**1. Introduction**

There are many infectious pathogens that are etiologic agent of central nervous system (CNS) diseases, including the broad categories of bacteria, fungi, parasites, and virus. These infections are an important cause of morbidity and mortality in the world. The viral CNS infections are associated with meningitis and encephalitis development principally. However, the viral infections also are related with diseases in the CNS characterized by the presence of leukocyte

© 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 IntechOpen. 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.

infiltration and inflammation, inducing a progressive damage [1], such as the progressive multifocal leukoencephalopathy with the John Cunningham virus (JC), AIDS-related dementia complex observed in HIV-1-infected patients, neurodevelopmental sequelae (mental retardation, cerebral palsy, and sensorineural hearing loss) caused by congenital cytomegalovirus (CMV) infection or cerebral mass lesions in immunocompromised adults CMV-infected, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) that affects the human T-cell lymphotropic virus type 1 (HTLV-1)-infected individuals.

untreatable and fatal. The relationship between progressive multifocal leukoencephalopathy and GSH still remains unknown. Moreover, JC virus has also been related with CNS tumors, astrocytomas, glioblastomas, neuroblastomas, and medulloblastomas in immunosuppressed and nonimmunosuppressed individuals [8]. However, GSH and GSH-related enzymes constitute an important mechanism of drug and multidrug resistance to glioblastomas, as described below [9]. CMV is a member of *beta*-herpesvirus subfamily, in the family Herpesviridae. It is the largest human herpesvirus, with a 230-kb ds DNA genome infection. Virus is spread from infected individual to noninfected individual by body fluids, such as urine, saliva, blood, tears, semen, and breast milk. In addition, a CMV-infected woman can pass the virus to her developing baby during pregnancy [10]. Congenital CMV infection causes serious neurodevelopmental sequelae, including mental retardation, cerebral palsy, and sensorineural hearing loss. CMV also is an increasingly important opportunistic pathogen in immunocompromised patients, inducing cerebral mass lesions. Antiviral therapy of children with symptomatic CNS congeni-

tal CMV infection is effective at reducing the risk of long-term disabilities [11].

O2

levels, leading an increase of H2

In muscle cells the CMV infection induces ROS production minutes after entry. This phenomenon is associated to the virus life cycle. The increase in ROS levels activates the transcriptional factor NF-κB, leading transactivation of the viral genes and inducing the transcription of viral proteins [12]. On the other hand, the infection induces increased levels of GSH to control the ROS generation in vitro. This GSH augment is essential to produce the viral progeny. These data suggested that CMV infection coordinates conditions where ROS levels should be controlled and oxidative stress minimized [13]. However, the CMV infection in peripheral blood erythrocytes of pregnant women induces reduced of GSH and GSH peroxidase

mia in pregnant women [14]. Although the CMV infection has been demonstrated in human brain cells in vitro*,* such as endothelial cells, astrocytes, neuronal cells, oligodendrocytes, and

HTLV-1 and HIV were classified to the genus *Lentivirus* within the family of Retroviridae, subfamily Orthoretrovirinae. This virus infects leukocytes, which circulate in the blood and lymphatic vessels and may infiltrate in the spinal cord or brain, inducing a neurological diseases [7]. These viruses can be transmitted vertically from mother to child during transplacental transfer, delivery, or breastfeeding, by sexual contact and parenterally through the transfusion of the blood, organ transplant, and blood components or through contaminated needles. HTLV-1 is the etiological agent of the adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic progressive disabling disease characterized by demyelination, axonal loss, neuronal degeneration, and gliosis. The main site of neurodegeneration is the thoracic spinal cord; this leads to a slowly progressive spastic paraparesis with low back pain and bowel, urinary, and sexual dysfunction. The treatment consists in diminishing the symptoms, using corticosteroid therapy [15, 16]. It was demonstrated that Tax, a HTLV-1-viral protein, induces an increase in ROS generation, causing DNA damage and cellular senescence [17]. Moreover, it was observed that the persistence of the virus in infected cells involves mitochondrial ROS production modulated by viral protein p13 [18]. The CD4+ T lymphocytes are the main targets of HTLV-1 infection, but it has been

microglia [11], these studies did not investigate the role of GSH in CMV infection.

levels. These effects were associated with hemolytic ane-

The Role of Glutathione in Viral Diseases of the Central Nervous System

http://dx.doi.org/10.5772/intechopen.76579

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In normal oxidative metabolism, the free radical formation is expected. During the 1950s, researchers observed the occurrence of reactive oxygen species (ROS) during molecule irradiation with X-rays and as an effect of normal enzyme metabolic activity. They started to propose that the formation of oxygen free radicals induced tissues and cell damage [2]. At the same time, it was suggested that the mice treatment with glutathione (GSH) inhibited the animal deaths caused by X-ray irradiation [2, 3].

GSH is a tripeptide synthesized in all mammalian cells from the amino acid precursors l-glutamate, l-cysteine, and glycine, through the reactions catalyzed by γ-glutamylcysteine and GSH synthetase. Physiologically, 98% of intracellular glutathione is found in reduced form, and only 2% is detected under oxidized form (GSSH) or joined with other molecules [4]. Glutathione (GSH) has an important role in cellular physiology and metabolism, including antioxidant activity and induction of cellular proliferation [5]. Furthermore, the GSHdependent antioxidant enzymes (glutathione peroxidase-1, glutathione reductase, glutathione S-transferase) cooperate and are interconnected reactions that eliminate ROS or controlled the redox state. Dysregulation of GSH synthesis was associated with many diseases, such as diabetes mellitus, cholestatic liver disease, endotoxemia, alcoholic liver disease, cancer, and neurodegenerative diseases. During aging the GSH content was decreased in the liver, lung, kidney, red blood cells, spleen lymphocytes, cerebral cortex, and cerebellum. This GSH concentration decline was related with the reduced expression of proteins involved in GSH synthesis. The GSH levels have been studied in Alzheimer's and Parkinson's diseases and others conditions [6]. However, the CNS is exposed to many situations that can induce a cell and tissue damage associated with ROS production. In this chapter, we will discuss some aspects of the balance of GSH levels and oxidative stress during viral infections in the CNS.
