Major depression is a debilitating disease. To date, the development of biomarkers of major depressive disorder (MDD) remains a challenge. Recently, alterations in the expression of microRNAs (miRNAs) from post-mortem brain tissue and peripheral blood have been linked to MDD. The goals of this study were to detect the differential miRNAs in cerebrospinal fluid (CSF) and serum of MDD patients. First, the relative expression levels of 179 miRNAs (relative high levels in serum) were analyzed by miRNA PCR Panel in the CSF of MDD patients. Then, the differentially altered miRNAs from CSF were further assessed by qRT-PCR in the serum of the same patients. Finally, the serum differentially altered miRNAs were further validated by qRT-PCR in the serum of another MDD patients. The CSF-results indicated that 11 miRNAs in MDD patients were significantly higher than these in control subjects, and 5 miRNAs were significantly lower than these in control subjects. The serum-results from the same patients showed that 3 miRNAs (miR-221-3p, miR-34a-5p, and let-7d-3p) of the 11 miRNAs were significantly higher than these in control subjects, and 1 miRNA (miR-451a) of 5 miRNAs was significantly lower than these in control subjects. The up-regulation of miR-221-3p, miR-34a-5p, let-7d-3p and down-regulation of miR-451a was further validated in another 32 MDD patients. ROC analysis showed that the area under curve of let-7d-3p, miR-34a-5p, miR-221-3p and miR-451a was 0.94, 0.98, 0.97 and 0.94, with specificity of 90.48%, 95.24%, 90.48% and 90.48%, and sensitivity of 93.75%, 96.88%, 90.63% and 84.85%, respectively. In addition, target gene prediction found that the altered miRNAs are involved in affecting some important genes and pathway related to MDD. Our results suggested that differentially altered miRNAs in CSF might be involved in MDD, and serum miR-221-3p, miR-34a-5p, let-7d-3p, and miR-451a might be able to serve as biomarkers for MDD.
Depression is a major social and health concern, and ketamine exerts a quick, remarkable and persistent anti-depressive effect. microRNAs (miRNAs) show remarkable potential in the treatment of clinical depression. Here, we determined the expression profile of miRNAs in the hippocampus of rats treated with ketamine (15 mg/kg). The results suggest that multiple miRNAs were aberrantly expressed in rat hippocampus after ketamine injection (18 miRNAs were significantly reduced, while 22 miRNAs were significantly increased). Among them, miR-206 was down-regulated in ketamine-treated rats. In both cultured neuronal cells in vitro and hippocampus in vivo, we identified that the brain-derived neurotrophic factor (BDNF) was a direct target gene of miR-206. Via this target gene, miR-206 strongly modulated the expression of BDNF. Moreover, overexpression of miR-206 significantly attenuated ketamine-induced up-regulation of BDNF. The results indicated that miRNA-206 was involved in novel therapeutic targets for the anti-depressive effect of ketamine.
Previous research has demonstrated that the behaviors observed in chronic unpredictable mild stressed (CUMS) rats are similar to the symptoms of depressed patients and that the abnormal expression of cerebral microRNAs is associated with depressive disorder. However, little is known regarding the expression profile of microRNAs induced by CUMS. In this study, we aimed to examine the hippocampal microRNA expression profile in CUMS rats. Forty adolescent male Sprague-Dawley rats were randomly divided into normal and model groups. The rats in the model group were stimulated daily with randomly applied mild stressors from among 14 different mild stressors. The stressors were changed every day and were applied for 35 consecutive days. On the 28th and 35th days after treatment, the weights, physical condition, sucrose preference, and open-field test scores of the rats of the two groups were evaluated. Successful induction of CUMS was considered if the differences of the above metrics between the two groups were statistically significant on the 28th and 35th days after treatment. Cerebral sucrose metabolism images of rats were obtained by 18F-FDG PET/CT. The rats were euthanized under anesthesia, and hippocampal tissues were collected for hematoxylin-eosin (HE) staining. In addition, the samples were used for microRNA array chip and qRT-PCR analysis. The target genes of different microRNAs were predicted using bioinformatic analysis, and the functions and signal pathways of these target genes were investigated by GO and KEGG analyses. Sixteen rats exhibited successful induction of CUMS. Cerebral F-FDG PET/CT imaging showed that the glucose metabolism rate of CUMS rats were significantly lower than normal rats in the central nucleus of the inferior colliculus (CIC, p = 0.022), the retrosplenial agranular area (RSA, p = 0.002), the second sensory cortex (S2, p = 0.028), the first auditory cortex (Au1, p = 0.012), the primary somatosensory cortex, barrel field (SIBF, p = 0.001), and the ventral posteromedial nucleus (VPM) of the right thalamus (p = 0.048). HE staining showed that hippocampal pyramidal cells CUMS rats were thinner, disordered, and exhibited irregular shapes, with many pyknotic cells. The microarray chip and qRT-PCR analysis revealed that five microRNAs were significantly up-regulated [miR-382-3p (p = 0.026), miR-183-5p (p = 0.018), miR-3573-5p (p = 0.042), miR-202-3p (p = 0.016), miR-493-3p (p = 0.009)], and only miR-370-3p was significantly down-regulated (p = 0.036). miRNA target gene prediction and functional annotation analysis showed significant enrichment in several GO terms and pathways associated with depression. Our findings provide supportive evidence for the abnormal expression of multiple CUMS-induced hippocampal microRNAs in rats as well as the involvement of these microRNAs in depressive disorder.
Ketamine has a rapid, obvious, and persistent antidepressant effect, but its underlying molecular mechanisms remain unknown. Recently, microRNAs (miRNAs) have emerged as important modulators of ketamine’s antidepressant effect. We investigated the alteration in miR-29b-3p in the brain of rats subjected to ketamine administration and chronic unpredictable mild stress (CUMS), and a sucrose preference test and forced swimming test were used to evaluate the rats’ depressive-like state. We used recombination adeno-associated virus (rAAV) or lentivirus-expressing miR-29b-3p to observe the change in metabotropic glutamate receptor 4 (GRM4). Cell culture and electrophysiological recordings were used to evaluate the function of miR-29b-3p. Ketamine dramatically increased miR-29b-3p expression in the prefrontal cortex of the normal rats. The dual luciferase reporter test confirmed that GRM4 was the target of miR-29b-3p. The miR-29b-3p levels were downregulated, while the GRM4 levels were upregulated in the prefrontal cortex of the depressive-like rats. The ketamine treatment increased miR-29b-3p expression and decreased GRM4 expression in the prefrontal cortex of the depressive-like rats and primary neurons. By overexpressing and silencing miR-29b-3p, we further validated that miR-29b-3p could negatively regulate GRM4. The silencing of miR-29b-3p suppressed the Ca2+ influx in the prefrontal cortex neurons. The miR-29b-3p overexpression contributed to cell survival, cytodendrite growth, increases in extracellular glutamate concentration, and cell apoptosis inhibition. The overexpression of miR-29b-3p by rAAV resulted in a noticeable relief of the depressive behaviors of the CUMS rats and a lower expression of GRM4. The miR-29b-3p/GRM4 pathway acts as a critical mediator of ketamine’s antidepressant effect in depressive-like rats and could be considered a potential therapeutic target for treating major depression disorder.
The cardiopulmonary bypass (CPB) is an important risk factor for the development of postoperative cognitive dysfunction (POCD). The pathological mechanism of the neuro-modulation receptor degradation protein ring finger protein 41 (Nrdp1) in CPB-induced cognitive dysfunction remains unclear. In the present study, aged Sprague-Dawley male rats and CPB treatment were selected to duplicate the POCD model. A hypoxia/reoxygeneration (H/R) model was established to evaluate the effect of Nrdp1 in vitro. Apoptosis in the hippocampus regions were measured using a terminal deoxynucleotidyl-transferase-mediated dUTP nick end labelling assay, the viability and apoptosis level of the cells were measured via an MTT assay and flow cytometry, respectively, and the expression levels of Nrdp1, erb-b2 receptor tyrosine kinase 3 (ErbB3), phosphorylated-protein kinase B (p-AKT) and cleaved (c-) caspase-3 were detected using western blot analysis. Then, Nrdp1 was upregulated and downregulated in vitro and in vivo through lentivirus infection to further investigate the effect of Nrdp1 in the rats following CPB. The results revealed that Nrdp1 is associated with hippocampus neuronal apoptosis and POCD following CPB in rats. The overexpression of Nrdp1 altered the cognitive function of the rats which was inhibited by CPB, and additionally inhibited the viability and increased the apoptosis of primary hippocampus neuron cells under H/R treatment. Furthermore, knockdown of Nrdp1 promoted the viability of primary hippocampus neuron cells and decreased the apoptosis of cells under H/R treatment. Further study indicated that Nrdp1 regulates the protein expression of ErbB3, p-AKT, cytochrome c, BCL2-associated X, apoptosis regulator, BCL2, apoptosis regulator and c-caspase-3. The results of the present study suggested that CPB may induce apoptosis in the hippocampus of aged rats. Nrdp1 serves an important role in regulating the apoptosis induced by CPB in vivo and in vitro through regulating ErbB3 and p-AKT protein levels.
