Melatonin supports alendronate in preserving bone matrix and prevents gastric inflammation in ovariectomized rats.

The anti-catabolic bisphosphonate alendronate is considered as the first-line medical treatment in post-menopausal osteoporosis; but several side effects, including gastric mucosal injury, are associated with its use. The aim was to elucidate whether combined treatment with melatonin plus alendronate would be more advantageous in the maintenance of bone and the prevention of gastric side effects. Under anaesthesia, female Sprague-Dawley rats underwent bilateral ovariectomy (OVX), while control group had sham surgery. Four weeks after the surgery, OVX rats were treated with saline, melatonin (25 µg/mL/d), alendronate (70 µg/kg/wk), melatonin + alendronate, melatonin + melatonin receptor antagonist (luzindole, 10 µg/kg/d) or alendronate + melatonin + luzindole for 8 weeks. Rats were euthanized at the end of 12th week. Runx2 expression, apoptotic cells, and trabecular thickness were evaluated in tibiae, while gastric tissues were analysed for oxidative injury parameters. In all OVX groups, Runx2 expression was depressed. Saline-treated OVX group presented an extreme decrease in calcified area in opposition to melatonin- or alendronate-treated groups, while the bones in alendronate + melatonin-treated group were similar to those of the sham-operated group. Concomitant with the improvements examined histologically in bone tissues, quantitative TUNEL (+) cells were similarly lower in alendronate- or melatonin-treated groups. Oxidative gastric damage was increased in saline- or alendronate-treated groups, which were depressed in the presence of melatonin. Although melatonin and alendronate exerted similar supportive effects on the maintenance of bone mass, melatonin may have a more advantageous impact by protecting against OVX-induced gastric injury, which was aggravated by alendronate use. HIGHLIGHTS: Our results demonstrate that alendronate and melatonin had similar supportive effects on the maintenance of bone mass, while melatonin prevented the gastric side effects of alendronate, making this combination an advisable therapeutic approach in the treatment of menopausal osteoporosis.

Glioblastoma: Role of Mitochondria N-acetylserotonin/Melatonin Ratio in Mediating Effects of miR-451 and Aryl Hydrocarbon Receptor and in Coordinating Wider Biochemical Changes.

A wide array of different factors and processes have been linked to the biochemical underpinnings of glioblastoma multiforme (GBM) and glioblastoma stem cells (GSC), with no clear framework in which these may be integrated. Consequently, treatment of GBM/GSC is generally regarded as very poor. This article provides a framework that is based on alterations in the regulation of the melatonergic pathways within mitochondria of GBM/GSC. It is proposed that the presence of high levels of mitochondria-synthesized melatonin is toxic to GBM/GSC, with a number of processes in GBM/GSC acting to limit melatonin's synthesis in mitochondria. One such factor is the aryl hydrocarbon receptor, which increases cytochrome P450 (CYP)1b1 in mitochondria, leading to the 'backward' conversion of melatonin to N-acetylserotonin (NAS). N-acetylserotonin has some similar, but some important differential effects compared with melatonin, including its activation of the tyrosine receptor kinase B (TrkB) receptor. TrkB activation is important to GBM/GSC survival and proliferation. A plethora of significant, but previously disparate, data on GBM/GSC can then be integrated within this framework, including miR-451, AMP-activated protein kinase (AMPK)/mTOR, 14-3-3 proteins, sirtuins, tryptophan 2,3-dioxygenase, and the kynurenine pathways. Such a conceptualization provides a framework for the development of more effective treatment for this poorly managed condition.

Melatonin ameliorates neurologic damage and neurophysiologic deficits in experimental models of stroke.

