Model-based dosing optimization and therapeutic drug monitoring practices of teicoplanin in patients with complicated or non-complicated methicillin-resistant staphylococcus aureus infection.

AIMS: This study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it. METHODS: Nonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function. RESULTS: A total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient's renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week. CONCLUSIONS: Both loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient's renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week.

Simvastatin ameliorates synaptic plasticity impairment in chronic mild stress-induced depressed mice by modulating hippocampal NMDA receptor.

BACKGROUND: In our previous study, we showed simvastatin exerts an antidepressant effect and inhibits neuroinflammation. Given the role of synaptic impairment in depression development, we investigate the effect of simvastatin on synaptic plasticity in depression and the related mechanisms. METHODS: Electrophysiological analysis, Golgi staining, and transmission electron microscope were performed to analyze the effect of simvastatin on synaptic impairment in depression. In addition, the localization and reactivity of N-methyl-D-aspartate receptor (NMDAR) subunits and the downstream signaling were investigated to explore the mechanism of simvastatin's effect on synaptic plasticity. RESULTS: Simvastatin ameliorated the reduction of the magnitude of long-term potentiation (LTP) in Schaffer collateral-CA1, restored hippocampal dendritic spine density loss, improved the number of spine synapses, reversed the reduction in BrdU-positive cells in chronic mild stress (CMS)-induced depressed mice, and ameliorated NMDA-induced neurotoxicity in hippocampal neurons. Dysfunction of NMDAR activity in the hippocampus is associated with depression. Simvastatin treatment reversed the surface expression and phosphorylation changes of NMDAR subunits in NMDA-treated hippocampal neurons and depressed mice. In addition, simvastatin further increased the levels of mature BDNF, activating TrkB-Akt-mTOR signaling, which is critical for synaptic plasticity. CONCLUSIONS: These findings suggest that simvastatin can improve the dysfunction of NMDAR and ameliorate hippocampal synaptic plasticity impairment in depressed mice.

Safety and clinical efficacy of linezolid in children: a systematic review and meta-analysis.

BACKGROUND: We aimed to evaluate the tolerability and efficacy of linezolid in children for treating suspected and diagnosed Gram-positive bacterial infections. METHODS: A systematic literature search was conducted up to April 23, 2021, using linezolid and its synonyms as search terms. Two reviewers independently identified and extracted relevant randomized controlled trials and prospective cohort studies. The extracted studies were included in a single-rate meta-analysis of adverse events and clinical outcomes using random-effects models. RESULTS: A total of 1082 articles were identified, and nine studies involving 758 children were included in the meta-analysis. The overall proportion of adverse events was 8.91% [95% confidence interval (CI) = 1.64%-36.52%], with diarrhea (2.24%), vomiting (2.05%), and rash (1.72%) being the most common. The incidences of thrombocytopenia and anemia were 0.68% and 0.16%, respectively. Some specific adverse events, including rash and gastrointestinal events, were more frequent in the oral administration subgroup. In terms of efficacy, the overall proportion of clinical improvement was 88.80% (95% CI = 81.31%-93.52%). Children with a history of specific bacteriological diagnosis or concomitant antibiotic therapy had a 1.13-fold higher clinical improvement than children without such histories. The proportion of microbial eradication was 92.68% (95% CI = 84.66%-96.68%). The proportion of all-cause mortality was 0.16% (95% CI = 0.00%-7.75%). CONCLUSIONS: Linezolid was well-tolerated in pediatric patients and was associated with a low frequency of adverse events, such as anemia, thrombocytopenia, and neutropenia. Moreover, linezolid was effective in children with diagnosed and suspected Gram-positive infections.

Modification of Vancomycin Dosing in Cardiac Surgery With Cardiopulmonary Bypass.

This study aims to assess the risk factors for insufficient vancomycin concentrations for its prophylactic use in adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and to modify the dosing regimen to achieve appropriate plasma concentrations. A total of 27 patients with vancomycin dosing of 1 to 1.5 g based on a weight cutoff of 67 kg were included, of which only 13 (48.15%) had vancomycin plasma concentration >15 mg/L at surgical closure. Risk factors of vancomycin concentration <15 mg/L at surgical-site closure were confirmed by multivariate logistic regression analysis, which showed that CPB duration was an independent predictor. Patients with CPB duration >4 hours had significantly lower vancomycin concentrations and lower proportion in achieving target vancomycin concentration at the end of CPB and surgical closure. For patients with CPB >4 hours, the modified dosing regimen that a second dose of 0.5 to 0.75 g added at 4 hours since the onset of CPB improved the target achievement of vancomycin concentration at surgical closure. Taken together, CPB duration >4 hours was the risk factor for insufficient vancomycin concentration at surgical closure, while our modified dosing could improve the vancomycin concentrations for its prophylactic use in patients undergoing cardiac surgery with CPB.

