Melatonin As A Coadjuvant in The Treatment Of Patients With Fibromyalgia Part 2
Oct 08, 2023
2.8. Novel Findings in Therapies According to Animal Models of FMS
To estimate whether alternative and/or complementary medical treatments may improve the results of this disorder, recent studies have considered that pharmacological interventions provide variable benefits and common side effects [133].
Cistanche can act as an anti-fatigue and stamina enhancer, and experimental studies have shown that the decoction of Cistanche tubulosa could effectively protect the liver hepatocytes and endothelial cells damaged in weight-bearing swimming mice, upregulate the expression of NOS3, and promote hepatic glycogen synthesis, thus exerting anti-fatigue efficacy. Phenylethanoid glycoside-rich Cistanche tubulosa extract could significantly reduce the serum creatine kinase, lactate dehydrogenase, and lactate levels, and increase the hemoglobin (HB) and glucose levels in ICR mice, and this could play an anti-fatigue role by decreasing the muscle damage and delaying the lactic acid enrichment for energy storage in mice. Compound Cistanche Tubulosa Tablets significantly prolonged the weight-bearing swimming time, increased the hepatic glycogen reserve, and decreased the serum urea level after exercise in mice, showing its anti-fatigue effect. The decoction of Cistanchis can improve endurance and accelerate the elimination of fatigue in exercising mice, and can also reduce the elevation of serum creatine kinase after load exercise and keep the ultrastructure of skeletal muscle of mice normal after exercise, which indicates that it has the effects of enhancing physical strength and anti-fatigue. Cistanchis also significantly prolonged the survival time of nitrite-poisoned mice and enhanced the tolerance against hypoxia and fatigue.
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Melatonin can maintain mitochondrial homeostasis and boost skeletal muscle resilience to damage by mending physiological levels of CoQ10 and other proteins (Figure 1). In addition, Suofu et al. [134] established that melatonin is produced in the mitochondria, the major site of free radical generation. This is extremely important in protecting these organelles and cells from damage due to the high capacity of indolamine. Moreover, melatonin has powerful neuroprotective qualities, including the ability to prevent mitochondrial cytochrome c release and subsequent caspase activation [135–137].
The potential positive effects of melatonin were stressed in reserpine-induced myalgic (RIM) rats whilst studying the processes related to the action of the indolamine. RIM rats exhibit FMS-like chronic pain symptoms and are excellent models for determining the pathogenesis of FMS and showing that mitochondrial dysfunction and oxidative stress, mediated by PGC-1, a main factor controlling mitochondrial biogenesis and shape; Mfn2, an outer mitochondrial membrane GTPase; and CoQ10, are implicated in FMS [138]. Several studies have found that RIM rats have decreased locomotor activity and body weight, as well as a considerable aversion to eating [139,140]. These findings are in line with the symptoms of FMS, including those in the revised fibromyalgia impact questionnaire (FIQR), as physical fitness has been observed to be associated with these symptoms [141,142]. Treatment with melatonin reduced FMS symptoms in RIM rats by supporting antioxidant responses in skeletal muscle and blood serum. Treatment of RIM rats with melatonin significantly improved their voluntary motor activity, increased both distances traveled and the rate of motor activity, and obtained values comparable to those in control rats. Long durations of inactivity, as in both RIM rats and FMS patients, cause changes in skeletal muscle, including increased production of ROS. This shows that oxidative stress may be a crucial factor in the development of muscle illness [138]. Many signaling pathways affecting muscle mass are regulated by mitochondria, and an imbalance in mitochondrial dynamics causes the formation of ROS and several other oxidative-associated factors, such as Mfn2 and PGC-1α [143,144]. Favero et al. found significant and moderate/strong expression of Mfn2 and PGC-1α, respectively, in control rats, despite their expression being drastically reduced (weak/very weak) in RIM animals [138]. After spontaneous exercise carried out daily, control rats exhibited a moderate/strong expression of myogenin, a transcriptional activator essential for the development of functional skeletal muscle in mice. Myogenin is, among other myogenic factors, the key player in the mechanisms of prenatal and postnatal myogenesis [145]. Consequently, the above-mentioned factors are broadly recognized for their contributions to maintaining muscle mass in addition to guaranteeing muscle regeneration and hypertrophy during the rodent life span [146].
In light of the information presented above, mitochondria are dynamic organelles that are critical for maintaining protein homeostasis in a variety of tissues, including skeletal muscle, in both health and sickness [147]. To verify these results, Favero et al. studied the expression of another marker of mitochondrial function, CoQ10 [138], which is not expressed in FMS patients [148–150]. The data obtained confirmed reduced CoQ10 expression in the skeletal muscle of RIM rats compared to control animals, implying that supplementation could alleviate the clinical symptoms associated with this illness [151]. Even CoQ10 supplementation provides a benefit in terms of relieving the sensation of pain in pregabalin-treated FM patients, possibly due to reduced mitochondrial oxidative stress and inflammation [152]. Figure 1 illustrates the hypothesized crucial function of mitochondria in FMS and the biosynthetic pathway mediated by PGC-1α.
