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Oxidative Stress Correlates with Headache Symptoms in Fibromyalgia: Coenzyme Q10 Effect on Clinical Improvement

  • Mario D. Cordero ,

    mdcormor@upo.es

    Affiliations Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC-Junta de Andalucía and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Sevilla, Spain, Departmento Citología e Histología Normal y Patológica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain

  • Francisco Javier Cano-García,

    Affiliation Departmento de Personalidad, Evaluación y Tratamiento Psicológicos. Facultad de Psicología Universidad de Sevilla, Sevilla, Spain

  • Elísabet Alcocer-Gómez,

    Affiliation Departmento de Personalidad, Evaluación y Tratamiento Psicológicos. Facultad de Psicología Universidad de Sevilla, Sevilla, Spain

  • Manuel De Miguel,

    Affiliation Departmento Citología e Histología Normal y Patológica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain

  • José Antonio Sánchez-Alcázar

    Affiliation Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC-Junta de Andalucía and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Sevilla, Spain

Oxidative Stress Correlates with Headache Symptoms in Fibromyalgia: Coenzyme Q10 Effect on Clinical Improvement

  • Mario D. Cordero, 
  • Francisco Javier Cano-García, 
  • Elísabet Alcocer-Gómez, 
  • Manuel De Miguel, 
  • José Antonio Sánchez-Alcázar
PLOS
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Abstract

Background

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 Q10 (CoQ10) supplementation on biochemical markers and clinical improvement were also evaluated.

Methods

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 CoQ10, catalase and lipid peroxidation (LPO) levels in BMCs. Bioenergetic status was assessed by measuring ATP levels in BMCs.

Results

We found decreased CoQ10, 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 CoQ10 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 CoQ10 supplementation restored biochemical parameters and induced a significant improvement in clinical and headache symptoms (P<0.001).

Discussion

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.

Introduction

Fibromyalgia (FM) is a common chronic pain syndrome with an unknown etiology, which has been associated with a wide spectrum of symptoms such as allodynia, debilitating fatigue, joint stiffness and depression. FM is diagnosed according to the classification criteria established by the American College of Rheumatology (ACR) [1]. Despite being a common disorder that affects at least 5 million individuals in the United States [2], its pathogenic mechanism remains elusive. In addition to the described symptoms, a high prevalence of FM has been found among patients with transformed migraine and headaches [3], [4]. Common genetic basis, synergetically working with other factors (emotional, personality features, stressful events and medication overuse) should cause a chronic antinociceptive system alteration and therefore a progressive increase (hyperalgesia) and diffusion (panalgesia) of pain. It has been hypothesized that episodic migraine, chronic daily headaches and FM may actually be a continuum of the same disorder [5].

Recently, oxidative stress has been proposed as a relevant event in the pathogenesis of FM and headaches [6], [7]. Previously, our group has detected decreased coenzyme Q10 (CoQ10) levels and increased mitochondrial reactive oxygen species (ROS) production in blood mononuclear cells (BMCs) from FM patients [8]. Furthermore, oxidative stress showed a significant correlation with clinical symptoms in FM [6].

CoQ10 levels and mitochondrial dysfunction have also been implicated in the pathophysiology of migraine, and it has been reported that oral CoQ10 supplementation improved clinical symptoms [9].

The aim of this paper was first to establish a possible correlation between oxidative stress parameters and severity of headaches in FM, and secondly to study the effects of oral CoQ10 supplementation on the improvement in headache symptoms.

Patients and Methods

Ethics Statement

Written informed consent and the approval of the ethical committee of University Pablo de Olavide and Universitary Hospital Virgen Macarena from Seville were obtained, according to the principles of the Declaration of Helsinki.

Patients

All samples were obtained after informed consent from patients and the approval of the local ethical committee was obtained according to the principles of the Declaration of Helsinki. The study consisted of 20 women diagnosed with FM and 15 healthy women. The inclusion criteria was fibromyalgia that had been diagnosed for the previous 2 to 3 years, based on the current ACR diagnostic criteria 1. Exclusion criteria were acute infectious diseases in the previous 3 weeks; past or present neurological, psychiatric, metabolic, autoimmune, allergy-related, dermal or chronic inflammatory disease; undesired habits (e.g., smoking, alcohol, etc.); oral diseases (e.g., periodontitis); medical conditions that required glucocorticoid treatment, use of analgesics, statin or antidepressant drugs; past or current substance abuse or dependence and pregnancy or current breastfeeding. Healthy controls had no signs or symptoms of FM and were free of any medication for at least 3 weeks before the study began. All patients and controls had taken no drugs or vitamin/nutritional supplement during the 3 week period prior to the collection of the blood samples. Before the study, the patients reported using paracetamol on demand. Clinical data was obtained from physical examination, and evaluated using the Fibromyalgia Impact Questionnaire (FIQ) including visual analogues scales about general and diffuse pain typical of FM (VAS), and Headache Impact Test (HIT-6).

Blood mononuclear cells

Heparinized blood samples were collected after 12-hours fasting from patients and healthy age and sex-matched control subjects. BMCs were purified from heparinized blood by isopycnic centrifugation using Histopaque-1119 and Histopaque-1077 (Sigma Chemical Co., St. Louis, MO, USA).

Measurement of CoQ10 levels

CoQ10 content in BMCs were analyzed by HPLC (Beckman Coulter, Brea, CA, USA; 166-126 HPLC) with ultraviolet detection (275 nm), according to the method described above [8].

Lipid peroxidation

Lipid peroxidation in cells was determined by analyzing the accumulation of lipoperoxides using a commercial kit from Cayman Chemical (Ann Arbor, Michigan, USA). TBARS are expressed in terms of malondialdehyde (MDA) levels. In these assays, an MDA standard is used to construct a standard curve against which unknown samples can be plotted.

Catalase determination

A spectrophotometric method described by Beer and Sizer (1952) [10] was used for measuring the breakdown of hydrogen peroxide by catalase. Briefly, activity was determined by using 35 µg of cell lysate, prepared in a lysis buffer composed of 0.9% NaCl, 20 mM Tris.ClH, pH = 7.6, 0.1% triton X-100, 1 mM phenylmethylsulfonylfluoride and 0.01% leupeptine with gentle shaking, in a kinetic spectrophotometric assay that measures a decrease in the absorbance of hydrogen peroxide.

ATP levels

ATP levels were determined by a bioluminescence assay using an ATP determination kit from Invitrogen-Molecular Probes (Eugene, OR, USA) according to the instructions of the manufacturer.

Oral CoQ10 supplementation

Ten volunteer patients were supplemented with CoQ10 (Pharma Nord, Vejle, Denmark) with soft gel capsules for 3 months (300 mg/day CoQ10 divided in three doses). After 3 months of treatment, heparinized blood samples were collected after 12-hours fasting and 24 hours after the last dose, and clinical symptoms were evaluated. The CoQ10 formulation consisted of soft gelatin capsules containing 100 mg of ubiquinone emulsified with diglyceryl monooleate, beeswax, soy lecithin and canola oil.

Statistical Analysis

All results