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LE Magazine August 2008


Melatonin prevents learning disorders in brain-lesioned newborn mice.

Perinatal brain injuries often result in irreversible learning disabilities, which manifest in early childhood. These injuries are chiefly ascribable to marked susceptibility of the immature brain to glutamate-induced excitotoxicity. No treatments are available. One well-characterized model of perinatal brain injuries consists in injecting the glutamate analog ibotenate into the brain of 5-day-old mice. The resulting excitotoxic lesions resemble the hypoxic-ischemic gray-matter lesions seen in full-term and near-term newborns, as well as the white-matter lesions of preterm newborns. We previously reported that these lesions disrupted odor preference conditioning in newborn mice. The aim of this study was to assess the effectiveness of the neuroprotector melatonin in preventing learning disabilities in newborn mice with ibotenate-induced brain injury. In postnatal day (P) 6-P7 pups, we tested psychomotor reflexes, spontaneous preference for maternal odors as an index of memory, ultrasonic vocalization responses to stroking as an index of sensitivity to tactile stimuli, and conditioned preference for an odor previously paired with stroking as an index of learning abilities. Without melatonin, conditioning was abolished, whereas spontaneous odor preference, psychomotor reflexes, and sensitivity to tactile stimuli were normal. Thus, abolition of conditioning was not associated with sensorimotor impairments. Histological analysis confirmed the efficacy of melatonin in reducing white-matter lesions induced by ibotenate. Furthermore, treatment with melatonin protected the ability to develop conditioning. Thus, melatonin, which easily crosses the blood-brain barrier and has been proven safe in children, may be effective in preventing learning disabilities caused by perinatal brain injuries in human preterm infants.

Neuroscience. 2007 Dec 12;150(3):712-9

Protective effect of melatonin against head trauma-induced hippocampal damage and spatial memory deficits in immature rats.

It is well known that head trauma induces the cognitive dysfunction resulted from hippocampal damage. In the present study, we aimed to demonstrate the effect of melatonin on hippocampal damage and spatial memory deficits in 7-day-old rat pups subjected to contusion injury. Melatonin was injected intraperitoneally at the doses of 5 or 20 mg/kg of body weight immediately after induction of traumatic injury. Hippocampal damage was examined by cresyl violet staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Spatial memory performance was assessed in the Morris water maze. Melatonin significantly attenuated trauma-induced neuronal death in hippocampal CA1, CA3 regions and dentate gyrus, and improved spatial memory deficits, which was equally effective at doses of 5-20 mg/kg. The present results suggest that melatonin is a highly promising agent for preventing the unfavorable outcomes of traumatic brain injury in young children.

Neurosci Lett. 2005 Sep 16;385(3):234-9

Does melatonin protect or treat brain damage from traumatic oxidative stress?

A variety of experimental studies have demonstrated the neuroprotective effects of melatonin, based on its antioxidant activity. In a prospective randomized study, the effects of melatonin were investigated in experimental head trauma-induced oxidative stress in rabbits. The experimental study was performed on 30 rabbits. The animals were divided into three groups. Group I (sham procedure): a right parietal craniotomy was performed on each animal, and the dura mater was left intact. Group II: experimental brain trauma (EBT) was performed on each animal using a 1 cm inner diameter x 10 cm long glass tube, through which a 20 g weight (0.5 cm diameter) was dropped onto the brain at the craniotomy site, causing a contusional head trauma. Group III: the same EBT model was performed, but 2.5 mg/kg melatonin was injected intraperitoneally four times (total dose 10 mg/kg); these injections were performed 20 min before the operation, during the trauma, 1 h later and 2 h later. The rabbits were sacrificed after the EBT at 24 h after the brain trauma. The activities of the three principal antioxidant enzymes-catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)-were determined, and the levels of malondialdehyde (MDA), a product of lipid peroxidation, and glutathione (GSH) were measured in brain homogenates. MDA levels were found to be higher in the EBT group than in the EBT+melatonin group or the sham procedure group. The SOD activity was found to be higher in the EBT group than in the sham procedure group. Enzymatic parameters (except for SOD) were significantly higher in melatonin-treated animals than in EBT animals. GSH levels in melatonin-treated animals were decreased compared with EBT animals. In conclusion, the data indicate that melatonin protects against free radical-mediated oxidative changes in brain tissue by boosting antioxidant enzymes, and in particular lowering lipid peroxidation in rabbits with EBT.

