Melatonin: A hypothesis for Kawasaki disease treatment.

Kawasaki disease (KD) is the most common cause of acquired heart disease with unknown etiology among children in developed countries. Acute inflammation of the vasculature, genetic susceptibility and immunopathogenesis based on a transmittable and infectious origin, are the pathologic events involved in the early inflammatory etiology and progression of this disease. However, the exact causes of KD remain unknown. Current proposed recommendations include three therapy lines; firstly, an initial standard therapy with intravenous immunoglobulin (IVIG) followed by aspirin. Secondly, in cases of high risk of coronary lesions, the adjunctive therapy with corticosteroid is commonly considered. Thirdly, in KD patients refractory to the previous therapies, tumor necrosis factor (TNF-α) antagonists are being used to modulate pro-inflammatory cytokines. In view of this status quo, our starting hypothesis is that the ubiquitous and non-toxic neurohormone melatonin could be of critical importance in developing novel adjuvant therapies against KD, as it occurs with a plethora of other diseases. Considering its pleiotropic properties, particularly its antiinflammatory and immunoregulatory capacities, melatonin should be of great therapeutic interest for helping to control the main pathologic features of KD patients. In addition, this multifunctional indole has a safe pharmacological profile, enhancing the therapeutic activity of several drugs and reducing their possible side effects. Consequently, melatonins actions to manage KD need to be tested in further clinical studies.

Corrigendum: Melatonin and Nitrones As Potential Therapeutic Agents for Stroke.

[This corrects the article on p. 281 in vol. 8, PMID: 27932976.].

Ischemic brain injury: New insights on the protective role of melatonin.

Stroke represents one of the most common causes of brain's vulnerability for many millions of people worldwide. The plethora of physiopathological events associated with brain ischemia are regulate through multiple signaling pathways leading to the activation of oxidative stress process, Ca2+ dyshomeostasis, mitochondrial dysfunction, proinflammatory mediators, excitotoxicity and/or programmed neuronal cell death. Understanding this cascade of molecular events is mandatory in order to develop new therapeutic strategies for stroke. In this review article, we have highlighted the pleiotropic effects of melatonin to counteract the multiple processes of the ischemic cascade. Additionally, experimental evidence supports its actions to ameliorate ischemic long-term behavioural and neuronal deficits, preserving the functional integrity of the blood-brain barrier, inducing neurogenesis and cell proliferation through receptor-dependent mechanism, as well as improving synaptic transmission. Consequently, the synthesis of melatonin derivatives designed as new multitarget-directed products has focused a great interest in this area. This latter has been reinforced by the low cost of melatonin and its reduced toxicity. Furthermore, its spectrum of usages seems to be wide and with the potential for improving human health. Nevertheless, the molecular and cellular mechanisms underlying melatonin´s actions need to be further exploration and accordingly, new clinical studies should be conducted in human patients with ischemic brain pathologies.

Melatonin and Nitrones As Potential Therapeutic Agents for Stroke.

Stroke is a disease of aging affecting millions of people worldwide, and recombinant tissue-type plasminogen activator (r-tPA) is the only treatment approved. However, r-tPA has a low therapeutic window and secondary effects which limit its beneficial outcome, urging thus the search for new more efficient therapies. Among them, neuroprotection based on melatonin or nitrones, as free radical traps, have arisen as drug candidates due to their strong antioxidant power. In this Perspective article, an update on the specific results of the melatonin and several new nitrones are presented.

Melatonin protects against oxygen and glucose deprivation by decreasing extracellular glutamate and Nox-derived ROS in rat hippocampal slices.

Therapeutic interventions on pathological processes involved in the ischemic cascade, such as oxidative stress, neuroinflammation, excitotoxicity and/or apoptosis, are of urgent need for stroke treatment. Melatonin regulates a large number of physiological actions and its beneficial properties have been reported. The aim of this study was to investigate whether melatonin mediates neuroprotection in rat hippocampal slices subjected to oxygen-glucose-deprivation (OGD) and glutamate excitotoxicity. Thus, we describe here that melatonin significantly reduced the amount of lactate dehydrogenase released in the OGD-treated slices, reverted neuronal injury caused by OGD-reoxygenation in CA1 and CA3 hippocampal regions, restored the reduction of GSH content of the hippocampal slices induced by OGD, and diminished the oxidative stress produced in the reoxygenation period. Furthermore, melatonin afforded maximum protection against glutamate-induced toxicity and reversed the glutamate released almost basal levels, at 10 and 30µM concentration, respectively. Consequently, we propose that melatonin might strongly and positively influence the outcome of brain ischemia/reperfusion.