[Show abstract][Hide abstract] ABSTRACT: Depression is a major public health concern in modern society, yet little is known about the molecular link between this condition and neuroinflammation. The inflammasome complex was recently shown to be implicated in depression. The present study show the implication of NLRP3-inflammasome in animal model of stress-induced depression. Accordingly, we show here that in the absence of a NLRP3-inflammasome prolonged stress does not provoke depressive behaviors or microglial activation in mice, or dampen hippocampal neurogenesis. Indeed, NLRP3 deletion or inhibition of microglial activation impairs the stress-induced alterations associated with depression. According to these findings in animal model, the inflammasome could be a target for new therapeutic interventions to prevent depression in patients.
[Show abstract][Hide abstract] ABSTRACT: Aims: Impairment in AMP-activated protein kinase (AMPK) activity and NLRP3-inflammasome activation are associated with several metabolic and inflammatory diseases. Herein, we investigated the role of AMPK/NLRP3-inflammasome axis in the molecular mechanism underlying pain perception. Results: Impairment in AMPK activation induced by Compound C or sunitinib, two AMPK inhibitors, provoked hyperalgesia in mice (P<0.001) associated with marked NLRP3-inflammasome protein activation and increased serum levels of IL-1β (24.56±0.82 pg/mL) and IL-18 (23.83±1.882 pg/mL) compared to vehicle groups (IL-1β: 8.15±0.44; IL-18: 4.92±0.4). This effect was rescued by increasing AMPK phosphorylation via Metformin treatment (P<0.001), caloric restriction diet (P<0.001), or NLRP3-inflammasome genetic inactivation using NLRP3 knockout (nlrp3-/-) mice (P<0.001).
Deficient AMPK activation and over-activation of NLRP3-inflammasome axis was also observed in blood cells from patients with Fibromyalgia (FM), a prevalent human chronic pain disease. In addition, Metformin treatment (200mg/daily), which increased AMPK activation, restored all biochemical alterations examined by us in blood cells and significantly improved clinical symptoms such as, pain, fatigue, depression, disturbed sleep and tender points in patients with FM.
Innovations and Conclusions: These data suggest that AMPK/NLRP3-inflammasome axis participates in chronic pain and that NLRP3-inflammasome inhibition by AMPK modulation may be a novel therapeutic target to fight against chronic pain and inflammatory diseases as FM.
[Show abstract][Hide abstract] ABSTRACT: Coenzyme Q₁₀ (Co Q₁₀) or ubiquinone was known for its key role in mitochondrial bioenergetics as electron and proton carrier; later studies demonstrated its presence in other cellular membranes and in blood plasma, and extensively investigated its antioxidant role. These two functions constitute the basis for supporting the clinical indication of Co Q₁₀. Furthermore, recent data indicate that Co Q₁₀ affects expression of genes involved in human cell signalling, metabolism and transport and some of the effects of Co Q₁₀ supplementation may be due to this property. Co Q₁₀ deficiencies are due to autosomal recessive mutations, mitochondrial diseases, ageing-related oxidative stress and carcinogenesis processes, and also a secondary effect of statin treatment. Many neurodegenerative disorders, diabetes, cancer, fibromyalgia, muscular and cardiovascular diseases have been associated with low Co Q₁₀ levels. Co Q₁₀ treatment does not cause serious adverse effects in humans and new formulations have been developed that increase Co Q₁₀ absorption and tissue distribution. Oral Co Q₁₀ treatment is a frequent mitochondrial energizer and antioxidant strategy in many diseases that may provide a significant symptomatic benefit.
