**The Role of Oxidants/Antioxidants, Mitochondrial Dysfunction, and Autophagy in Fibromyalgia Dysfunction, and Autophagy in Fibromyalgia**

**The Role of Oxidants/Antioxidants, Mitochondrial** 

DOI: 10.5772/intechopen.70695

Alejandra Guillermina Miranda-Díaz and Simón Quetzalcóatl Rodríguez-Lara Simón Quetzalcóatl Rodríguez-Lara Additional information is available at the end of the chapter

Alejandra Guillermina Miranda-Díaz and

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70695

#### **Abstract**

[77] Vermeer M, Kuper HH, van der Bijl AE, et al. The provision al ACR/EULAR definition of remission in RA: A comment on the patient global assessment criterion. Rheumatology.

[78] Gracely RH, Schweinhardt P. Key mechanisms mediating fibromyalgia. Clinical and

[79] Cagnie B, Coppieters I, Denecker S, et al. Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI. Seminars Arthritis Rheumatism.

Experimental Rheumatology. 2015;**33**(Suppl. 88):S3-S6

2012;**51**:1076-1080

12 Discussions of Unusual Topics in Fibromyalgia

2014;**44**:68-75

Fibromyalgia (FM) is a syndrome that presents primarily in women and is characterized by generalized pain, muscle rigidity, poor quality of sleep, fatigue, cognitive dysfunction, anxiety, episodes of depression, overall sensitivity, and deterioration in the performance of day-to-day activities. In the pathophysiology of fibromyalgia neuroendocrine factors, anomalies of the autonomous nervous system, genetic characteristics, and environmental and psychosocial factors are implicated. Alterations to the cells of the central nervous system that are present in fibromyalgia are due to the toxic effects of free radicals by the high concentrations of polyunsaturated fatty acids of the membranes that are easily oxidized and the low level of protective antioxidant enzymes. In FM, defects are produced in any part of the cycle in the generation of adenosine-5′-triphosphate (ATP) by the mitochondria, which can alter energy production by the mitochondria and cause the characteristic symptoms of FM. The degradation of the mitochondria dependent on autophagy or mitophagy is an important process for maintaining the critical integrity of the mitochondria and limiting the production of reactive oxygen species (ROS). Therefore, the deregulation of autophagy and mitochondrial dysfunction could represent key aspects in the pathophysiology of FM. Management with antioxidants, vitamins, coenzyme Q10, and melatonin, in addition to the antidepressants and structural analogs of the gamma-aminobutyric acid, could modify the florid symptomatology that patients with FM have.

**Keywords:** fibromyalgia, oxidative stress, mitochondrial dysfunction, autophagy, antioxidants, antioxidant vitamins

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1. Introduction**

#### **1.1. Fibromyalgia**

Fibromyalgia (FM) is a syndrome characterized by generalized pain, muscle rigidity, poor quality of sleep, fatigue, cognitive dysfunction, anxiety, episodes of depression, overall sensitivity, and deterioration in the performance of day-to-day activities [1, 2]. The incidence of FM is higher in women than in men in all decades of life, and it generally appears between 30 and 35 years of age [3, 4]. The prevalence of FM increases with age, reaching a maximum peak around the seventh decade. Fibromyalgia affects about 5% of the population worldwide [5]. According to the classification of the American College of Rheumatology, the definition of FM encompasses two variables: (a) bilateral pain above and below the waist with centralized pain and (b) chronic generalized pain for 3 months with pain on palpation in at least 11 of 18 specific body sites (sensitive spots) [6]. In the presentation of FM alterations to the central and autonomous nervous system, and alterations to the neurotransmitters, hormones, the external immune system, psychiatric conditions, and stress factors are involved [7]. Along with pain there are frequent disturbances in sleep, fatigue, morning rigidity, a subjective sensation of the accumulation of bodily fluids, paresthesias of the extremities, depression, headache, dizziness, and intestinal disturbances, which cause a decrease in quality of life [8]. The current review describes the oxidative stress, mitochondrial alterations, autophagy, antioxidants, and alternatives to the pharmacological management of FM.

10 and 20% in clinics for patients with rheumatic diseases, while in clinics not specialized for rheumatic illnesses the prevalence is >2.1–5.7% [15]. Amitriptyline is the most common prescription drug for the management of FM. Amitriptyline has the ability to influence the

The Role of Oxidants/Antioxidants, Mitochondrial Dysfunction, and Autophagy in Fibromyalgia

http://dx.doi.org/10.5772/intechopen.70695

15

Oxygen is used by the eukaryotic cells for metabolic transformations and the production of energy by the mitochondria. Under physiologic conditions, there is a beneficial endogenous production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that interact as signaling molecules in multiple physiological mechanisms (**Figure 1**). The ROS have bactericide activity of the phagocytes, act in the transduction of signals, and in the regulation of cellular growth and the redox state of the cell, among other mechanisms [17]. When the ROS or RNS are produced in excess or are not eliminated by the antioxidants, the oxidative stress with the capacity to damage the macromolecules (carbohydrates, proteins, lipids, DNA, and organelles) is produced [18, 19]. In relation to FM, it is important to mention that the cells of the central nervous system are highly vulnerable to the toxic effects of free radicals when

**Figure 1. Formation of reactive oxygen and nitrogen species in mitochondria.** The process is mediated by oxidative phosphorylation and the activity of the mitochondrial NO synthase: In physiological conditions, the production of ROS and RNS is reduced by multiple enzymatic scavengers that involved SOD, GPx, and catalase. When the mitochondria suffer an insult, the increase of the leakage of electrons to the matrix leads to an overload to the capacity of the enzymatic systems and leads to toxicity of the cell. Vectors of reactions and products. The physiological pathway for formation of

oxidative stress. Leakage of electron to matrix. Pathophysiological pathway for formation of ROS and RNS.

autonomic nervous system [16].

**2. Oxidative stress**

#### **1.2. Etiology**

The etiology and the pathophysiological mechanisms of FM are still unknown and continue to be a challenging clinical entity for researchers and clinicians [9]. Some studies suggest that the involvement of the hypothalamus-pituitary–adrenal axis and the autonomic nervous system in response to stress is present in patients who are vulnerable to suffering with FM or its symptoms [10]. Neuroendocrine factors, anomalies of the autonomic nervous system, genetic characteristics, environmental changes, psychosocial changes, and oxidative stress are involved in the pathophysiology of FM [11]. There is a high prevalence of FM among relatives of patients who also suffer from it, which is attributed to the combination of environmental and genetic factors [12]. Genetic studies suggest that the association with polymorphisms of the serotoninergic, dopaminergic, and catecholaminergic pathways found is implicated in the transmission and modulation of pain [11]. One theory of etiology suggests that infections are capable of activating inflammatory cytokines that could modify the central and peripheral perception of pain in FM. FM is characterized by chronic pain of unknown origin. Evidence suggests that sensitized neurons in the spinal cord of the dorsal horn are responsible for processing increased pain from peripheral nociceptive signals, glial activation, apparently by cytokines and excitatory amino acids that could play a role in the initiation and perpetuation of the pain due to acute or repetitive tissue injury [13]. Three FM subgroups have been described based on the predominant symptoms, depending on the following domains: psychosocial (depression/anxiety), cognitive (catastrophic/pain control), and neurobiology (sensitivity) [14]. The proportion of new patients with FM varies between 10 and 20% in clinics for patients with rheumatic diseases, while in clinics not specialized for rheumatic illnesses the prevalence is >2.1–5.7% [15]. Amitriptyline is the most common prescription drug for the management of FM. Amitriptyline has the ability to influence the autonomic nervous system [16].
