Early-life stress and antidepressants modulate peripheral biomarkers in a gene–environment rat model of depression

Background

Availability of peripheral biomarkers for depression could aid diagnosis and help to predict treatment response. The objective of this work was to analyse the peripheral biomarker response in a gene–environment interaction model of depression. Genetically selected Flinders Sensitive Line (FSL) rats were subjected to maternal separation (MS), since early-life trauma is an important antecedent of depression. An open-ended approach based on a proteomic analysis of serum was combined with the evaluation of depression-associated proteins.

Methods

Rats experienced MS and chronically received escitalopram (ESC) or nortryptiline (NOR). Serum proteins were compared by two-dimensional gel electrophoresis. Corticosterone, cytokines, BDNF and C-reactive protein (CRP) were measured by immunoassays.

Results

Comparing FSL with the control Flinders Resistant Line (FRL), Apo-AI and Apo-AIV, α1-macroglobulin, glutathione peroxidase and complement-C3 were significantly modulated. Significant increases were detected in leptin, interleukin (IL) 1α and BDNF. CRP levels were significantly reduced.The impact of early-life stress was assessed by comparing FSL + MS versus FSL. Apo-E, α1-macroglobulin, complement-C3, transferrin and hemopexin were significantly modulated.The effect of stress in antidepressant response was then evaluated. In the comparison FSL + ESC + MS versus FSL + ESC, albumin, α1-macroglobulin, glutathione peroxidase and complement-C3 were modulated and significant reductions were detected in IL4, IL6, IL10, CRP and BDNF. By comparing FSL + NOR + MS versus FSL + NOR proteins like Apo-AIV, pyruvate dehydrogenase, α1-macroglobulin, transferrin and complement-C3 showed different levels.

Conclusions

Lipid metabolism and immunity proteins were differently expressed in FSL in comparison with FRL. Exposure to MS induced changes in inflammation and transport proteins which became apparent in response to antidepressant treatments. Modulated proteins could suggest biomarker studies in humans.     

Effect of oral anticoagulant therapy on thrombospondin-1 and von Willebrand factor in patients with stable heart failure

INTRODUCTION: Heart failure (HF) is associated with coagulation activation, abnormal inflammation and endothelial dysfunction. High levels of von Willebrand factor (VWF) may manifest endothelial dysfunction and hypercoagulable state. The haemostatic activity of VWF is a function of multimers size; only large multimers of VWF are haemostatically active. Thrombospondin-1 (TSP-1) reduces the average multimer size of VWF. Patients with HF are in risk of thromboembolic events and oral anticoagulation therapy (OAT) has been shown to prevent it. This study was designed to evaluate whether VWF and TSP-1 levels are modified by OAT in stable HF patients. The effect of OAT on markers of inflammation and coagulation was also investigated. MATERIALS AND METHODS: Fifty-nine patients with stable HF were studied and 33 of them received OAT. VWF, TSP-1, fibrinogen, prothrombin fragment 1+2 (F1+2), tissue factor (TF), D-dimer, endogenous thrombin generation (ETG), C reactive protein (CRP), tumour necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6) were measured. RESULTS: Stable HF patients receiving OAT had higher VWF (p=0.02) and lower TSP-1 (p=0.02), ETG and F1+2 (p=0.003) than patients without OAT. However, there were no significant differences in the levels of fibrinogen, TF, D-dimer, CRP, IL6 and TNFalpha. The TSP-1/VWF ratio in patients receiving AOT was significantly lower than in patients without OAT (p=0.005). CONCLUSION: OAT may have a dual effect on the haemostatic profile in stable HF by reducing thrombin generation and increasing the VWF. The decrease of TSP-1 induced by OAT may be clinically effective in neoangiogenesis. The increase of VWF in patients receiving anticoagulant treatment may also reflect an effect of OAT on endothelial dysfunction.     

Prognostic values of alpha2-macroglobulin, fibrinogen and albumin in regards to mortality and frailty in old rats

The study aimed to determine if acute phase proteins (APP) are markers of frailty in old rats. We evaluated in male Wistar rats at 96 weeks of age (n=72) whether single measurements of alpha(2)-macroglobulin, fibrinogen and albumin are predictive of mortality, body weight loss and inflammatory status during a 10-week follow-up period. Rats were clustered depending on levels of these APP at baseline. Rats with extremely high levels of alpha(2)-macroglobulin or fibrinogen (upper quartiles), or extremely low level of albumin (lower quartile), had an 11.6, 8.1 and 5.3-fold higher risk of mortality, respectively, than other rats. Body weight loss was negatively correlated with alpha(2)-macroglobulin, a trend was observed with fibrinogen (P=0.08) but not with albumin. Rats with fibrinogen levels >4.0 g/L or alpha(2)-macroglobulin levels >91 mg/L (respective top halves) at 96 weeks of age had higher levels of alpha(2)-macroglobulin and fibrinogen and lower levels of albumin throughout the follow-up period and higher levels of sTNFR-1 and lipopolysaccharide-binding protein at 106 weeks of age. Highest levels of alpha(2)-macroglobulin, fibrinogen and lowest albumin were predictive of mortality, whereas moderate levels of alpha(2)-macroglobulin and fibrinogen were, according to body weight loss and inflammatory status, markers of frailty in old rats.