**Multiple Sclerosis and Its Relationship with Oxidative Stress, Glutathione Redox System, ATPase System, and Membrane Fluidity**

Genaro G. Ortiz, Fermín P. Pacheco‐Moisés,

Erandis D. Torres‐Sánchez, Tanya E. Sorto‐Gómez,

Mario Mireles‐Ramírez, Alfredo León‐Gil,

Héctor González‐Usigli, Luis J. Flores‐Alvarado,

Erika D. González‐Renovato,

Angelica L. Sánchez‐López,

Margarita Cid‐Hernández and

Irma E. Velázquez‐Brizuela

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/64737

#### **Abstract**

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) with a focus on inflammation, demyelination, and damage to axons leading to neurological deficits. MS pathology is associated with excessive reactive oxygen species (ROS) and generation of reactive nitrogen species (RNS), causing oxidative/nitrosa‐ tive stress. Deregulation of glutathione homeostasis and alterations in glutathione‐ dependent enzymes are implicated in MS. Reactive oxygen species enhance both monocyte adhesion and migration across brain endothelial cells. In addition, ROS can activate the expression of the nuclear transcription factor‐kappa, which upregulates the expression of many genes involved in MS, such as tumor necrosis factor‐α and nitric oxide synthase, among others, leading to mitochondrial dysfunction and energy deficits that result in mitochondrial and cellular calcium overload. Loss of mitochondrial membrane potential can increase the release of cytochrome c, one pathway that leads to neuronal apoptosis. Clinical studies suggest that omega‐3 long‐chain polyunsaturat‐ ed fatty acids (PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti‐inflammatory, antioxidant, and neuroprotective effects in MS and animal models of MS. Here, we review the relationship of oxidative stress, the

© 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.

glutathione redox system, the ATPase system, and membrane fluidity with the development of MS. In addition, we describe the main findings of a clinical trial conducted with relapsing‐remitting MS patients who received a diet supplemented with 4 g/day of fish oil or olive oil. The effects of PUFAs supplementation on the parame‐ ters indicated above are analyzed in this work.

**Keywords:** multiple sclerosis, oxidative stress, mitochondria, membrane fluidity, AT‐ Pase

#### **1. Introduction**

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with partially known etiology. It is the most common cause of neurological disability in young adults. Nutrition is commonly accepted as one of the possible environ‐ mental factors involved in the pathogenesis of MS. Omega‐3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are fatty acids that possess several carbon–carbon double bonds. A diet supplemented with PUFAs has clinical and biochemical effects in patients with autoimmune diseases such as MS. Eicosapen‐ taenoic acid and DHA are found in high proportions in fish oil, and these molecules may have anti‐inflammatory, antithrombotic, antioxidant, immunomodulatory functions, and neuro‐ protective effects on the synaptogenesis and biogenesis of the neuronal membrane. Oxidative stress (OS) that is characterized by excessive production of reactive oxygen species and a reduction in antioxidant defense mechanisms have been implicated in the pathogenesis of MS. In consequence, a reduction in this phenomenon could be beneficial for MS patients [1]. In this work, we describe the relationship of several oxidative stress markers (glutathione redox system, mitochondrial ATPase activity, and membrane fluidity) with the development of MS. Furthermore, we describe the main findings of a clinical trial conducted with relapsing– remitting MS patients who received a diet supplemented with 4 g/day of fish oil or olive oil.

Pathologically, MS is characterized by perivenous infiltration of lymphocytes and macro‐ phages in the brain parenchyma. There are four clinical manifestations of MS: relapsing– remitting, primary progressive, secondary progressive, and progressive‐relapsing. The MS lesions are typically scattered, and the clinical picture can vary from a benign self‐limiting disorder to severe and highly disabling disease. MS is a multifactorial disease involving genetic, immunological, and environmental factors that trigger the autoimmune process leading to the pathological changes of the disease. In this regard, it has been proposed that a viral infection in which self‐antigens that generate molecular mimicry with myelin proteins cause a loss of tolerance against it, which results in the destruction of myelin mediated by activated T lymphocytes in white matter of the brain and sometimes extending into the gray matter, resulting in defects in the conduction of nerve impulses that leads to symptoms, depending on the affected site of the brain or spinal cord [1] (**Figure 1**).

According to the areas of myelin destruction, sensory or motor symptoms are affected (balance or vision disorders). The symptoms can change between an "outbreak" or relapse (emergence of new neurological symptoms or worsening of previous ones) and remission. Demyelinating lesions or "plaques" of different sizes and locations are spread throughout the CNS, and the onset of symptoms and response to treatment is unique to each patient [2].

glutathione redox system, the ATPase system, and membrane fluidity with the development of MS. In addition, we describe the main findings of a clinical trial conducted with relapsing‐remitting MS patients who received a diet supplemented with 4 g/day of fish oil or olive oil. The effects of PUFAs supplementation on the parame‐

**Keywords:** multiple sclerosis, oxidative stress, mitochondria, membrane fluidity, AT‐

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with partially known etiology. It is the most common cause of neurological disability in young adults. Nutrition is commonly accepted as one of the possible environ‐ mental factors involved in the pathogenesis of MS. Omega‐3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are fatty acids that possess several carbon–carbon double bonds. A diet supplemented with PUFAs has clinical and biochemical effects in patients with autoimmune diseases such as MS. Eicosapen‐ taenoic acid and DHA are found in high proportions in fish oil, and these molecules may have anti‐inflammatory, antithrombotic, antioxidant, immunomodulatory functions, and neuro‐ protective effects on the synaptogenesis and biogenesis of the neuronal membrane. Oxidative stress (OS) that is characterized by excessive production of reactive oxygen species and a reduction in antioxidant defense mechanisms have been implicated in the pathogenesis of MS. In consequence, a reduction in this phenomenon could be beneficial for MS patients [1]. In this work, we describe the relationship of several oxidative stress markers (glutathione redox system, mitochondrial ATPase activity, and membrane fluidity) with the development of MS. Furthermore, we describe the main findings of a clinical trial conducted with relapsing– remitting MS patients who received a diet supplemented with 4 g/day of fish oil or olive oil.

Pathologically, MS is characterized by perivenous infiltration of lymphocytes and macro‐ phages in the brain parenchyma. There are four clinical manifestations of MS: relapsing– remitting, primary progressive, secondary progressive, and progressive‐relapsing. The MS lesions are typically scattered, and the clinical picture can vary from a benign self‐limiting disorder to severe and highly disabling disease. MS is a multifactorial disease involving genetic, immunological, and environmental factors that trigger the autoimmune process leading to the pathological changes of the disease. In this regard, it has been proposed that a viral infection in which self‐antigens that generate molecular mimicry with myelin proteins cause a loss of tolerance against it, which results in the destruction of myelin mediated by activated T lymphocytes in white matter of the brain and sometimes extending into the gray matter, resulting in defects in the conduction of nerve impulses that leads to symptoms,

depending on the affected site of the brain or spinal cord [1] (**Figure 1**).

ters indicated above are analyzed in this work.

Pase

150 Trending Topics in Multiple Sclerosis

**1. Introduction**

**Figure 1.** Immune‐mediated destruction of myelin components in multiple sclerosis. Pathway Builder Online Tool was used to draw the figure [27].
