**6. Discussion and conclusion**

obtained from HTLV-1-infected individuals. This result suggested that the increase in CD69

mentation of GSH. Thus, increases in GSH levels could be beneficial to the activation of HTLV-

The neurodegeneration is associated with decontrolled inflammatory responses into the CNS. Inflammatory cytokines induce nitric oxide (NO) and ROS production for innate immune cells and microglial cells. The incubation of microglia cells in the presence of viral protein gp120 was observed to increase in ROS production [36]. Besides, gp120 induces secretion of tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), leading to neuronal cell death, subsequently [40]. The inflammatory microenvironment reduces the glutamate uptake, inducing accumulation of this excitatory amino acid and excitotoxic neurodegeneration. Although, any study has not related the viral infection, GSH intracellular levels, and excitotoxic neurodegeneration, the literature suggested that antioxidant

The strategy used to treat children with symptomatic CNS congenital CMV infection and immunosuppressed individuals CMV-infected is based on doses of ganciclovir. This is an acyclic deoxyguanosine nucleoside analogue [41]. In vivo *s*tudies using mice model infected with CMV demonstrated that the treatment with ganciclovir reduced a viral load and TNFα levels. Moreover, the results suggested that antiviral therapy suppressed the oxidative damage by downregulation of malondialdehyde and upregulation of GSH levels in mice serum [42]. Unfortunately, the role

No antiviral treatment intervention exists for HTLV-1 infection. The HAM/TSP treatment is limited to symptomatic therapy. Usually, symptomatic patients are treated with corticosteroid pulse therapy. During last decades the antiviral therapy against HIV was improved, resulting in a significant reduction AIDS-related mortality and increasing HIV-infected patient survival. The *h*ighly *a*ctive *a*ntiretroviral *t*herapy (HAART) is started with the combination of two nucleoside analogue transcriptase reverse inhibitors and one non-analogue nucleoside transcriptase reverse inhibitor or protease inhibitor plus ritonavir-boosted. The analysis of T

 lymphocytes obtained from the peripheral blood of HIV-1-infected patients showed an increase in GSH levels and decrease in GSSG levels during HAART at 1 year. In this study the patients received one protease inhibitor (indinavir or ritonavir) in combination with two nucleoside analogs (lamivudine plus zidovudine or plus stavudine), suggesting that the HAART ameliorates the oxidative alterations related with HIV-1 infection [43]. However, the effects of HAART on GSH levels may be different in other cell types. Human aortic endothelial cells pre-exposed to HAART produced higher levels of ROS than untreated cells after phorbol myristate acetate stimulation. After the HAART treatment, T-lymphocyte cell adhesion on human aortic endothelial cell monolayer increases significantly. However, the addition of NAC or GSH induced the inhibition of these effects, suggesting that the modulation of

of ganciclovir in CNS oxidative damage related with CMV infection remains unknown.

T cell and to the elimination of HTLV-1-infected cells [19].

responses can prevent the neuron death directly or indirectly.

antioxidant levels activated the endothelium [44].

**5. Effects of antiviral therapy in GSH levels in the CNS**

lymphocytes from HTLV-1 infected donors was correlated with an aug-

expression on CD8+

72 Glutathione in Health and Disease

1-specific CD8+

CD4+

In this chapter we explore some aspects about neurodegenerative diseases associated with viral infection, GSH, and oxidative stress. Worldwide, many individuals are afflicted by JC, CMV, HTLV-1, and HIV-1 and develop some neurological diseases. However, studies that describe how the oxidative stress is involved in disease development remain insufficient. The oxidative stress in the CNS is associated to many neurodegenerative diseases. ROS, including reactive nitrogen species, are important mediator of brain and spinal cord damage. They are related with inflammation and mitochondrial and proteasomal dysfunction. The vulnerability of the CNS is associated with the higher consumption of oxygen than other tissues. Oxygen is important in ATP generation process, which is responsible for energy support used during normal CNS function. Physiological ROS levels are essential to neuronal functions, such as enhancing synaptic plasticity, long-term potentiation, and memory formation. However, the brain endogenous antioxidant defenses have not been enough to your demand. Moreover, the complexity of the cell composition of this tissue and the elevated oxygen levels corroborate to elevated capacity of the CNS in ROS production. All cellular macromolecules are susceptible to oxidative harm. ROS level elevation activates the detoxification and repair pathways.

second messenger, modifying inflammatory gene transcription and, consequently, amplifying the inflammation. During reactive microgliosis an increase of GSSG levels is observed. Studies in Parkinson have been suggested that dopaminergic neurons from substance nigra can be

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

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

75

The glutathione transferase (GST) activity can be relate to sensibility of neurons of ROS. GSTs conjugate molecules, including xenobiotics, with GSH, and then, this conjugated molecules can be actively transported to extracellular medium by ABCC transporters. Moreover, GSTs are involved in c-Jun N-terminal kinase (JNK) signaling pathway. ROS causes GSTs-JNK-c-Jun complex formation blocking JNK signaling pathway and preventing the events associated with this signaling cascade. GST gene polymorphisms have been identified and produce an important impact in enzyme activity. Some studies demonstrated that GST gene polymorphism carries have a positive correlation with brain cancer, Alzheimer's disease, and Parkinson's disease development risk [54]. The positive correlation between GST gene polymorphisms and hepatocellular carcinoma caused by hepatitis B virus chronic infection [55] and uterine cancer associated to human papilloma virus infection was described [56] (**Figure 3**). However, the relationship between GST gene polymorphisms and viral diseases of the CNS remains