Population pharmacokinetic analysis, renal safety, and dosing optimization of polymyxin B in lung transplant recipients with pneumonia: A prospective study.

Objectives: This study aims to characterize the population pharmacokinetics of polymyxin B in lung transplant recipients and optimize its dosage regimens. Patients and methods: This prospective study involved carbapenem-resistant organisms-infected patients treated with polymyxin B. The population pharmacokinetic model was developed using the NONMEM program. The clinical outcomes including clinical treatment efficacy, microbiological efficacy, nephrotoxicity, and hyperpigmentation were assessed. Monte Carlo simulation was performed to calculate the probability of target attainment in patients with normal or decreased renal function. Results: A total of 34 hospitalized adult patients were included. 29 (85.29%) patients were considered of clinical cure or improvement; 14 (41.18%) patients had successful bacteria elimination at the end of the treatment. Meanwhile, 5 (14.71%) patients developed polymyxin B-induced nephrotoxicity; 19 (55.88%) patients developed skin hyperpigmentation. A total of 164 concentrations with a range of 0.56-11.66 mg/L were obtained for pharmacokinetic modeling. The pharmacokinetic characteristic of polymyxin B was well described by a 1-compartment model with linear elimination, and only creatinine clearance was identified as a covariate on the clearance of polymyxin B. Monte Carlo simulations indicated an adjusted dosage regimen might be needed in patients with renal insufficiency and the currently recommended dose regimens by the label sheet of polymyxin B may likely generate a subtherapeutic exposure for MIC = 2 mg/L. Conclusion: Renal function has a significant effect on the clearance of polymyxin B in lung transplant recipients, and an adjustment of dosage was needed in patients with renal impairments.

Population Pharmacokinetics of Colistin Sulfate in Critically Ill Patients: Exposure and Clinical Efficacy.

Background: Presently, colistin is commercially available in two different forms, namely, colistin sulfate and its sulphomethylated derivative, colistimethate sodium (CMS). However, in the currently reported studies, most of the clinical studies on colistin for parenteral use are referred to as CMS. Data on the pharmacokinetics (PK), clinical efficacy, and side effects of colistin sulfate in clinical use have not been reported. Methods: This retrospective study was performed on carbapenem-resistant organism (CRO)-infected patients treated with colistin sulfate for more than 72 h. The population pharmacokinetic model was developed using the NONMEM program. The clinical outcomes including clinical treatment efficacy, microbiological eradication, and nephrotoxicity were assessed. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) in patients with normal or decreased renal function. Results: A total of 42 patients were enrolled, of which 25 (59.52%) patients were considered clinical treatment success and 29 (69.06%) patients had successful bacteria elimination at the end of treatment. Remarkably, no patient developed colistin sulfate-related nephrotoxicity. A total of 112 colistin concentrations with a range of 0.28-6.20 mg/L were included for PK modeling. The PK characteristic of colistin was well illustrated by a one-compartment model with linear elimination, and creatinine clearance (CrCL) was identified as a covariate on the clearance of colistin sulfate that significantly explained inter-individual variability. Monte Carlo simulations showed that the recommended dose regimen of colistin sulfate, according to the label sheet, of a daily dose of 1-1.5 million IU/day, given in 2-3 doses, could attain PTA > 90% for MICs ≤ 0.5 µg/mL, and that a daily dose of 1 million IU/day could pose a risk of subtherapeutic exposure for MIC ≥1 µg/ml in renal healthy patients. Conclusion: Renal function significantly affects the clearance of colistin sulfate. A dose of 750,000 U every 12 h was recommended for pathogens with MIC ≤1 µg/ml. The dosage recommended by the label inserts had a risk of subtherapeutic exposure for pathogens with MIC ≥2 µg/ml. Despite higher exposure to colistin in patients with acute renal insufficiency, dose reduction was not recommended.

Efficacy and Pharmacodynamic Target Attainment for Ceftazidime-Avibactam Off-Label Dose Regimens in Patients with Continuous or Intermittent Venovenous Hemodialysis: Two Case Reports.