Frontiers in Bioscience 01/2014; 19:619-33. · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recently, Coenzyme Q10 (CoQ10) deficiency has been implicated in the pathophysiology of fibromyalgia (FM). It is our objective to present the findings of the FM evaluation before and after oral CoQ10 treatment using the American College of Rheumatology (ACR) Diagnostic Criteria of 1990 and 2010, and Symptom Checklist-Revised (Scl-90-R). Four patients with FM were examined using the trigger points, the Fibromyalgia Impact Questionnaire, visual analog scale (pain, fatigue, and sleep), Widespread Pain Index, symptom severity scale, and Scl-90-R. Previously, CoQ10 contents from patients were analyzed by high-performance liquid chromatography. All patients showed CoQ10 deficiency. All patients meet the ACR 1990 and 2010 criteria. After treatment, all patients showed an important improvement in clinical symptoms in all evaluation methods. According to our results, and evaluated by three methods, patients with FM are candidates for treatment with CoQ10. However, more controlled clinical trials and investigations are needed to clarify the precise mechanism(s) by which CoQ10 may contribute in pathological and therapeutic processes of FM and to provide data on its effectiveness in FM.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Major depressive disorder (MDD) is a very prevalent disease which pathogenic mechanism remains elusive. There are some hypotheses and pilot studies suggesting that cytokines may play an important role in MDD. In this respect, we have investigated the role of NLRP3 inflammasome complex in the maturation of caspase-1 and the processing of its substrates, IL-1β and IL-18, in blood cells from MDD patients.
Forty MDD patients were selected for this study, twenty without treatments and twenty treated with amitriptyline, a common tricyclic antidepressant. Blood samples from twenty healthy volunteers were included in the study. The inflammasome activation was studied by Western blot and real-time PCR of NLRP3 and caspase 1 and serum levels of IL-1β and 18.
We observed increased gene expression of NLRP3 and caspase-1 in blood cells, and increased serum levels of IL-1β and IL-18 in non-treated patients. IL-1β and IL-18 correlated with Beck Depression Inventory (BDI) scores of MDD patients. Interestingly, amitriptyline treatment reduced NLRP3 and caspase-1 gene expression, and IL-1β and IL-18 serum levels. As it is well established that oxidative stress is associated with NLRP3 inflammasome activation, we next studied mitochondrial ROS and lipid peroxidation (LPO) levels in MDD patients. Increased levels of mitochondrial ROS and LPO were observed in MDD patients, however oxidative damage was higher in MDD patients treated with amitriptyline.
These findings provide new insight into the pathogenesis of MDD and the effects of amitriptyline treatment on NLRP3 inflammasome activation and IL-1β and IL-18 serum levels.
Brain Behavior and Immunity 10/2013; DOI:10.1016/j.bbi.2013.10.017 · 5.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims:
Fibromyalgia (FM) is a prevalent chronic pain syndrome characterized by generalized hyperalgesia associated with a wide spectrum of symptoms such as fatigue and joint stiffness. Diagnosis of FM is difficult due to the lack of reliable diagnostic biomarkers, while treatment is largely inadequate. We have investigated the role of coenzyme Q10 (CoQ10) deficiency and mitochondrial dysfunction in inflammasome activation in blood cells from FM patients, and in vitro and in vivo CoQ10 deficiency models.
Mitochondrial dysfunction was accompanied by increased protein expression of interleukin (IL)-1β, NLRP3 (NOD-like receptor family, pyrin domain containing 3) and caspase-1 activation, and an increase of serum levels of proinflammatory cytokines (IL-1β and IL-18). CoQ10 deficiency induced by p-aminobenzoate treatment in blood mononuclear cells and mice showed NLRP3 inflammasome activation with marked algesia. A placebo-controlled trial of CoQ10 in FM patients has shown a reduced NLRP3 inflammasome activation and IL-1β and IL-18 serum levels.
These results show an important role for the NLRP3 inflammasome in the pathogenesis of FM, and the capacity of CoQ10 in the control of inflammasome.
These findings provide new insights into the pathogenesis of FM and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.
