These results show that quercetin

These results show that quercetin can restore the enzyme activity of the cholinergic system nonneural induced by demyelination. The AChE activity has been used as an indicator of human cell aging with lowered levels commonly associated with older human red blood Clarithromycin [51]. The enzymes AChE and BuChE are reliable and robust markers of inflammation, and the measure of their activities could be potentially useful as a guide in predicting their development as well as the prognosis and response to the treatment of neurodegenerative diseases [52]. It is known that lymphocytes possess a complete cholinergic system including ACh, choline acetyltransferase, muscarinic and nicotinic receptors, and AChE enzyme [11], [53]. Acetylcholine synthesized and released from lymphocytes has been considered an immunomodulatory molecule, acting via both muscarinic and nicotinic receptors present in these cells [54], [55]. In the EB group, MDA contents were increased when compared with the control group. These results agree in part with those obtained in patients with MS, where oxidative stress parameters in blood and cerebrospinal fluid were consistently found to be increased [56], [57]. We observed a protective effect of quercetin on lipid peroxidation in the pons of demyelinated rats [17]. In this study, a similar effect was observed for the serum MDA content. The lipid peroxidation is considered an important pathophysiological marker to several neurodegenerative diseases [58], including demyelination diseases [1]. Oxidative stress is kept in check by a number of endogenous antioxidant enzymes, and it is likely that the balance of oxidative stress and antioxidant response mechanisms may be crucial in determining the degree of tissue injury. Of particular interest is SOD and CAT, which catalyze the detoxification of superoxide radical and hydrogen peroxide, respectively. An increase in the SOD activity induced by demyelination was observed, whereas a reduction in the CAT activity was observed during demyelination. Quercetin was able to restore the activity of these enzymes. This increase of SOD activity in the EB group could be associated with high production of superoxide radical as a response to inflammatory and oxidative stress present in the demyelination. In addition, an increase in SOD activity leads to a higher production of hydrogen peroxide. A decrease in CAT activity can show inefficiency in the enzymatic antioxidant system in detoxifying hydrogen peroxide. These results were in agreement with other authors that have shown lower CAT activity in MS [59], [60], [61] and in the EB demyelination model [62]. In contrast, it has been described that CAT enzymatic activity is elevated in patients with MS [63]. Erythrocytes of MS patients are more susceptible to cell lysis, and erythrocytes' membrane fluidity defects are closely interrelated with inflammation intensity and lipid peroxidation process in the demyelination episodes [64]. A study by Shah et al [65] showed similar changes in the oxidative status in the erythrocyte hemolysates obtained from patients with other autoimmune diseases, which suggests a significant increase in the level of lipid peroxidation, in agreement with what we found in our study. In the CNS, this pro-oxidative state is accompanied with an enhancement in the demyelization process, leading to a severe degree of neurologic injury [66], [67] due to lipid peroxidation–mediated chemical cross-linking and aggregation. The pro-oxidative state leads to the formation of new compounds and modified structures, among them, advanced oxidation protein products [68]. In conclusion, the results show that the demyelination model by EB promoted alterations in peripheral cholinergic signaling associated with an increase in oxidative stress. In addition, a worsening in Na+,K+-ATPase enzyme activity was also observed. The working hypothesis for the present research was that quercetin can protect Na+,K+-ATPase activity in the CNS, reestablish the peripheral cholinesterases activities, and reduce oxidative stress during demyelination events in rats. In line with our hypothesis, our findings reveal that quercetin is able to modulate the enzymes of the cholinergic system, reduce the lipid peroxidation, and restore the SOD, CAT, and Na+,K+-ATPase activities induced by demyelination. A better understanding of the underlying biology, an improvement in the design of clinical trials specifically made for assessing neuroprotection, and new technologies for developing novel therapies with natural compounds, such as quercetin, are necessary and will certainly contribute to new developments in this area of research.