Limited data are available for ceftazidime-avibactam (CZA) dosing in patients receiving renal replacement therapy, especially the data on the dosing in patients receiving intermittent hemodialysis (IHD). In this report, we firstly described a case in which CZA was administered as 2.5 g after each time of IHD, and a dose of 1.25 g was added on the 48th-hour for the 72-h interdialytic interval. Plasma concentrations of CZA measured at different time indicated that > 50% of administered ceftazidime and avibactam were removed during the 4-h hemodialysis. In addition, we described another case on continuous venovenous hemodialysis (CVVHD), in which CZA was administered as 2.5 g q12h in 2-h infusions. The dose regimen for these two cases could achieve trough concentration of ceftazidime higher than fourfold of the MIC and trough concentration of avibactam higher than the threshold of 1 µg/mL during the treatment, and exert efficient antimicrobial effect.

Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients.

Background: Linezolid is associated with myelosuppression, which may cause failure in optimally treating bacterial infections. The study aimed to define the pharmacokinetic/toxicodynamic (PK/TD) threshold for critically ill patients and to identify a dosing strategy for critically ill patients with renal insufficiency. Methods: The population pharmacokinetic (PK) model was developed using the NONMEM program. Logistic regression modeling was conducted to determine the toxicodynamic (TD) threshold of linezolid-induced myelosuppression. The dosing regimen was optimized based on the Monte Carlo simulation of the final model. Results: PK analysis included 127 linezolid concentrations from 83 critically ill patients at a range of 0.25-21.61 mg/L. Creatinine clearance (CrCL) was identified as the only covariate of linezolid clearance that significantly explained interindividual variability. Thirty-four (40.97%) of the 83 patients developed linezolid-associated myelosuppression. Logistic regression analysis showed that the trough concentration (Cmin) was a significant predictor of myelosuppression in critically patients, and the threshold for Cmin in predicting myelosuppression with 50% probability was 7.8 mg/L. The Kaplan-Meier plot revealed that the overall median time from the initiation of therapy to the development of myelosuppression was 12 days. Monte Carlo simulation indicated an empirical dose reduction to 600 mg every 24 h was optimal to balance the safety and efficacy in critically ill patients with CrCL of 30-60 ml/min, 450 mg every 24 h was the alternative for patients with CrCL <30 ml/min, and 600 mg every 12 h was recommended for patients with CrCL ≥60 ml/min. Conclusion: Renal function plays a significant role in linezolid PKs for critically ill patients. A dose of 600 mg every 24 h was recommended for patients with CrCL <60 ml/min to minimize linezolid-induced myelosuppression.

Intraventricular colistin sulphate as a last resort therapy in a patient with multidrug-resistant Acinetobacter baumannii induced post-neurosurgical ventriculitis.

Limited therapeutic options exist for multidrug-resistant/extensively drug-resistant Acinetobacter baumannii (MDR/XDR-Ab) meningitis/ventriculitis. A combination of intravenous and intraventricular (IVT)/intrathecal (IT) polymyxins achieves good therapeutic outcomes for cases of healthcare-associated MDR/XDR-Ab meningitis/ventriculitis. Colistin is commercially available as colistin sulphate and its sulphomethylated derivative. However, the effect and safety of colistin sulphate in the treatment of MDR/XDR-Ab meningitis/ventriculitis has not been reported. We report on a 66-year-old male patient who developed post-neurosurgical ventriculitis caused by MDR-Ab. IVT concomitant intravenous colistin sulphate was used as a last-resort antimicrobial therapy, the patient's ventriculitis was dramatically improved, and the concentrations of CSF colistin were higher than the MIC breakpoint throughout the treatment. Meanwhile, no nephrotoxicity or neurotoxicity was observed during the treatment.

Trough polymyxin B plasma concentration is an independent risk factor for its nephrotoxicity.