This review summarizes the numerous reports that have documented the neuroprotective actions of melatonin in experimental models of ischemia/reperfusion injury (stroke). In these investigations, which have used three species (rat, gerbil, and cat), melatonin was universally found to reduce brain damage that normally occurs as a consequence of the temporary interruption of blood flow followed by the reflow of oxygenated blood to the brain. The exogenous administration of melatonin in these experimental stroke models reduced infarct volume, lowered the frequency of apoptosis, increased the number of surviving neurons, reduced reactive gliosis, lowered the oxidation of neural lipids and oxidatively damaged DNA, induced bcl-2 gene expression (the activity of which improves cell survival), upregulated excision repair cross-complementing factor 6 (an essential gene for preferential DNA excision repair), restrained poly(ADP ribose) synthetase (which depletes cellular NAD resulting in the loss of ATP) activity, and improved neurophysiologic outcomes. Under no circumstances did melatonin exacerbate the damage associated with ischemia/reperfusion injury. As well as the beneficial pharmacologic actions of melatonin, several studies show that a relative deficiency of endogenous melatonin exaggerates neural damage due to stroke; this suggests that even physiologic concentrations of melatonin normally serve to protect the brain against damage. The primary action to explain melatonin's protective effects may relate to its ubiquitous direct and indirect antioxidative actions, although other beneficial functions of melatonin are not precluded.

Oxidative stress and persistent pulmonary hypertension of the newborn treated with inhaled nitric oxide and different oxygen concentrations.

OBJECTIVES: The aim of this study was to determine the effects of inhaled NO with different oxygen concentrations on the inflammatory cascade in newborns with hypoxic respiratory failure secondary to persistent pulmonary hypertension. METHODS: 60 newborns received iNO and 30 of them received an initial oxygen concentration of 45% (group 1), while the other 30 newborns received an initial oxygen concentration of 80% (group 2). The levels of inflammatory cytokines (IL-6, IL-8, TNF-α) were measured. The clinical outcome was also recorded. RESULTS: The findings show that interleukin concentrations (IL-6, IL-8, TNF-α) were significantly decreased between 0 and 72 hours (p < 0.01) in the newborns exposed to initial oxygen concentration of 45% and significantly increased in the other group. CONCLUSIONS: When inhaled, NO was co-administered with concentration of O(2) <45%, anti-inflammatory responses occurred, in accord with evidence in the published literature. The benefits of iNO on the clinical outcome in the current study demonstrate that inhaled NO in both groups was associated with improved short-term oxygenation.

Melatonin as pharmacologic support in burn patients: a proposed solution to thermal injury-related lymphocytopenia and oxidative damage.

OBJECTIVE: To review the data that support the clinical use of melatonin in the treatment of burn patients, with special emphasis on the stimulation of the oxidative defense system, the immune system, circadian rhythm of sleep/wakefulness, and the reduction in the toxicity of therapeutic agents used in the treatment of burn victims. DATA SOURCE: A MEDLINE/PubMed search from 1975 to July 2006 was conducted. STUDY SELECTION: The screening of the literature was examined using the key words: burn patients, lymphocytopenia, skin oxidative stress, antioxidant, melatonin, and free radicals. DATA EXTRACTION AND SYNTHESIS: Thermal injury often causes damage to multiple organs remote from the original burn wound and may lead to multiple organ failure. Animal models and burn patients exhibit elevated free radical generation that may be causative in the local wound response and in the development of burn shock and distant organ injury. The suppression of nonspecific resistance and the disturbance in the adaptive immune system makes burn patients vulnerable to infections. Moreover, there is loss of sleep and the toxicity produced by drugs habitually used in the clinic for burn patients. Melatonin is a powerful antioxidant and is a potent protective agent against damage after experimental thermal injury. Some actions of melatonin as a potential supportive pharmacologic agent in burn patients include its: role as a scavenger of both oxygen and nitrogen-based reactants, stimulation of the activities of a variety of antioxidative enzymes, reduction in proinflammatory cytokines, inhibition of adhesion molecules, chronobiotic effects, and reduction in the toxicity of the drugs used in protocols to treat thermal injury patients. CONCLUSIONS: These combined actions of melatonin, along with its low toxicity and its ability to penetrate all morphophysiologic membranes, could make it a ubiquitously acting and highly beneficial molecule in burn patients.