Exp Brain Res. 2005 Jun;163(3):406-10

Melatonin secretion after head injury: a pilot study.

PRIMARY OBJECTIVE: To investigate the circadian rhythm of serum melatonin in patients with traumatic brain injury (TBI) during Intensive Care Unit (ICU) stay and its relationship with core body temperature fluctuations and measures of severity of their condition. METHODS AND PROCEDURES: The pilot study was conducted in the ICU of a general hospital in Athens, Greece. Blood melatonin was determined in eight patients consecutively admitted at the ICU following severe head injury, eight times per day during the first and second day following admission. Core body temperature was recorded at hourly intervals. Patients were also assessed with the Glasgow Coma Score (GCS) and the APACHE II score. RESULTS: Melatonin concentrations were lower than the normally reported values. Mean night-time melatonin levels were higher than mean daytime levels both on the first and second days, although not statistically significant. Diurnal variation of melatonin was associated with the GCS. Thus, patients with low GCS (n = 4) did not exhibit a consistent diurnal variation of melatonin, whereas those with high GCS (n = 4) retained the normally expected fluctuations. CONCLUSIONS: ICU-treated TBI patients exhibit reduced melatonin levels and a circadian secretion profile which is related to the severity of the injury. Patients with more severe head trauma exhibit a clearly disrupted pattern of melatonin secretion, whereas those with less severe trauma preserve a relatively intact diurnal rhythm. Furthermore, the diurnal secretion pattern of melatonin appeared to be dissociated from the circadian rhythm of core body temperature. These preliminary findings may have implications for the management of TBI patients.

Brain Inj. 2006 Jul;20(8):873-8

Melatonin protects against ischemia/reperfusion-inducedoxidative damage to mitochondria in fetal rat brain.

We investigated the effects of melatonin on ischemia/reperfusion-induced oxidative damage to mitochondria in fetal rat brain. The utero-ovarian arteries were occluded bilaterally for 20 min in female Wistar rats on day 19 of pregnancy to induce fetal ischemia. Reperfusion was achieved by releasing the occlusion and restoring circulation for 30 min. A sham operation was performed in control rats. Melatonin (10 mg/kg) or vehicle was injected intraperitoneally 60 min prior to occlusion. We measured the respiratory control index (RCI) and the adenosine 5-diphosphate (ADP)/oxygen ratio as indicators of mitochondrial respiratory activity, as well as the concentration of thiobarbituric acid-reactive substances (TBARS) in the mitochondria of fetal brain. Ischemia/reperfusion significantly elevated the concentration of TBARS and significantly reduced the RCI as well as the ADP/oxygen ratio. Melatonin treatment reversed the ischemia/reperfusion-induced reductions in the RCI (2.29 +/- 0.06-2.64 +/- 0.09, P < 0.05) and in the ADP/oxygen ratio (1.48 +/- 0.03-1.57 +/- 0.02, P < 0.05), and also reduced the elevation in concentration of TBARS (11.00 +/- 0.34-7.57 +/- 0.74 nM/mg protein, P < 0.01), resulting in values similar to those in untreated, sham-ischemic animals. The results indicate that administration of melatonin to pregnant rats may prevent ischemia/reperfusion-induced oxidative mitochondrial damage in fetal rat brain.

J Pineal Res. 2001 Sep;31(2):167-72

Effect of melatonin on brain oxidative damage induced by traumatic brain injury in immature rats.

Progressive compromise of antioxidant defenses and free radical-mediated lipid peroxidation, which is one of the major mechanisms of secondary traumatic brain injury (TBI), has also been reported in pediatric head trauma. In the present study, we aimed to demonstrate the effect of melatonin, which is a potent free radical scavenger, on brain oxidative damage in 7-day-old rat pups subjected to contusion injury. Whereas TBI significantly increased thiobarbituric acid reactive substances (TBARS) levels, there was no compensatory increase in the antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) 24 hours after TBI in 7-day-old rats. Melatonin administered as a single dose of 5 mg/kg prevented the increase in TBARS levels in both non-traumatized and traumatized brain hemispheres. In conclusion, melatonin protects against oxidative damage induced by TBI in the immature brain.

