Effect of Melatonin Administration on Mitochondrial Activity and Oxidative Stress Markers in Patients with Parkinson's Disease 2021ncbi.nlm.nih.gov/pmc/articl...
Abstract
Mitochondrial dysfunction and oxidative stress are extensively linked to Parkinson's disease (PD) pathogenesis. Melatonin is a pleiotropic molecule with antioxidant and neuroprotective effects. The aim of this study was to evaluate the effect of melatonin on oxidative stress markers, mitochondrial complex 1 activity, and mitochondrial respiratory control ratio in patients with PD. A double-blind, cross-over, placebo-controlled randomized clinical trial study was conducted in 26 patients who received either 25 mg of melatonin or placebo at noon and 30 min before bedtime for three months. At the end of the trial, in patients who received melatonin, we detected a significant diminution of lipoperoxides, nitric oxide metabolites, and carbonyl groups in plasma samples from PD patients compared with the placebo group. Conversely, catalase activity was increased significantly in comparison with the placebo group. Compared with the placebo group, the melatonin group showed significant increases of mitochondrial complex 1 activity and respiratory control ratio. The fluidity of the membranes was similar in the melatonin group and the placebo group at baseline and after three months of treatment. In conclusion, melatonin administration was effective in reducing the levels of oxidative stress markers and restoring the rate of complex I activity and respiratory control ratio without modifying membrane fluidity. This suggests that melatonin could play a role in the treatment of PD.
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The results of our double-blind, cross-over trial suggest the existence of an active, persistent oxidative stress status in PD that is linked to lower mitochondrial complex I activity in platelets. These data are in consonance with previously reported data in platelets [21, 22], muscle biopsy [23], and substantia nigra [24]. Free radicals are by-products of the mitochondrial respiratory chain and at low concentrations are involved in homeostasis and normal cell signaling. However, increased generation of reactive oxygen species is linked to PD and complex I is one of the main sites of electron leakage to oxygen which leads to the production of the superoxide anion [1, 25]. Furthermore, the assembly of mitochondrial supercomplexes is highly susceptible to oxidative stress. For example, oxidation of phospholipids (particularly, cardiolipin) induces the disaggregation of the supercomplex formed by complex I and complex III, loss of facilitated CoQ channeling, decreased ATP synthesis [26], increased production of reactive oxygen species [27], and favors the release of cytochrome c to cytosol leading to apoptosis [28]. Furthermore, the ratio of reduced CoQ to oxidized CoQ and the ratio of reduced CoQ to total CoQ were decreased significantly in novo PD patients [29]. Interestingly, oxidation of cardiolipin in the substantia nigra is enhanced by rotenone, an inhibitor of complex I, in a model of PD [30]. Therefore, it can be expected that inhibition of cardiolipin oxidation allows a correct functioning of the mitochondria. Accordingly, as shown in a model of PD, adequate levels of cardiolipin are crucial for efficient electron transport between CoQ and complex [31] and to maintain normal mitochondrial cristae structure and correct assembly of the electron chain supercomplexes [32].
Intervention with daily supplementation of 50 mg of melatonin, for three months, resulted in a significant reduction of oxidative stress markers. These data are according to the reported previously [6] and were paralleled with significant increases of catalase, complex I activity, and respiratory control ratio. In consonance, previous data showed that melatonin increases the levels of reduced glutathione [33], decreases malondialdehyde levels, and stimulates gene expression of important antioxidant enzymes such as superoxide dismutase, complex I, and catalase [34, 35] in rat models of PD. In addition, melatonin prevents cardiolipin loss and oxidation which avoids mitochondrial membrane permeabilization induced by reactive oxygen species and other factors [36]. Reduced glutathione levels are increased by melatonin action, and glutathione also contributes to maintain the correct mitochondrial redox status and the integrity of the mitochondrial membranes [37]. Melatonin also has anti-inflammatory effects by diminishing cyclooxygenase type 2 activity in PD patients [6] and in MPTP-induced PD in mice [38]. Additionally, melatonin lowers the activation of inducible nitric oxide synthase, a well-known pathological marker of neuroinflammation [39, 40], and also decreases protein lipase A2, lipoxygenase, and cytokine activities owing to its antioxidant actions [41]. Therefore, nitrosative stress and inflammation are diminished by the action of melatonin.
Herein, we find that administration of melatonin is capable of diminishing oxidative stress markers and restoring the enzymatic activity of complex I and the coupling between electron transport and phosphorylation (ATP synthesis) processes (i.e., the RCR). Interestingly, membrane fluidity was not modified by melatonin treatment. Consistent with this proposal, melatonin treatment prevented the loss of the integrity and function of the striatal mitochondria in a chronic model of PD by preserving the normal levels of ATP and mitochondrial respiration [26, 42], and the loss of the mitochondrial membrane potential that may trigger the activation of the permeability transition pore [43]. Furthermore, melatonin significantly decreased neuronal death and mitochondrial fragmentation in an in vitro model of PD [44, 45]. Interestingly, it has been proposed that melatonin physically interacts with complex I at its amphipathic ramp close to the site of electron leakage: the iron-sulfur cluster N2 [46], reverses the decrease in mitochondrial complex 1 activity that is induced by toxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [47], and upregulates the expression levels of subunits 1, 3 [48] ND1, ND2, ND4, and ND4L of complex I [49].
Taken together, our data showed that melatonin supplementation recovers mitochondrial function and diminishes oxidative stress. Thus, this indolamine could play a role as an adjuvant in the treatment of PD.
PD is a very complex syndrome, and there are multiple interactions of crucial phenomena such as intracellular mitochondrial dynamics, altered protein degradation, mitochondrial dysfunction, α-synuclein aggregation, calcium homeostasis, and impaired neurotransmitter function. Accordingly to that, a complete molecular map has been proposed that shows all the pathways involved in PD and covers everything from genes, molecules, and cells to metabolic alterations [50]. Considering the above, the limitations of our study were the lack of measurements of the effects of melatonin on some of these phenomena. However, our intention was to evaluate a small part of the mitochondrial defects associated with PD."
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