Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, being characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. ...Among several putative factors that may contribute to PD pathogenesis, inflammatory mechanisms may play a pivotal role. The involvement of microglial activation as well as of brain and peripheral immune mediators in PD pathophysiology has been reported by clinical and experimental studies. These inflammatory biomarkers evaluated by imaging techniques and/or by biological sample analysis have become valuable tools for PD diagnosis and prognosis. Regardless of the significant increase in the number of people suffering from PD, there are still no established disease-modifying or neuroprotective therapies for it. There is growing evidence of protective effect of anti-inflammatory drugs on PD development. Herein, we reviewed the current literature regarding the central nervous system and peripheral immune biomarkers in PD and advances in diagnostic and prognostic tools as well as the neuroprotective effects of anti-inflammatory therapies.
The renin angiotensin system (RAS) plays an important role in inflammation and fibrosis. The classical axis of the RAS, formed by angiotensin converting en-zyme (ACE), angiotensin II (Ang II) and ...angiotensin receptor type 1 (AT1), activates several cell functions and molecular signaling pathways related to tissue injury, inflammation and fibrosis. In sharp contrast, the RAS axis composed by angiotensin converting enzyme 2 (ACE2), angiotensin-(1-7) and Mas receptor exerts opposite effects in relation to inflammatory response and tissue fibrosis.
In this review, we have the aim to summarize recent findings on the anti-inflammatory and anti-fibrogenic role of ACE2/Ang-(1-7)/Mas axis in the context of basic research, experimental human dis-eases and clinical studies.
Several studies showed that ACE2/Angiotensin-(1-7)/Mas axis reduces cytokine release and inhibits signaling pathways of tissue fibrosis in experimental models of human diseases including atherosclerosis, cerebral ischemia, obesity, chronic kidney disease, liver diseases and asthma. On the other hand, very few data was provided by clinical studies.
Experimental studies clearly support the anti-inflammatory and anti-fibrotic effects of ACE2/ Ang-(1-7)/Mas axis. Clinical studies, especially phase III and IV trials, will be necessary to establish the therapeutic role of ACE2/Ang-(1-7)/Mas axis in controlling inflammation in different human diseases.
Atrial fibrillation (AF), the most common arrhythmia in clinical practice, is associated with an increase in mortality and morbidity due to its high potential to cause stroke and systemic ...thromboembolism. Inflammatory mechanisms may play a role in the pathogenesis of AF and its maintenance. We aimed to evaluate a range of inflammatory markers as potentially involved in the pathophysiology of individuals with nonvalvular AF (NVAF). A total of 105 subjects were enrolled and divided into two groups: patients with NVAF (n = 55, mean age 72 ± 8 years) and a control group of individuals in sinus rhythm (n = 50, mean age 71 ± 8 years). Inflammatory-related mediators were quantified in plasma samples by using Cytometric Bead Array and Multiplex immunoassay. Subjects with NVAF presented significantly elevated values of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF), interferon-gamma, growth differentiation factor-15, myeloperoxidase, as well as IL-4, interferon-gamma-induced protein (IP-10), monokine induced by interferon-gamma, neutrophil gelatinase-associated lipocalin, and serum amyloid A in comparison with controls. However, after multivariate regression analysis adjusting for confounding factors, only IL-6, IL-10, TNF, and IP-10 remained significantly associated with AF. We provided a basis for the study of inflammatory markers whose association with AF has not been addressed before, such as IP-10, in addition to supporting evidence about molecules that had previously been associated with the disease. We expect to contribute to the discovery of markers that can be implemented in clinical practice hereafter.
► Plasma levels of GDNF were investigated in bipolar disorder (BD) type I patients and matched controls. ► Hypothesis: BD is associated with altered circulating levels of GNDF. ► BD patients in ...euthymia had increased plasma levels of GDNF and these levels were correlated with age and the severity of manic symptoms.
