Research Letters

Increased temporal cortex CREB concentrations and antidepressant treatment in major depression

Insomnia, inflammation, and depression are often co-occurring conditions. The mechanisms underlying these conditions remain unclear.

We collected microarray datasets of depression and insomnia from GEO and analyzed them for differentially expressed genes (DEGs). We then overlapped the DEGs with a list of inflammatory response-related genes to identify genes associated with all three conditions. We next performed analyses of enrichment analyses, KEGG mapping, and protein-protein interaction to identify hub genes. Furthermore, we established a depression rat model with inflammation and insomnia to validate the potential genes. At last, a two-sample Mendelian randomization (MR) study was conducted to confirm the association of identified target genes with depression outcomes.

We obtained 32 common DEGs associated with the depression, insomnia and inflammatory, and found that the PI3K-AKT signaling pathway might be involved in the inflammatory response in insomnia and depression. CREB1, CYBB, FYN, and CCR5 were identified as targets for the next validation. In model rats, the CCR5 and PI3K-AKT pathways were significantly up-regulated, while the model group exhibited significantly lower hippocampal p-CREB protein expression. The MR study suggested a potential causal relationship between CREB1 and the risk of depression (OR = 1.11, p = 0.013).

The identified potential genes and pathways require further laboratory and clinical evidence verification.

We identified four potential inflammatory related-genes (CREB1, CYBB, FYN, and CCR5). CREB1 may be a potential inflammatory response-related biomarker and drug target for depression and insomnia, as validated by the followed rat model and MR study.

Bupleurum chinense DC. (B. chinense) is the dried root of B. chinense, belonging to the Umbelliferae family. B. chinense has been reported since ancient times for its effect of soothing the liver and relieving depression. Additionally, its important role in treating depression, depressed mood disorders and anti-inflammation has been proven in previous studies. However, its specific mechanism of action remains unknown.

The key targets and metabolites of the antidepressant effect of B. chinense were investigated based on the cAMP signalling pathway. The study examined the mechanism for the antidepressant effect of B. chinense by target prediction, analysis of related metabolites and potential metabolic pathways.

A network pharmacology approach was used to predict the antidepressant targets and pathways of B. chinense. A depression rat model was established through the CUMS (chronic unpredictable mild stress) procedure. The depression model was assessed by body weight, sugar-water preference, water maze and enzyme-linked immunosorbent assay (ELISA) indicators (5hydroxytryptamine, etc.). The key metabolic pathways were screened by correlations between metabolites and key targets. Finally, a quantitative analysis of key targets and metabolites was experimentally validated.

B. chinense significantly ameliorated the reduction in body weight, sugar-water preference rate and cognitive performance in the water maze experiment in rats with depression induced by CUMS. ELISA, Western blotting (WB) and reverse transcription-polymerase chain reaction (RT-PCR) assays showed that B. chinense significantly improves the expression of protein kinase cyclic adenylic acid (cAMP)-activated catalytic subunit alpha (PRKACA), cAMP-response element-binding protein (CREB) and cAMP activation in the rat brain induced by CUMS. According to metabolic pathway analysis, B. chinense shows an antidepressant effect primarily by regulating the cAMP metabolic pathway.

B. chinense upregulated PRKACA and CREB expression and the level of the key metabolite cAMP in the cAMP/PKA/CREB pathway while reducing the inflammatory response to depression treatment. These new findings support future research on the antidepressant effects of B. chinense.