[Show abstract][Hide abstract] ABSTRACT: Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Its pathophysiological mechanisms are difficult to identify and current drug therapies demonstrate limited effectiveness. Both mitochondrial dysfunction and coenzyme Q10 (CoQ10) deficiency have been implicated in FM pathophysiology. We have investigated the effect of CoQ10 supplementation. We carried out a randomized, double-blind, placebo-controlled trial to evaluate clinical and gene expression effects of forty days of CoQ10 supplementation (300mg/day), in twenty FM patients. This study was registered with controlled-trials.com (ISRCTN 21164124). An important clinical improvement was shown after CoQ10 vs placebo treatment showing a reduction of FIQ (P<0.001), and a most prominent reduction in pain (P<0.001), fatigue and morning tiredness (P˂0.01) subscales from FIQ. Furthermore, we observed an important reduction in pain visual scale (P<0.01) and a reduction in tender points (P<0.01), including recovery of inflammation, antioxidant enzymes, mitochondrial biogenesis and AMPK gene expression levels, associated with phosphorilation of AMPK activity. These results lead to the hypothesis that CoQ10 have a potential therapeutic effect in FM, and indicate new potential molecular targets for the therapy of this disease. AMPK could be implicated in the pathophysiology of FM.
[Show abstract][Hide abstract] ABSTRACT: In order to analyze the association between body mass index (BMI), lipid profile and clinical symptoms in patients with fibromyalgia, we assessed BMI levels, lipid profile and its association with clinical symptoms in 183 patients with fibromyalgia. The patients were evaluated using tender points, FIQ and Visual Analogue Scales of pain (VAS). Serum lipid profile analysis (total cholesterol, triglyceride, HDL, LDL and VLDL), and biochemical parameters were measured in the biochemistry laboratory. The BMI distribution of the nonobese, overweight and obese patients' groups were relatively even with 37.7, 35.5 and 26.8 %, respectively, with a mean BMI of 27.3 ± 4.9. The number of tender points showed significantly positive correlation with higher BMI (P < 0.05). A total of 57.9 % of patients showed increased levels of total cholesterol, 63.4 % increased levels of LDL cholesterol and 19.9 % high levels of triglycerides. BMI, total cholesterol and triglycerides showed high association with some clinical parameters. Overweight and lipid profile could be associated with fibromyalgia symptoms. A treatment program with weight loss strategies, and control in diet and increased physical activity is advised to patients.
Rheumatology International 01/2013; 34(3). DOI:10.1007/s00296-012-2647-2 · 1.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology and a wide spectrum of symptoms such as allodynia, debilitating fatigue, joint stiffness and migraine. Recent studies have shown some evidences demonstrating that oxidative stress is associated to clinical symptoms in FM of fibromyalgia. We examined oxidative stress and bioenergetic status in blood mononuclear cells (BMCs) and its association to headache symptoms in FM patients. The effects of oral coenzyme Q(10) (CoQ(10)) supplementation on biochemical markers and clinical improvement were also evaluated.
We studied 20 FM patients and 15 healthy controls. Clinical parameters were evaluated using the Fibromyalgia Impact Questionnaire (FIQ), visual analogues scales (VAS), and the Headache Impact Test (HIT-6). Oxidative stress was determined by measuring CoQ(10), catalase and lipid peroxidation (LPO) levels in BMCs. Bioenergetic status was assessed by measuring ATP levels in BMCs.
We found decreased CoQ(10), catalase and ATP levels in BMCs from FM patients as compared to normal control (P < 0.05 and P < 0.001, respectively) We also found increased level of LPO in BMCs from FM patients as compared to normal control (P < 0.001). Significant negative correlations between CoQ(10) or catalase levels in BMCs and headache parameters were observed (r = -0.59, P < 0.05; r = -0.68, P < 0.05, respectively). Furthermore, LPO levels showed a significant positive correlation with HIT-6 (r = 0.33, P<0.05). Oral CoQ(10) supplementation restored biochemical parameters and induced a significant improvement in clinical and headache symptoms (P < 0.001).
The results of this study suggest a role for mitochondrial dysfunction and oxidative stress in the headache symptoms associated with FM. CoQ10 supplementation should be examined in a larger placebo controlled trial as a possible treatment in FM.