Physiol Res. 2005;54(6):631-7

Melatonin accelerates the process of wound repair in full-thickness incisional wounds.

The pineal gland hormone melatonin is known to have both anti-inflammatory and immunomodulatory effects. Given this, we propose that melatonin is an ideal candidate to enhance the process of wound healing. The present study assessed the effects of exogenously administered melatonin (1.2 mg/kg intra-dermal), on scar formation using a full-thickness incisional rat model of dermal wound healing. Melatonin treatment significantly improved the quality of scarring, both in terms of maturity and orientation of collagen fibres. An increase in nitric oxide synthase (NOS) activity and therefore nitric oxide production is detrimental during inflammation but is favourable during granulation tissue formation. Melatonin treatment significantly decreased inducible NOS (iNOS) activity during the acute inflammatory phase but significantly increased iNOS activity during the resolving phase. Cyclooxygenase-2, which has been shown to have anti-inflammatory effects, was elevated in the melatonin-treated rats following wounding. In addition, melatonin treatment also accelerated the angiogenic process, increasing the formation of new blood vessels and elevating the level of vascular endothelial growth factor protein expression during granulation tissue formation. Melatonin treatment increased arginase activity (which generates proline, a building block for collagen synthesis) from earlier time points. The protein profiles of hemoxygenase-1 (HO-1) and HO-2 isoforms, vital participants in the repair process, were also up-regulated upon melatonin treatment. This study has therefore demonstrated, for the first time, that melatonin can significantly improve the quality of wound healing and scar formation.

J Pineal Res. 2008 May;44(4):387-96

Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages.

Inflammation is a complex phenomenon involving multiple cellular and molecular interactions which must be tightly regulated. Cyclooxygenase-2 (COX) is the key enzyme that catalyzes the two sequential steps in the biosynthesis of PGs from arachidonic acid. The inducible isoform of COX, namely COX-2, plays a critical role in the inflammatory response and its over-expression has been associated with several pathologies including neurodegenerative diseases and cancer. Melatonin is the main product of the pineal gland with well documented antioxidant and immuno-modulatory effects. Since the action of the indole on COX-2 has not been previously described, the goal of the present report was to test the effect of melatonin on the activities of COX-2 and inducible nitric oxide synthase (iNOS), using lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as a model. Melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), prevented COX-2 activation induced by LPS, without affecting COX-1 protein levels. The structurally related compound 6-methoxy-melatonin only partially prevented the increase in COX-2 protein levels induced by the toxin. Likewise melatonin prevented iNOS activation and reduced the concentration of products from both enzymes, PGE(2) and nitric oxide. Another endogenous antioxidant like N-acetyl-cysteine (NAC) did not reduced COX-2 significantly. The current finding corroborates a role of melatonin as an anti-inflammatory agent and, for the first time, COX-2 and iNOS as molecular targets for either melatonin or its metabolites AFMK and AMK. These anti-inflammatory actions seem not to be exclusively mediated by the free radical scavenging properties of melatonin. As a consequence, the present work suggests these substances as a new class of potential anti-inflammatory agents without the classical side effects due to COX-1 inhibition.

J Neuroimmunol. 2005 Aug;165(1-2):139-49

Melatonin: potential functions in the oral cavity.

BACKGROUND: Melatonin is synthesized and secreted by the pineal gland and other organs. The pattern of melatonin secretion is controlled by an endogenous circadian timing system and conveys information about the light-dark cycle to the organism, thereby organizing its seasonal and circadian rhythms. Melatonin has powerful antioxidant effects, functions in an immunomodulatory role, may protect against certain cancers, delays some age-related processes, stimulates the synthesis of type I collagen fibers, and promotes bone formation. METHODS: An extensive review was made (e.g., using PubMed, Science Direct, and Web of Knowledge) of the literature. RESULTS: Melatonin, which is released into the saliva, may have important implications for dental disorders, especially in periodontal disease. Diseases of the periodontium are known to be aggravated by free radicals and by alterations in the immune response to microorganisms that are present in plaque. In response to periodontal inflammation, the blood and salivary levels of melatonin may increase. CONCLUSION: Melatonin may play a role in protecting the oral cavity from tissue damage that is due to oxidative stress, and it may contribute to the regeneration of alveolar bone through the stimulation of type I collagen fiber production and the modulation of osteoblastic and osteoclastic activity.