BackgroundPostoperative cognitive dysfunction (POCD) is a postoperative complication after surgery and anesthesia. Whether ABO blood types are associated with POCD in elderly patients undergoing unilateral total hip arthroplasty surgery in China is unclear.Material/MethodsFirstly, 142 elderly patients were divided into a POCD group and a non-POCD group according to the Mini Mental State Examination (MMSE) scores and ABO blood types were analyzed. Secondly, according to ABO blood type, the selected 226 patients were divided into 4 groups: type A group, type B group, type AB group, and type O group. Then, all patients completed the MMSE before and after surgery. Finally, the occurrence of POCD was recorded and related data were analyzed.ResultsFirstly, there was a significant difference in both groups in terms of distribution of ABO blood types, and elderly patients who developed POCD were more likely to have type A blood and less likely to have type O blood. Secondly, compared with elderly patients with type A blood, those with type O had higher MMSE scores on the first day and the seventh day after surgery. Finally, the risk of developing POCD was significantly higher in patients with type A blood and on the first day and the seventh day after surgery the risk of developing POCD was significantly lower in patients with type O blood.ConclusionsElderly patients with type A blood have higher risk of developing early POCD and those with type O blood have less risk of developing early POCD.
Mounting evidence suggests that activation of microglia and inflammatory response play an important role in the pathogenesis of depression. A single or repeated sub-anesthetic dose of ketamine administration induced fast and potent antidepressant effect. We investigated the effect of ketamine on microglia activation and pro-inflammatory cytokines levels in hippocampus of depression-like rats. Methods Forty-eight rats were equally randomized into four groups Control+saline group, Control+ketamine group, Chronic unpredictable mild stress (CUMS)+saline group and CUMS+ketamine group. 0.9% saline or 10 mg/kg ketamine was given once daily for 7 consecutive days. The sucrose preference test (SPT) open field test (OFT) and forced swimming test (FST) were performed before and day 7 after drug treatment. The hippocampus was subsequently harvested for the detection of levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and levels of CD11b and Iba1. The CD11bpositive cells in the CA3 and DG region of the hippocampus were also stained by immunohistochemistry. Results CUMS induced the decrease of sucrose solution intake volume, the increase of the immobility time, the up-regulation of TNF-α, IL-1β, IL-6, CD11b and Iba1 levels of the hippocampus and the increase of CD11b-positive microglia in the CA3 and DG region of the hippocampus. Ketamine administration could reverse this effect. Conclusion Ketamine's antidepressant effect on depression-like rats is accompanied by the inhibition of microglia activation and pro-inflammatory cytokines levels in the hippocampus.
Decreased mitochondrial Complex I activities and a 4,977‐bp deletion in mitochondrial DNA (mtDNA) have been reported in patients with Parkinson's disease. Based on the assumption of possible links between this 4,977‐bp deletion and the etiology of Parkinson's disease, we analyzed mtDNA of blood cells from 15 patients with young‐onset Parkinson's disease after the DNA was amplified by polymerase chain reaction. We could not detect the 4,977‐bp mtDNA deletion in any of these patients. This result suggests that Parkinson's disease is not a mitochondrial disease due to the 4,977‐bp mtDNA deletion. The 4,977‐bp deletion in mtDNA appears to be an age‐related phenomenon.
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