Neurotrophic factors regulate the survival and growth of neurons, and influence synaptic efficiency and plasticity. Several studies suggest the existence of a relationship between changes in neurotrophic levels and bipolar disorder (BD). The glial cell-line derived neurotrophic factor (GDNF) influences monoaminergic neurons and glial cells, but its role in BD patients is controversial. In order to elucidate it we evaluated plasma levels of GDNF in a sample of 70 BD patients (35 in mania and 35 in euthymia) and compared with 50 healthy controls matched for age, gender and educational levels. GDNF plasma levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients were assessed by a Mini-International Neuropsychiatric Interview (MINI-plus), Young Mania and Hamilton Depression Rating Scales. Plasma GDNF levels were significantly increased in BD patients in euthymia compared with BD patients in mania and healthy controls (p<0.05). GDNF plasma levels were correlated with age (ρ=0.30, p<0.05) and negatively correlated with manic symptoms in BD patients (ρ=−0.54, p<0.05). Our results provide evidence that peripheral levels of GDNF are related with different mood states in BD, reinforcing the involvement of neurotrophic factors in its physiopathology.
Illustration summarizing the major findings of the current work.
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•Intranasal MPTP infusion is a suitable model for prodromal PD.•MPTP mice display olfactory discrimination and social ...memory impairment.•MPTP mice present compulsive and anxiety-like behaviors.•Intranasal MPTP infusion induces enhanced levels of IL-17A in the SNpc.•Intranasal MPTP infusion induces decreased levels of BDNF in the SNpc.
Recent evidence has supported a pathogenic role for neuroinflammation in Parkinson’s disease (PD). Inflammatory response has been associated with symptoms and subtypes of PD. However, it is unclear whether immune changes are involved in the initial pathogenesis of PD, leading to the non-motor symptoms (NMS) observed in its prodromal stage. The current study aimed to characterize the behavioral and cognitive changes in a toxin-induced model of prodromal PD-like syndrome. We also sought to investigate the role of neuroinflammation in prodromal PD-related NMS. Male mice were subjected to bilateral intranasal infusion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or saline (control group), followed by comprehensive behavioral, pathological and neurochemical analysis. Intranasal MPTP infusion was able to cause the loss of dopaminergic neurons in the substantia nigra (SN). In parallel, it induced impairment in olfactory discrimination and social memory consolidation, compulsive and anxiety-like behaviors, but did not influence motor performance. Iba-1 and GFAP expressions were increased in the SN, suggesting an activated state of microglia and astrocytes. Consistent with this, MPTP mice had increased levels of IL-10 and IL-17A, and decreased levels of BDNF and TrkA mRNA in the SN. The striatum showed increased IL-17A, BDNF, and NFG levels compared to control mice. In conclusion, neuroinflammation may play an important role in the early stage of experimental PD-like syndrome, leading to cognitive and behavioral changes. Our results also indicate that intranasal administration of MPTP may represent a valuable mouse model for prodromal PD.
The etiology of Parkinson's disease (PD) is complex and not fully understood, most probably because of the multiplicity of factors involved. Inflammatory and abnormal immune responses have been ...hypothesized to play a crucial role in PD. Not only in the brain, but also peripherally, inflammation is believed to contribute to the onset and progression of the neurodegenerative process seen in PD. Furthermore, increased inflammatory responses have been described both in the brain and peripheral blood of PD subjects. Although PD is considered a motor disorder, nonmotor symptoms are extremely frequent and disabling. Cognitive impairment and mood alterations are such symptoms that deserve increased attention since on the one hand they can appear even before typical motor disturbances are recognized, and on the other hand they are associated with high morbidity and mortality. A growing body of evidence suggests the existence of a link between inflammatory-immune responses and the occurrence of depression and cognitive impairment in PD patients. However, not all data are equally conclusive and are sometimes even conflicting. The aim of this brief review is to give an overview of the possible role that inflammation and immunomodulation may play in PD together with their putative impact on mood and cognitive alterations. What clearly emerges from this work is the fact that studies performed until now lack standardized and comparable methods to analyze both clinical and biological parameters. It is thus difficult to conclusively link mood and cognitive changes to underlying pathological mechanisms. Additional studies in this direction are warranted to convincingly establish or refute any causative relation.
To investigate the influence of interleukin-6 (IL-6) and soluble tumor necrosis factor receptors (sTNFR) in fatigued Parkinson's disease (PD) patients. Forty-four PD patients were evaluated, and ...fatigue was assessed with the Parkinson Fatigue Scale. Logistic regression analysis was used to evaluate the contribution of disease severity scores and cytokine levels on fatigue scores. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic values of IL-6 in fatigue. Fatigued PD patients had worse cognitive function and depressive symptoms. These patients had worse PD signs and symptoms, displayed more advanced stages of PD, and had greater functional dependence. There was a significant difference in IL-6 serum levels (p=0.026), but there was no difference in sTNFR levels. Total scores on the Unified Parkinson Disease Rating Scale (β=1.108; p=0.004) and IL-6 levels (β=12.843; p=0.020) were found to be significant predictors of fatigue scores. A ROC curve revealed that IL-6 concentrations of 1.18pg/ml represented the best cut-off value for detecting fatigue (sensitivity of 0.941 and specificity of 0.704). Fatigued PD patients have poor clinical outcomes and elevated IL-6 serum levels when compared with non-fatigued patients. These results suggest that IL-6 may play a role in the pathophysiology of fatigue in PD.