AIMS: Data regarding clinical pharmacokinetic/toxicodynamic (PK/TD) of polymyxin B is short of direct quantitative data. This study aims to investigate the risk factors of polymyxin B associated acute kidney injury (AKI) and to assess the relationship between polymyxin B plasma levels and its nephrotoxicity. METHODS: A retrospective study was performed in adult patients treated with polymyxin B. Risk factors associated with AKI and plasma trough concentrations of polymyxin B were identified via medical record review. A multivariate logistic regression model was established and the risk of polymyxin B-associated AKI were predicted by a receiver operating characteristic curve, with maximal Youden index used to identify safety thresholds among the study population. RESULTS: Fifty-four adult patients were included in the study. AKI was detected in 14 patients during polymyxin B treatment (25.9%, 14 out of 54). Cmin (odds ratio [OR] 2.071; 95% confidence interval [CI] 1.235-3.472) and baseline serum creatinine (OR 1.024; 95% CI 1.005-1.043) were significant independent risk factors for developing AKI. The area under the ROC curve of the combined predictor was larger based on the above factors. When the Youden index was at maximum, the optimal cut-off point was 6.678 of the ROC curve. When Cmin ≥ 3.13 mg/L, the probability of AKI was more than 50%. CONCLUSION: In this study, when the calculated combined predictor value was >6.678, there was an increased risk of AKI. Maintaining a polymyxin B Cmin level below 3.13 mg/L may be helpful in reducing the incidence of polymyxin B associated nephrotoxicity.

Model Based Identification of Linezolid Exposure-toxicity Thresholds in Hospitalized Patients.

Evidence supports linezolid therapeutic drug monitoring as the exposure-response relationship has been identified for toxicity among patients receiving linezolid, but the data to establish the upper limit are limited and the published toxicity thresholds range widely. The purpose of this study was to determine the linezolid exposure-toxicity thresholds to improve the safety of linezolid. This is a multicenter retrospective study of adult patients treated with linezolid from 2018 to 2019. The population pharmacokinetic model of linezolid was established based on 270 plasma concentrations in 152 patients, which showed creatinine clearance and white cell count are covariates affecting the clearance of linezolid, and serum albumin is the covariate affecting the volume of distribution. Classification and regression tree analysis was used to determine the linezolid exposure thresholds associated with an increased probability of toxicity. Among 141 patients included for toxicity analysis, the rate of occurring toxicity was significantly higher among patients with an AUC0-24, d1 ≥163 mg h/L, AUC0-24, d2 ≥207 mg h/L, AUC0-24, ss ≥210 mg h/L, and Cmin,d2 ≥6.9 mg/L, Cmin,ss ≥6.9 mg/L, while no threshold was discovered for Cmin, d1. Those exposure thresholds and duration of linezolid treatment were independently associated with linezolid-related toxicity in the logistic regression analyses. In addition, the predictive performance of the AUC0-24 and Cmin thresholds at day 2 and steady state were close. Considering that the AUC estimation is cumbersome, Cmin threshold at 48 h and steady state with a value of ≥6.9 mg/L is recommended to improve safety, especially for patients with renal insufficiency and patients with low serum albumin.

Population pharmacokinetic and optimization of polymyxin B dosing in adult patients with various renal functions.

AIMS: Current FDA-approved label recommends that the dosage of polymyxin B should be adjusted according to renal function. However, the correlation between polymyxin B pharmacokinetics (PK) and creatinine clearance (CrCL) is poor. This study aimed to develop a population PK model of polymyxin B in adult patients with various renal functions and to identify a dosing strategy. METHODS: A retrospective PK study was performed in 32 adult patients with various renal function. Nonlinear mixed effects modelling was applied to build a population PK model of polymyxin B followed by Monte Carlo simulations which designed polymyxin B dosing regimens across various renal function. RESULTS: Polymyxin B PK analyses included 112 polymyxin B concentrations at steady state from 32 adult patients, in which 71.9% of them were critically ill. In the final PK model, CrCL was the significant covariate on CL (typical value 1.59 L/h; between-subject variability 13%). The mean (SD) individual empirical Bayesian estimate of CL was 1.75 (0.43) L/h. In addition, a new dosing strategy combining the PK/pharmacodynamic (PD) targets and Monte Carlo simulation indicated that the reduction of polymyxin B dose in patients with renal insufficiency improved the probability of achieving optimal exposure. For severe infections caused by organisms with minimum inhibitory concentration (MIC) ≥ 2 mg/L, a high daily dose of polymyxin B might be possible for bacterial eradication, but the risk of nephrotoxicity is increased. CONCLUSIONS: Renal function plays a significant role in polymyxin B PK, and the dose of polymyxin B should be adjusted according to CrCL in patients with renal insufficiency.

Sirtuins family as a target in endothelial cell dysfunction: implications for vascular ageing.