The major studies relating viral infection and glia cells have been developed in HIV-1 model infection. Microglial cells exposed to HIV viral protein Nef release IFNβ. Then, IFNβ induces iNOS expression and NO production [57]. Furthermore, HIV-1 protein Tat induces NADPH oxidase activity in astrocytes. ROS produced by NADPH oxidase activity was related to chemokine (CCL2, CXCL8, and CXCL10) production, and it was inhibited by the treatment of astrocytes with NAC or NADPH oxidase inhibitors [58]. Together these results suggested that the HIV infection induces glia cell activation, ROS, and RNS which are directly involved in production of inflammatory mediators. The imbalance of prooxidants induces oxidative

The studies in viral diseases of the CNS have suggested an important link between GSH, immune response, and antiviral response. The findings indicated that the GSH replenishment can be used in highly active antiviral treatment. However, in asymptomatic HTLV-1 carries, this clinical approach should be the opposite result. The importance to study the relationship

This work was supported by grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Oncobiologia Program. The author thanks Renata

Novaes and Raquel C. de Albuquerque to collaborate in GSH-related works.

associated to GSH deficiency, becoming these cells more vulnerable to ROS [53].

unknown.

stress and cell damage (**Figure 3**).

**Acknowledgements**

**Conflict of interest**

The authors declare no conflict of interests.

between GSH levels and viral neurological diseases is clear.

**Figure 3.** The imbalance of pro-oxidants induces oxidative stress and cell damage. The vulnerability of the CNS: ↓GSH and ↑O2 consumption. Inflammation triggers microglia. Activated microglia releases inflammatory cytokines, ROS, and RNS. Microglia and astrocytes can be activated via pattern recognition receptors. During astrocyte activation, these cells released ROS, RNS, and chemokines. In this microenvironment neurons presented macromolecule oxidation, mitochondrial disruption, and, consequently, cell death.

The failure in these processes produces oxidation of proteins; lipids and DNA; consequently, organelle dysfunction; and after that neuronal damage. The critical organelle affected is the mitochondria, whose disruption induces reduction in ATP generation and apoptosis or necrosis [51]. As previously described the viral infection induced an increase in ROS production directly in CNS cells or indirectly by the infiltrated activated immune system cells, which use ROS release as mechanism to control the infection (**Figure 3**).

Glial cells (astrocytes and microglia) play important roles in maintaining CNS homeostasis through some processes, including reduction of oxidative stress. During neurodegenerative disorder glial cells release some factors to reestablish integrity and repair damaged cells. However, during the chronic inflammation, the glial activation causes an increase of ROS production and other neurotoxic mediators, leading a neuronal damage [52]. The principal cell type involved in CNS inflammation is the microglia. Microglia expresses some pattern recognition receptors that are engaged by pathogen-associated molecular patterns, triggering microglia activation. Activated microglia produced inflammatory mediators, such as prostaglandin E2 , interleukin-1β TNFα, ROS (peroxide—H<sup>2</sup> O2 , superoxide—O<sup>2</sup> •−), and reactive species nitrogenous (RNS: NO; NOO\_ peroxynitrite). This phenomenon induces neuron damage. Damaged dopaminergic neurons release matrix metalloproteinase 3, α-synuclein, and neuromelanin that superactivated microglia, inducing reactive microgliosis, enhancing of the neurotoxicity-related mediators, such ROS (**Figure 3**). Moreover, ROS exerts an important effect on microglia as the second messenger, modifying inflammatory gene transcription and, consequently, amplifying the inflammation. During reactive microgliosis an increase of GSSG levels is observed. Studies in Parkinson have been suggested that dopaminergic neurons from substance nigra can be associated to GSH deficiency, becoming these cells more vulnerable to ROS [53].

The glutathione transferase (GST) activity can be relate to sensibility of neurons of ROS. GSTs conjugate molecules, including xenobiotics, with GSH, and then, this conjugated molecules can be actively transported to extracellular medium by ABCC transporters. Moreover, GSTs are involved in c-Jun N-terminal kinase (JNK) signaling pathway. ROS causes GSTs-JNK-c-Jun complex formation blocking JNK signaling pathway and preventing the events associated with this signaling cascade. GST gene polymorphisms have been identified and produce an important impact in enzyme activity. Some studies demonstrated that GST gene polymorphism carries have a positive correlation with brain cancer, Alzheimer's disease, and Parkinson's disease development risk [54]. The positive correlation between GST gene polymorphisms and hepatocellular carcinoma caused by hepatitis B virus chronic infection [55] and uterine cancer associated to human papilloma virus infection was described [56] (**Figure 3**). However, the relationship between GST gene polymorphisms and viral diseases of the CNS remains unknown.

The major studies relating viral infection and glia cells have been developed in HIV-1 model infection. Microglial cells exposed to HIV viral protein Nef release IFNβ. Then, IFNβ induces iNOS expression and NO production [57]. Furthermore, HIV-1 protein Tat induces NADPH oxidase activity in astrocytes. ROS produced by NADPH oxidase activity was related to chemokine (CCL2, CXCL8, and CXCL10) production, and it was inhibited by the treatment of astrocytes with NAC or NADPH oxidase inhibitors [58]. Together these results suggested that the HIV infection induces glia cell activation, ROS, and RNS which are directly involved in production of inflammatory mediators. The imbalance of prooxidants induces oxidative stress and cell damage (**Figure 3**).

The studies in viral diseases of the CNS have suggested an important link between GSH, immune response, and antiviral response. The findings indicated that the GSH replenishment can be used in highly active antiviral treatment. However, in asymptomatic HTLV-1 carries, this clinical approach should be the opposite result. The importance to study the relationship between GSH levels and viral neurological diseases is clear.