•Fatigue is a common problem in Parkinson's disease.•Fatigue is associated with poor clinical outcomes in Parkinson's disease.•IL-6 serum levels are elevated in fatigued Parkinson's disease patients.
Abstract Background Schizophrenia (SZ) has been associated with an imbalance in the inflammatory cytokine TNF-α. The objectives of this study were to compare TNF-α and its soluble receptors' serum ...levels in individuals with SZ with the levels found in a group of healthy volunteers and to investigate the possible association between these biomarkers and the dimensions and severity of symptoms, clinical outcomes and response to treatment in patients with SZ. Methods Fifty-four chronically medicated SZ outpatients and 118 healthy controls were included in the study. TNF-α levels were measured by Cytometric Bead Assay (CBA), and serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1) and soluble tumor necrosis factor receptor 2 (sTNFR2) were measured by ELISA. Results sTNFR1 and sTNFR2 were significantly elevated in patients with SZ as compared to the healthy control group. In the group of individuals with SZ, the levels of both types of soluble TNF receptors showed a negative correlation with global functioning. sTNFR1 levels were higher in the treatment-resistant patients as compared to the non-treatment-resistant patients and the controls. sTNFR1 levels were also heightened in patients with SZ and concomitant depression. Conclusion Our findings reinforce that SZ is associated with an inflammatory profile and suggest that sTNFR1 is a marker of a treatment-resistance and severe clinical course in SZ.
The etiopathogenesis of autism spectrum disorders (ASD) is largely unknown, but it seems to involve dysfunction in several biological systems. Among many possible biological pathways, the immune ...system has emerged as potentially involved. Recent studies have shown association between cytokines (molecules that mediate immune cell interaction) and ASD. Adipokines are cytokines secreted mainly by adipose tissue and may have systemic effects. The main objective of this study was to compare the plasma levels of three adipokines between patients with ASD and healthy controls. Another aim was to correlate the levels of these adipokines and the severity of autistic symptoms as measured by the Social Responsiveness Scale (SRS).
We collected plasma from 30 patients and 19 controls and measured the levels of adiponectin, leptin and resistin using a commercially available kit. We also used the SRS as a tool to assess the severity of autistic symptoms.
We found decreased levels of resistin, increased levels of leptin and unaltered levels of adiponectin in plasma from ASD subjects in comparison with controls. There was also a negative correlation between the levels of adiponectin and the severity of symptoms as assessed by the SRS.
There are significant changes in the plasma levels of adipokines from patients with ASDs. They suggest the occurrence of systemic changes in ASD and may be hallmarks of the disease.
Objectives. To evaluate the association between inflammatory biomarkers, neurotrophic factors, birth conditions, and the presence of motor development abnormalities in preterm neonates. Methods. ...Plasma and urinary levels of cytokines (IL-1β, IL-6, IL-10, TNF, and IL-12p70), chemokines (CXCL8/IL-8, CCL2/MCP-1, CCL5/RANTES, CXCL10/IP-10, and CXCL9/MIG), and neurotrophic factors (BDNF and GDNF) were evaluated in 40 preterm neonates born between 28 and 32 incomplete weeks of gestation, at four distinct time points: at birth (umbilical cord blood) (T0), at 48 (T1), at 72 hours (T2), and at 3 weeks after birth (T3). Biomarkers levels were compared between different time points and then associated with Test of Infant Motor Performance (TIMP) percentiles. Results. Maternal age, plasma, and urinary concentrations of inflammatory molecules and neurotrophic factors were significantly different between groups with normal versus lower than expected motor development. Higher levels of GDNF were found in the group with lower than expected motor development, while IL-1β and CXCL8/IL-8 values were higher in the group with typical motor development. Conclusion. Measurements of cytokines and neurotrophic factors in spot urine may be useful in the follow-up of motor development in preterm neonates.
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