The vascular endothelium is a protective barrier between the bloodstream and the vasculature that may be disrupted by different factors such as the presence of diseased states. Diseases like diabetes and obesity pose a great risk toward endothelial cell inflammation and oxidative stress, leading to endothelial cell dysfunction and thereby cardiovascular complications such as atherosclerosis. Sirtuins are NAD+-dependent histone deacetylases that are implicated in the pathophysiology of cardiovascular diseases, and they have been identified to be important regulators of endothelial cell function. A handful of recent studies suggest that disbalance in the regulation of endothelial sirtuins, mainly sirtuin 1 (SIRT1), contributes to endothelial cell dysfunction. Herein, we summarize how SIRT1 and other sirtuins may contribute to endothelial cell function and how presence of diseased conditions may alter their expressions to cause endothelial dysfunction. Moreover, we discuss how the beneficial effects of exercise on the endothelium are dependent on SIRT1. These mainly include regulation of signaling pathways related to endothelial nitric oxide synthase phosphorylation and nitric oxide production, mitochondrial biogenesis and mitochondria-mediated apoptotic pathways, oxidative stress and inflammatory pathways. Sirtuins as modulators of the adverse conditions in the endothelium hold a promising therapeutic potential for health conditions related to endothelial dysfunction and vascular ageing.

Lovastatin Prevents Depressive Behaviors and Increased Hippocampal Neurogenesis in Streptozotocin-Induced Diabetic Mice.

Depression is a progressive and chronic syndrome and commonly related to several neuropsychiatric comorbidities, of which depression is the most studied. Population-based studies have suggested a positive role of statins in ameliorating depression risk. However, the role of statins in the treatment of diabetes-related depression has not been well examined. Herein, we investigated the effects of lovastatin (LOV) on depressive phenotypes in streptozotocin-induced diabetic mice. The data suggested that the treatment of LOV at 10 or 20 mg/kg for 3 weeks markedly prevented diabetes-associated depressive behaviors reflected by better performance in the sucrose preference test, tail suspension test, and novelty-suppressed feeding test. The study further showed that these treatments improved the hippocampal neurogenesis as evidenced by increased bromodeoxyuridine-positive cells in the dentate gyrus with higher expression of mature brain-derived neurotrophic factor and increased phosphorylation of cAMP-response element-binding protein. As expected, diabetic mice treated with LOV showed significant improvement of hyperlipidemia rather than hyperglycemia. These results suggest that LOV may be employed as a drug for the treatment of diabetes-related depression.

Simvastatin prevents and ameliorates depressive behaviors via neuroinflammatory regulation in mice.

BACKGROUND: Statins play a beneficial role in the treatment of coronary artery disease and are widely prescribed to prevent hypercholesterolemia. Previous studies have demonstrated that statins also have anti-inflammatory and immunomodulatory properties, and these are being explored for potential benefits in depression. However, the role of statins in the treatment of depression has not been well examined. METHODS: We investigated the effects of simvastatin on depressive behaviors and neuroinflammation in lipopolysaccharide (LPS) and chronic mild stress (CMS) induced depression model in mice. Sucrose preference test (SPT), forced swimming test (FST), novelty-suppressed feeding test (NSFT) were used to detect the depressive behaviors. The microglial activation was detected by immunohistochemistry analysis and the pro-inflammatory cytokines expressions including IL-1ß, TNF-α and IL-6 were examined by Western blot analysis. RESULTS: Our data indicated that oral administration of simvastatin at 20 mg/kg significantly prevented and ameliorated depressive behaviors reflected by better performance in the SPT, FST and NSFT. Moreover, simvastatin markedly prevented and ameliorated LPS and CMS-induced neuroinflammation, as shown by the suppressed activation of microglia in hippocampus and decreased hippocampal pro-inflammatory cytokines expressions including IL-1ß, TNF-α, IL-6, which might be mediated via the inhibition of NF-κB pathway, as shown by the decreased nuclear NF-κB p65 expression. LIMITATIONS: The interpretation of the evidence of a positive treatment effect of simvastatin on the depressive manifestations, multifaceted etiology of depression, and confirmation of this finding from animal models to humans is needed. CONCLUSION: These results suggest that simvastatin has the potential to be employed as a therapy for depression associated with neuroinflammation.

Endothelial dysfunction in diabetes and hypertension: Role of microRNAs and long non-coding RNAs.