J Periodontol. 2007 Jun;78(6):1094-102

Comparative study of the effects of melatonin and epitalon on the protracted memory under the shuttle labyrinth test conditions in rats in the course of aging.

The influence of the chronic administration of melatonin (epiphyseal hormone) and epitalon (a synthetic tetrapeptide increasing melatonin production) on the learning process and the protracted memory has been studied in LIO rats in the course of aging for 2 years under standard illumination regime (12L :12D). The daily administration of melatonin (Sigma, USA) with drinking water (in 10 mg/liter dose at night) in rats beginning with the age of 4 months did not influence the learning processes in young and adult animals but it was found to contribute to optimization of the brain cognitive function in rats in the course of aging, by improving the protracted memory process. Epitalon administered in a daily dose of 0.1 microg per animal beginning with the age of 4 months showed mnemotropic properties (decreasing the extent of memory disorders) in old rats under conditions of the shuttle labyrinth test.

Eksp Klin Farmakol. 2006 Nov-Dec;69(6):13-6

Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms.

It is known since many years that the pineal hormone melatonin (MLT) may play anticancer activity through several mechanisms, including antiproliferative and immunostimulating effects. Moreover, it exerts an important antioxidant action. Therefore, MLT could be useful in the treatment of human neoplasms, either alone or in association with chemotherapy. The present study was performed to evaluate the influence of a concomitant MLT administration on efficacy and toxicity of several chemotherapeutic combinations in metastatic solid tumor patients, suffering from non-small cell lung cancer (NSCLC) or gastrointestinal tumors. The study included 370 patients who were randomized to receive chemotherapy alone or chemotherapy plus MLT (20 mg/day orally in the evening every day). NSCLC patients received cisplatin (CDDP) plus etoposide or CDDP plus gemcitabine. Colorectal cancer patients were treated with oxaliplatin plus 5-fluorouracil (5-FU), or weekly CPT-11 or 5-FU and folates (FA). Finally, gastric cancer patients received CDDP, epirubicin, 5-FU and FA or weekly 5-FU plus FA. The overall tumor regression rate achieved in patients concomitantly treated with MLT was significantly higher than that found in those treated with chemotherapy alone. Moreover, the 2-year survival rate was significantly higher in patients concomitantly treated with MLT. These results confirm in human the anticancer therapeutic properties of the pineal hormone MLT, which may enhance the efficacy of the standard anticancer chemotherapies.

Pathol Biol (Paris). 2007 Apr-May;55 (3-4):201-4

Delayed melatonin administration promotes neuronal survival, neurogenesis and motor recovery, and attenuates hyperactivity and anxiety after mild focal cerebral ischemia in mice.

Melatonin is a potent antioxidant with neuroprotective activity in animal models of ischemic stroke, which based on its lack of serious toxicity has raised hopes that it might be used for human stroke treatment in the future. This study investigated how subacute delivery of melatonin, starting at 24 hr after stroke onset, and continuing for 29 days (4 mg/kg/day; via drinking water), influences neuronal survival, endogenous neurogenesis, motor recovery and locomotor activity in C57Bl6/j mice submitted to 30-min middle cerebral artery occlusion. Histologic studies showed that melatonin improved neuronal survival and enhanced neurogenesis, even when applied 1 day after stroke. Cell survival was associated with a long-lasting improvement of motor and coordination deficits, evaluated by the grip strength and RotaRod tests, as well as with attenuation of hyperactivity and anxiety of the animals as revealed in open field tests. The robust functional neurologic improvements encourage proof-of-concept studies with melatonin in human stroke patients.

J Pineal Res. 2008 Feb 14

Effect of pinealectomy and melatonin replacement on morphological and biochemical recovery after traumatic brain injury.