PLoS ONE 04/2012; 7(4):e35677. DOI:10.1371/journal.pone.0035677 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Amitriptyline is a commonly prescribed tricyclic antidepressant, which has been shown to impair mitochondrial function and increase oxidative stress in a variety of in vitro assays. Coenzyme Q(10) (CoQ(10)), an essential component of the mitochondrial respiratory chain and a potent antioxidant, has been proposed as a mitochondrial dysfunction marker. In order to evaluate the putative mitochondrial toxicity of amitriptyline, we have analyzed CoQ(10) and ATP levels, oxidative damage and mitochondrial mass in peripheral blood cells from control healthy volunteers and psychiatric patients with depressive episodes treated or non-treated with amitriptyline. In patients not following amitriptyline treatment, CoQ(10) and ATP levels and mitochondrial mass were reduced when compared to normal individuals while lipid peroxidation was clearly increased. All these alterations were aggravated in patients following oral amitriptyline therapy. These results suggest that mitochondrial dysfunction could be involved in the pathophysiology of depression and may be worsened by amitriptyline treatment. CoQ(10) supplementation is postulated to counteract the adverse effects of amitriptyline treatment in psychiatric patients.
Journal of Psychiatric Research 11/2011; 46(3):341-5. DOI:10.1016/j.jpsychires.2011.11.002 · 3.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We examined lipid peroxidation (LPO) in blood mononuclear cells (BMCs) and plasma, as a marker of oxidative damage, and its association to clinical symptoms in Fibromyalgia (FM) patients.
We conducted a case-control and correlational study comparing 65 patients and 45 healthy controls. Clinical parameters were evaluated using the Fibromyalgia Impact Questionnaire (FIQ), visual analogues scales (VAS), and the Beck Depression Inventory (BDI). Oxidative stress was determined by measuring LPO in BMCs and plasma.
We found increased LPO levels in BMCs and plasma from FM patients as compared to normal control (P<0.001). A significant correlation between LPO in BMCs and clinical parameters was observed (r = 0.584, P<0.001 for VAS; r = 0.823, P<0.001 for FIQ total score; and r = 0.875, P<0.01 for depression in the BDI). We also found a positive correlation between LPO in plasma and clinical symptoms (r = 0.452, P<0.001 for VAS; r = 0.578, P<0.001 for FIQ total score; and r = 0.579, P<0.001 for depression in the BDI). Partial correlation analysis controlling for age and BMI, and sex, showed that both LPO in cells and plasma were independently associated to clinical symptoms. However, LPO in cells, but not LPO in plasma, was independently associated to clinical symptoms when controlling for depression (BDI scores).
The results of this study suggest a role for oxidative stress in the pathophysiology of fibromyalgia and that LPO in BMCs rather than LPO in plasma is better associated to clinical symptoms in FM.
PLoS ONE 10/2011; 6(10):e26915. DOI:10.1371/journal.pone.0026915 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Coenzyme Q(10) (CoQ(10)) is an essential electron carrier in the mitochondrial respiratory chain and a strong antioxidant. Low CoQ(10) levels have been detected in patients with Fibromyalgia (FM). The purpose of the present work was to assess the effect of CoQ(10) on symptoms of five patients with FM. Patients were evaluated clinically with Visual Analogical Scale of pain (VAS), and Fibromyalgia Impact Questionnaire (FIQ). Patients with CoQ(10) deficiency showed a statistically significant reduction on symptoms after CoQ(10) treatment during 9 months (300 mg/day). Determination of deficiency and consequent supplementation in FM may result in clinical improvement. Further analysis involving more scientifically rigorous methodology will be required to confirm this observation.
[Show abstract][Hide abstract] ABSTRACT: Fibromyalgia (FM) is a chronic pain syndrome of unknown etiology, which affects predominantly women. Among the alterations that have been implicated in the pathophysiology of FM, there have been postulated disturbances in serotonin levels and metabolism, and their implication in symptoms. The aim of the present study was to assess the correlation levels between low levels of serotonin and severity of symptoms in FM.
We determined serotonin levels using an ELISA kit in serum from 38 FM patients and 25 healthy individual. Results were correlated with symptoms regarding pain, depression, impact of disease (FIQ) and age.
Serotonin levels were decreased by 45% compared to healthy individual. An important correlation was observed between serotonin levels and predetermined parameters of pain, depression, FIQ and age.
Serotonin levels are correlated with severity of FM. In addition, there is an interesting correlation between serotonin levels and age of patients.