The vascular endothelium acts as a barrier between the blood flow and the inner lining of the vessel wall, and it functions as a filtering machinery to filter out any unwanted transfer of materials from both sides (i.e. the blood and the surrounding tissues). It is evident that diseases such as diabetes, obesity, and hypertension disturb the normal endothelial functions in humans and lead to endothelial dysfunction, which may further precede to the development of atherosclerosis. Long non-coding RNAs and micro RNAs both are types of non-coding RNAs which, in the recent years, have increasingly been studied in the pathophysiology of many diseases including diabetes, obesity, cardiovascular diseases, neurological diseases, and others. Recent findings have pointed out important aspects on their relevance to endothelial function as well as dysfunction of the system which may arise from presence of diseases such as diabetes and hypertension. Diabetes or hypertension-mediated endothelial dysfunction show characteristics such as reduced nitric oxide synthesis through suppression of endothelial nitric oxide synthase activity in endothelial cells, reduced sensitivity of nitric oxide in smooth muscle cells, and inflammation - all of which have been either shown to be directly caused by gene regulatory mechanisms of non-coding RNAs or shown to be having a correlation with them. In this review, we aim to discuss such findings on the role of these non-coding RNAs in diabetes or hypertension-associated endothelial dysfunction and the related mechanisms that may pave the way for alleviating endothelial dysfunction and its related complications such as atherosclerosis.

Knockdown of hippocampal cysteinyl leukotriene receptor 1 prevents depressive behavior and neuroinflammation induced by chronic mild stress in mice.

RATIONALE: Numerous studies have demonstrated that neuroinflammation is associated with depression-like symptoms and neuropsychological disturbances, and cysteinyl leukotriene receptor 1 (CysLT1R) was reported to be involved in neuroinflammation. The pathophysiological role of CysLT1R has been reported in several types of brain damage. However, the role of CysLT1R in depression remains to be elucidated. OBJECTIVES: We aimed to investigate the effect of hippocampal CysLT1R downregulation on depressive behaviors and neuroinflammatory responses in mice exposed to chronic mild stress (CMS). RESULTS: We firstly found that expression of hippocampal CysLT1R was gradually increased over CMS exposure, while 3 weeks treatment with fluoxetine reversed the increment of hippocampal CysLT1R expression. Hippocampal CysLT1R knockdown suppressed CMS-induced depressive-like behaviors as evidenced by decreases in immobility time in tail suspension test (TST), decreased latency to feed in novelty-suppressed feeding (NSF) test, and by increase in the number of entries and decrease in time spent in the open arm in elevated plus maze (EPM) test. Increments of hippocampal NF-κB p65, IL-1ß, and TNF-α induced by CMS were also prevented by hippocampal CysLT1R knockdown beforehand. CONCLUSIONS: Hippocampal CysLT1R participates in depression, and knockdown of hippocampal CysLT1R prevents CMS-induced depressive-like behaviors and neuroinflammation, suggesting that suppression of CysLT1R could prevent the development of depression.

Hippocampal PPARδ Overexpression or Activation Represses Stress-Induced Depressive Behaviors and Enhances Neurogenesis.

BACKGROUND: Emerging data have demonstrated that peroxisome proliferator-activated receptor δ (PPARδ) activation confers a potentially neuroprotective role in some neurodegenerative diseases. However, whether PPARδ is involved in depression is unknown. METHODS: In this study, PPARδ was firstly investigated in the chronic mild stress (CMS) and learned helplessness (LH) models of depression. The changes in depressive behaviors and hippocampal neurogenesis were investigated after PPARδ overexpression by microinfusion of the lentiviral vector, containing the coding sequence of mouse PPARδ (LV-PPARδ), into the bilateral dentate gyri of the hippocampus or PPARδ activation by repeated systemic administration of PPARδ agonist GW0742 (5 or 10mg/kg.d, i.p., for 21 d). RESULTS: We found that both CMS and LH resulted in a significant decrease in the PPARδ expression in the hippocampi of mice, and this change was reversed by treatment with the antidepressant fluoxetine. PPARδ overexpression and PPARδ activation each suppressed the CMS- and LH-induced depressive-like behavior and produced an antidepressive effect. In vivo or in vitro studies also showed that both overexpression and activation of PPARδ enhanced proliferation or differentiation of neural stem cells in the hippocampi of mice. CONCLUSIONS: These results suggest that hippocampal PPARδ upregulation represses stress-induced depressive behaviors, accompanied by enhancement of neurogenesis.