Numerous studies showed that melatonin, a free radical scavenger, is neuroprotective. In this study, we investigated the effect of pinealectomy and administration of exogenous melatonin on oxidative stress and morphological changes after experimental brain injury. The animals were divided into six groups, each having 12 rats. Group 1 underwent craniotomy alone. Group 2 underwent craniotomy followed by brain trauma and received no medication. Group 3 underwent craniotomy followed by brain trauma and received melatonin. Group 4 underwent pinealectomy and craniotomy alone. Group 5 underwent pinealectomy and craniotomy followed by brain injury and received no medication. Group 6 underwent pinealectomy and craniotomy followed by brain trauma and received melatonin. Melatonin (100 mg/kg) was given intraperitoneally immediately after trauma to the rats in Groups 3 and 6. Pinealectomy caused a significant increase in the malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH), and xanthine oxidase (XO) levels, and a decrease in GSH levels as compared to the control group. Trauma to pinealectomized rats causes significantly higher oxidative stress. Exogeneous melatonin administration significantly reduced MDA, XO and NO levels, increased GSH levels, and attenuated tissue lesion area. These findings suggest that reduction in endogenous melatonin after pinealectomy makes the rats more vulnerable to trauma, and exogenous melatonin administration has an important neuroprotective effect.

Int J Dev Neurosci. 2006 Oct;24(6):357-63.

Blood pressure modulation and cardiovascular protection by melatonin: potential mechanisms behind.

The production of the pineal hormone melatonin is synchronized with day-night cycle via multisynaptic pathway including suprachiasmatic nucleus linking several physiological functions to diurnal cycle. The recent data indicate that impaired melatonin production is involved in several cardiovascular pathologies including hypertension and ischemic heart disease. However, the mechanisms of melatonin effect on cardiovascular system are still not completely understood. The activation of melatonin receptors on endothelial and vascular smooth muscle cells and antioxidant properties of melatonin could be responsible for the melatonin effects on vascular tone. However, the data from in vitro studies are controversial making the explanation of the melatonin effect on blood pressure in vivo difficult. In vivo, melatonin also attenuates sympathetic tone by direct activation of melatonin receptors, scavenging free radicals or increasing NO availability in the central nervous system. The central and peripheral antiadrenergic action of chronic melatonin treatment might eliminate the mechanisms counter-regulating decreased blood pressure, providing thus additional cardioprotective mechanism. The extraordinary antioxidant activity and antilipidemic effects of melatonin may enhance the modulation of blood pressure by melatonin and probably play the most important role in the amelioration of target organ damage by chronic melatonin treatment. Further investigation of these mechanisms should provide novel knowledge about pathophysiological mechanisms of cardiovascular diseases, additional explanation for their circadian and seasonal variability and potentially generate new impulses for the development of therapeutic arsenal.

Physiol Res. 2007;56(6):671-84.

Melatonin as modulator of pancreatic enzyme secretion and pancreatoprotector.

Melatonin, the main product of the pineal gland, is also released from the gastrointestinal endocrine-neurocrine (EE) cells. The concentrations of melatonin produced in the gut exceeds that originating from central nervous system. In spite of the presence of melatonin receptors in the pancreatic tissue little is known about the role of this indole in the pancreas. Our experimental studies have shown that exogenous melatonin, as well as this produced endogenously from its precursor; L-tryptophan, strongly stimulates pancreatic amylase secretion when given intraperitoneally, or into the gut lumen. This was accompanied by significant increases of CCK plasma level. Above pancreatostimulatory effects of luminal administration of melatonin, were completely reversed by bilateral vagotomy, capsaicin deactivation of sensory nerves or pretreatment of the rats with CCK1 receptor antagonist; tarazepide as well as serotonin antagonist; ketanserin. Melatonin, as well as its precursor; L-tryptophan, effectively protects the pancreas against the damage induced by caerulein overstimulation or ischemia/reperfusion. The beneficial effects of melatonin or L-tryptophan on acute pancreatitis could be related to the ability of melatonin to scavenge the free radicals, to activate antioxidative enzymes and to modulate the cytokine production.

J Physiol Pharmacol. 2007 Dec;58 Suppl 6:65-80

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