The importance of melatonin in mitochondrial homeostasis is based on the mitochondria generating huge amounts of ROS in eukaryotic cells [153–155], and because of the role played by melatonin in the regulation of glutathione disulfide (GSSG)/glutathione (GSH) equilibrium. The antioxidant effect of melatonin and its ability to increase GSH levels may be of great importance for mitochondrial physiology by reducing the mitochondrial damage caused by free radicals and decreasing the loss of electrons in the inner mitochondrial membrane, where the electron transport chain, an oxide-reducing protein system formed by complexes I, II, III, and IV, resides [154,155]. In addition, melatonin has been shown to increase the number of mitochondria in cells when given long-term [156]. Experiments with radioactive melatonin reveal that this indolamine has binding sites in mitochondria [157]. Similarly, melatonin protects the brains of fetal rats against oxidant-mediated mitochondrial damage [158] and stimulates mitochondrial respiration in the livers of mice with accelerated senescence [159]. Alternatively, melatonin also exerts its protective action based on its ability to position itself between the polar heads of polyunsaturated fatty acids within cell membranes, consequently reducing lipid peroxidation and preserving optimal fluidity in the membranes [160–163]. A combined treatment of melatonin and folic acid, in a rat model of reserpine-induced fibromyalgia, may be useful in the treatment of FMS, thanks to its ability to target all mediators that contribute to the perpetuation of pain, from mastocytosis and related pro-inflammatory, vasoactive and neuro-sensitizing mediators to oxidative stress processes [164].
Therefore, the strong point of melatonin is caused by its higher efficiency in mitochondria compared to several kinds of antioxidants that have limited access to the same organelle. Ramis et al. [165] used a similar strategy, claiming that mitochondria-targeted antioxidants aggregate within the mitochondria at hundreds of times higher quantities and protect these vital organelles from oxidative damage.
3. Conclusions
Fibromyalgia is a chronic disease that leads to bouts of pain, which can be triggered by overexertion, mood disorders, such as states of anxiety or depression, and sleep disturbances. Despite having a benign character, because it does not produce physical sequelae, nor does it influence the patient’s survival, the impact it causes on the quality of life can be limiting. It is very important to establish a firm diagnosis because it saves a pilgrimage in search of diagnoses or treatments and allows for setting realistic goals. FMS has no cure, so the goal of treatment is to reduce pain and treat the accompanying symptoms, to improve the quality of life of these patients. In this way, pain relievers, muscle relaxants, and antidepressant drugs which increase serotonin levels, can improve FMS symptoms.
Antioxidants that target the mitochondria, such as melatonin, have scientific value and should be considered for enhancing mitochondrial health and/or disorders associated with the mitochondria. However, the main mechanism by which melatonin exerts analgesic effects is still unclear. Before evaluating the clinical applications of melatonin in the prevention and/or treatment of FMS in humans, a thorough understanding of the underlying mechanisms of its observed effects in nociception is required. FMS continues to have an unknown etiology, and this field of study progresses slowly. However, future studies, such as those with the mitochondria, and specifically those that focus on the mechanisms of neuroinflammation and central sensitization, could answer many questions and continue to support the potential of melatonin as an adjuvant molecule in fibromyalgia, taking into account the close relationship between melatonin, mitochondrial oxidative stress balance, and the proper integrated functioning of the nervous system.
Author Contributions: Conceptualization, D.G.-F., A.B.R. and M.G.; methodology, D.G.-F., M.G., M.Y.C., and M.Á.G.; computer support, D.G.-F., M.Y.C., and M.Á.G.; formal analysis, D.G.-F., M.Y.C., M.Á.G., A.B.R., J.J.G., L.L.-P., and M.G.; writing—original draft preparation, D.G.-F., and M.G.; writing—review and editing, D.G.-F., A.B.R., M.G., L.L.-P. and J.J.G.; visualization, D.G.-F., M.Y.C., M.Á.G., A.B.R., J.J.G., L.L.-P., and M.G.; supervision, A.B.R., and M.G.; project administration, A.B.R.; funding acquisition, A.B.R., and M.G. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the Junta de Extremadura (GR21042) and Gobierno de Aragón (B56_23D).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: M.G. holds a research fellowship from the Junta de Extremadura (ref. TA18029).
Conflicts of Interest: The authors declare no conflict of interest.
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