Serotonin transporter gene-linked polymorphic region polymorphisms are associated with anxiety, neuroticism, affective disorders and vulnerability to stressful life events; however, the relevant physiological mechanisms are not well understood. Serotonin transporter knockout mice have been widely used as a model of allelic variation of serotonin transporter function in humans; herein, wild-type mice and heterozygous and homozygous knockout mice models were established to explore the behavioural changes related to different genotypes and the possible physiological mechanisms. Behavioural changes were assessed using behavioural tests, namely, elevated plus maze, open field, Morris water maze and rotarod tests. Serum indicators were detected using the enzyme-linked immunosorbent assay. Compared with wild-type mice, homozygous mice showed significant anxiety-like behaviours in the plus maze and open field tests; conversely, anxiety-like behaviours in heterozygous mice were less pronounced. Homozygous mice also showed cognitive impairment and motor inhibition in the Morris water maze and rotarod tests. Serotonin levels decreased in both heterozygous and homozygous mice, and 5-hydroxytryptophan, protein kinase A, adenylyl cyclase, cyclic adenosine monophosphate response element-binding protein and brain-derived neurotrophic factor levels were lower in homozygous mice than in wild-type and heterozygous mice, whereas no statistical differences were found between wild-type and heterozygous mice. Additionally, there was a correlation between serological and behavioural indicators. This study provided experimental evidence that the cyclic adenosine monophosphate–protein kinase A–cyclic adenosine monophosphate response element-binding protein–brain-derived neurotrophic factor pathway may be involved in the regulation of polymorphism to stress and enriched the behavioural and physiological characteristics of serotonin transporter knockout mice.

Recent researches suggest that there is a relationship between the pathogenesis of depression and serum Brain Derived Neurotrophic Factor (BDNF) levels. Therefore, the purpose of this clinical trial was to determine effect of magnesium supplementation on serum Level of BDNF, magnesium and depression status in patients with depression.

A double blind randomized clinical trial was conducted on 46 depressed subjects. The participants were randomly allocated into the magnesium (MG) and the placebo (PG) group and received 500 mg magnesium and placebo daily for 8 weeks. Beck's test was conducted and blood samples were taken at baseline and after the intervention period for analysis of serum magnesium and BDNF.

No significant differences were observed in assessed variables between the two groups at the baseline. At the end of intervention, supplementation with magnesium oxide had a significant effect on Beck's test (P = 0.01) and serum magnesium (P = 0.001), but had no significant effect on BDNF levels (P = 0.507) between the two groups.

Daily intake of 500 mg magnesium oxide for at least 8 weeks improved Beck's test score and serum magnesium in depressed patients, but had no significant effect on BDNF levels between the two groups, Which Further research is recommended.

Curtailment of sleep in modern society leads to a spectrum of neuropsychiatric disorders. Mounting evidence suggests that sleep deprivation (SD) is a risk factor for depression. Most recently, various reports have revealed the role of sleep in neuronal plasticity, learning and memory, and mood. SD studies provide insights into the cellular and molecular processes that are sensitive to sleep loss and have shown that SD negatively affects various brain regions. Citalopram (CTM), a selective serotonin reuptake inhibitor (SSRI), is the most-frequently used antidepressant in clinical practice. The identification of an SD-induced impairment in the CaMKII-CREB-BDNF signaling pathway, which is implicated in synaptic plasticity and the beneficial effects of CTM on this pathway represent a novel treatment target for neuropsychiatric disorders associated with sleep loss. In this chapter, we provide an overview of CTM use in SD-induced depression.

Phosphodiesterases (PDE) are a diverse family of enzymes (11 isoforms so far identified) responsible for the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which are involved in several cellular and biochemical functions. Phosphodiesterase 4 (PDE4) is the major isoform within this group and is highly expressed in the mammalian brain. An inverse association between PDE4 and cAMP levels is the key mechanism in various pathophysiological conditions like airway inflammatory diseases−chronic obstruction pulmonary disease (COPD), asthma, psoriasis, rheumatoid arthritis, and neurological disorders etc. In 2011, roflumilast, a PDE4 inhibitor (PDE4I) was approved for the treatment of COPD. Subsequently, other PDE4 inhibitors (PDE4Is) like apremilast and crisaborole were approved by the Food and Drug Administration (FDA) for psoriasis, atopic dermatitis etc. Due to the adverse effects like unbearable nausea and vomiting, dose intolerance and diarrhoea, PDE4 inhibitors have very less clinical compliance. Efforts are being made to develop allosteric modulation with high specificity to PDE4 isoforms having better efficacy and lesser adverse effects. Interestingly, repositioning PDE4Is towards neurological disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS) and sleep disorders, is gaining attention. This review is an attempt to summarize the data on the effects of PDE4 overexpression in neurological disorders and the use of PDE4Is and newer allosteric modulators as therapeutic options. We have also compiled a list of on-going clinical trials on PDE4 inhibitors in neurological disorders.