**4. Glutathione system and multiple sclerosis**

**Figure 4.** Effect of nitric oxide in inflammation. Pathway Builder Online Tool was used to draw the figure [27].

chain by nitric oxide, which in turn causes a decrease in Na+

+

glutamate antagonist [10].

154 Trending Topics in Multiple Sclerosis

Paraclinical studies have shown an increased metabolism of the RNS in serum, lymphocytes, and cerebrospinal fluid of MS patients, which correlate to pathology studies. ONOO-

closely associated with acute inflammatory lesions [9]. Damage to axons is mediated by the following: (1) failure in mitochondrial energy metabolism due to inhibition of the respiratory

‐dependent glutamate transporters, (2) over‐expression of glutamate receptors, (3) oligoden‐ droglial excitotoxicity, (4) massive influx of extracellular Ca++, (5) activation of proteases, and (6) impaired axonal transport. These mechanisms produce glutamate excitotoxicity and increased generation of nitric oxide leading to nitrosative stress. Nitric oxide is a highly toxic element that by itself blocks nerve conduction, especially in demyelinated axons, and stimu‐ lates apoptosis. When nitric oxide is combined with the superoxide anion, it generates a potent free radical, the pro‐oxidant peroxynitrite. Glutamate in turn causes neurodegeneration through the AMPA and NMDA receptors in oligodendrocytes and astrocytes (**Figure 3**). It is possible to explain the role of mediators using an experimental model of autoimmune encephalitis: Protection against the experimental disease occurs after administration of a

Under physiologic conditions, nitric oxide is produced from L‐arginine by constitutive nitric oxide synthase (cNOS) and participates in a variety of important biological functions such as immunoregulation of inflammatory reactions, the downregulation of tumor necrosis factor (TNF)‐α production, MHC II expression in macrophages, induction of apoptosis in CD4 cells, physiological regulation of the mitochondrial respiratory chain, inhibition of antigen presen‐ tation, and leukocyte adhesion and migration. However, during inflammatory reactions, exposure of macrophages to interferon (IFN)‐γ and TNF‐α results in the activation of the

is also

/K+ ATPase activity and alters Na

In a recent study, the oxidation of DNA in the nucleus of oligodendrocytes and oxidation of lipids in the myelin of oligodendrocytes and axons were observed. This oxidation was associated with the active process of demyelination and neurodegeneration. Active lesions in relapsing‐remitting MS (RRMS) and progressive course patients were associated with inflammation, lipid peroxidation, and DNA oxidation [11]. Similarly, Ortiz et al. [12] observed an increase in serum lipid peroxides and nitrite/nitrate levels and the activity of glutathione peroxidase in patients with RRMS compared to healthy individuals.

Reduced ubiquinone and vitamin E levels, and reduced activity of the enzyme glutathione peroxidase in lymphocytes and granulocytes were reported (with a decrease in 51 and 78%, respectively), as well as a decrease in glutathione reductase activity in granulocytes (27%) and lymphocytes (8%) [13]. In contrast, in 2012, Tasset et al. [14] found an increase in activity of the glutathione reductase in patients with RRMS when compared to control subjects (1.3 ± 0.9 vs 0.3 ± 0.19, P < 0.01), and an increased ratio of reduced glutathione to oxidized glutathione (GSH/GSSG) in these patients (28.2 ± 39.6 vs 4.0 ± 2.9, P < 0.01). Similarly, an increase was found in the levels of oxidized glutathione and also increased concentrations of isoprostanes and malondialdehyde (MDA) in patients with MS [15, 16].

#### **4.1. Glutathione deficiency and multiple sclerosis**

There are several reports in the literature that relate the decrease or alteration of glutathione (GSH) metabolism with several neurodegenerative diseases. Biochemical analysis of postmor‐ tem brains has provided evidence for the generation of oxidative stress during the course of the disease since the total GSH content is reduced by 40–50% compared to controls. Also in several brain regions, we have found increased levels of lipid peroxidation [17]. The ratio GSH/ GSSG (usually 10:1) is considered consistent with the concept of oxidative stress as an important part in the pathogenesis of MS. Moreover, low concentrations of GSH appear to be an important indicator of oxidative stress during the progression of MS. Although the decrease in GSH alone is not responsible for the degeneration of glial cells and neurons, reduced GSH could increase the susceptibility to other stressful factors and contribute to neuronal damage at glia and neuron cells. Glutathione has been reported to protect mitochondrial complex I activity against nitrosative stress, as S‐nitrosoglutathione is formed. When this complex increases its content of nitrotyrosine and nitrosothiol groups in response to nitrosative stress, its activity is inhibited and therefore ATP production is diminished, which causes neuronal degeneration [10]. The role of glial cells in generating ROS in MS and the selective vulnerability of neurons is due to activated glial cells surrounding these neurons, as these glial cells are also directly involved in GSH levels. The engagement of the glutathione system in astroglial cells contributes to the reduction in its antioxidant defenses and so poor glial defense could contribute to existing neuronal damage (**Figure 5**) [10]. Furthermore, the specific activities of some enzymes that metabolize GSH are high, as in the case of glutathione peroxidase, glutathione reductase, and glutathione S‐transferase. Other products of OS are also elevated, as in the case of 4‐hydroxynonenal (4‐HNE, a product of lipid peroxidation of polyunsaturated omega‐6 fatty acids) [17].

**Figure 5.** Genetic defect in glutathione synthesis and neurodegenerative diseases. Pathway Builder Online Tool was used to draw the figure [27].

A new proposal is that a genetic defect of glutathione synthesis may be the initial event in the failure of the antioxidant defenses. In neurodegenerative diseases, a decreased GSH level is accompanied by dysfunction of the mitochondrial complex I and complex IV and promotes oxidative stress [18]. We found a significant decrease in GSH levels in the cerebrospinal fluid of patients with this disease, and, in addition, proton magnetic resonance studies have shown a 50% decrease in GSH levels in the frontal cortex of patients with MS (**Figure 5**).
