans and animals. However, the mechanisms behind the comorbidity are multi‐factorial and complicated. There is still no causal chain to explain the comorbidity exactly. Moreover, Selective serotonin reuptake inhibitors, insulin and metformin, which are recommended for treating diabetes mellitus‐induced depression, were found to be a risk factor in some complications of diabetes.Aims: Given these problems, many researchers made remarkable efforts to analyze diabetes complicating depression from different aspects, including insulin resistance, stress and Hypothalamic–Pituitary–Adrenal axis, neurological system, oxidative stress, and inflammation. Drug therapy, such as Hydrogen Sulfide, Cannabidiol, Ascorbic Acid and Hesperidin, are conducive to alleviating diabetes mellitus and depression. Here, we reviewed the exact pathophysiology underlying the comorbidity between depressive disorder and diabetes mellitus and drug therapy.Methods: The review refers to the available literature in PubMed and Web of Science, searching critical terms related to diabetes mellitus, depression and drug therapy.Results: In this review, we found that brain structure and function, neurogenesis, brain‐derived neurotrophic factor and glucose and lipid metabolism were involved in the pathophysiology of the comorbidity. Obesity might lead to diabetes mellitus and depression through reduced adiponectin and increased leptin and resistin. In addition, drug therapy displayed in this review could expand the region of potential therapy.Conclusions: The review summarizes the mechanisms underlying the comorbidity. It also overviews drug therapy with anti‐diabetic and anti‐depressant effects.

Our previous studies have shown that glutamate and hippocampal neuron apoptosis are key signals and direct factors associated with diabetes-related depression, and structural and functional damage to the hippocampal neurovascular unit has been associated with diabetes-related depression. However, the underlying mechanism remains unclear. We hypothesized that diabetes-related depression might be associated with the glutamate (Glu)/metabotropic glutamate receptor2/3 (mGluR_2/3)/phosphoinositide 3-kinase (PI3K) pathway, activated by glucocorticoid receptors in the hippocampal neurovascular unit. To test this hypothesis, rat hippocampal neurovascular unit models, containing hippocampal neurons, astrocytes, and brain microvascular endothelial cells, were treated with 150 mM glucose and 200 µM corticosterone, to induce diabetes-related depression. Our results showed that under conditions of diabetes complicated by depression, hippocampal neurovascular units were damaged, leading to decreased barrier function; elevated Glu levels; upregulated glucocorticoid receptor, vesicular glutamate transporter 3 (VGLUT-3), and metabotropic glutamate receptor 2/3 (mGluR_2/3) expression; downregulated excitatory amino acid transporter 1 (EAAT-1) expression; and alteration of the balance of key proteins associated with the extracellular signal-regulated kinase (ERK)/glial cell-derived neurotrophic factor (GDNF)/PI3K signaling pathway. Moreover, the viability of neurons was dramatically reduced in the model of diabetes-related depression, and neuronal apoptosis, and caspase-3 and caspase-9 expression levels, were increased. Our results suggest that the Glu/mGluR_2/3/PI3K pathway, induced by glucocorticoid receptor activation in the hippocampal neurovascular unit, may be associated with diabetes-related depression. This study was approved by the Laboratory Animal Ethics Committee of The First Hospital of Hunan University of Chinese Medicine, China (approval No. HN-ZYFY-2019-11-12) on November 12, 2019.

Objectives. Evodia rutaecarpa (ER) is a well-known herbal Chinese medicine traditionally used for analgesia in dysmenorrhea, headaches, abdominal pain, etc. Notably, the analgesic effect of wine-processed Evodia rutaecarpa (PER) was more potent than that of raw ER. This research aimed to investigate the mechanism and pharmacodynamic substance basis of raw ER and PER on smooth muscle cells of dysmenorrhea mice. Methods. Metabolomics methods based on UPLC-Q-TOF-MS were utilized to analyse the differential components of ER before and after wine processing. Afterwards, the uterine smooth muscle cells were isolated from the uterine tissue of dysmenorrhea and normal mice. The isolated dysmenorrhea uterine smooth muscle cells were randomly divided into four groups: model group, 7-hydroxycoumarin group (1mmol/L), chlorogenic acid (1mmol/L), and limonin (50μmol/L). The normal group consisted of the isolated normal mouse uterine smooth muscle cells, which were repeated 3 times in each group. The cell contraction and the expression of P2X3 and Ca²⁺ in vitro were determined using immunofluorescence staining and laser confocal; ELISA was used for detection of PGE2, ET-1, and NO content after 7-hydroxycoumarin, chlorogenic acid, and limonin administered for 24h. Results. The metabolomics results suggested that seven differential compounds were identified in the extracts of raw ER and PER, including chlorogenic acid, 7-hydroxycoumarin, hydroxy evodiamine, laudanosine, evollionines A, limonin, and 1-methyl-2-[(z)-4-nonenyl]-4 (1H)-quinolone. The in vitro results showed that 7-hydroxycoumarin, chlorogenic acid, and limonin were able to inhibit cell contraction and PGE2, ET-1, P2X3, and Ca²⁺ in dysmenorrhea mouse uterine smooth muscle cells and increase the content of NO. Conclusion. Our finding suggested that the compounds of the PER were different from those of the raw ER, and 7-hydroxycoumarin, chlorogenic acid, and limonin could improve dysmenorrhea in mice whose uterine smooth muscle cell contraction was closed with endocrine factors and P2X3-Ca²⁺ pathway.

Aim. To investigate the mechanism via which FKN/CX3CR1 signaling abnormalities mediate N-methyl-D-aspartic acid receptor (NMDA) overexcitation-induced hippocampal neuronal injury in diabetic rats complicated with depression (DD). Methods. Sixty rats were randomly divided into 5 groups. The depression-like behaviors of the rats were evaluated by open field test and Morris water maze. The pathological changes of hippocampus in DD rats were observed by HE staining. The blood levels of inflammatory factors (IL-1β, TNF-α, and IL-6) and neurotransmitters (D-serine and glutamic acid) were determined by enzyme-linked immunosorbent assay (ELISA). The expressions of BDNF, A1 receptor (A1R), A2 receptor (A2R), A3 receptor (A3R), calmodulin dependent kinase II (CaMKII), CX3CR1, CX3CL1 (FKN), NR2A, and NR2B proteins were detected by immunohistochemistry and Western-blotting. Results. Compared with the normal control group, blood glucose level increased significantly and body weight decreased in T2DM group and T2DMC group. In addition, the number of spontaneous activities significantly decreased and the capability of learning and memory was attenuated in T2DMC group and Chronic Stress group. The blood levels of IL-1β, TNF-α, IL-6, glutamate (Glu), and D-serine significantly increased in each model group. After intervention with CX3CR1 antibody, the expressions of BDNF, CaMK II, A1R, and A3R increased and those of A2R, CX3CR1, FKN, NR2A, and NR2B decreased. Conclusion. In the diabetic state, the binding of FKN to CX3CR1 increases, which regulates a variety of adenosine receptors. When it exerts its effect on neurons, the overactivation of NR results in neuronal injury and causes depression.