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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melatonin (0.3 to 0.4 mg/kg) dissolved in 0.5 ml dimethylsulphoxide (DMSO) was injected i.v. into six baboons, and their cardiovascular parameters were monitored. Left ventricular end-diastolic and end-systolic volumes, stroke volume, cardiac output, and left ventricular ejection fraction were measured, using conventional radionuclide ventriculography, and compared to normal values previously established. These parameters were also measured after an i.v. administration of only DMSO. The only statistical significant change due to melatonin was the increase in the cardiac output and left ventricular ejection fraction. With the reduced heart rate the increase in cardiac output implies a positive inotropic action on the heart by melatonin. There are indications that DMSO possibly suppresses cardiovascular actions of melatonin.
J Pineal Res
PMID:The effect of intravenous administration of melatonin on cardiovascular parameters of the baboon (Papio ursinus). 179 27

The diurnal rhythm of plasma melatonin was studied in 46 Chinese patients with acute cerebral hemorrhage. The state of consciousness of each patient was assessed clinically. The individual sites of lesion were determined by computerized tomography scanning. One to five days after stroke, blood samples were collected by venipuncture at 1000 and 1400 h in the daytime and 0200 and 0400 h at night. Plasma melatonin was extracted by dichloromethane and determined by radioimmunoassay. It was found that patients with lesions in the brain stem or in the third and lateral ventricles had melatonin levels significantly different from the other subjects in that these values were lower and lacking a nocturnal rise. These results are consistent with the presumptive retina-pineal pathway proposed in humans. Dramatic blunting or obliteration of the nocturnal melatonin surge in the blood was also observed in some patients with lesions in the frontal lobe, fronto-parietal lobe, parieto-temporal lobe, and basal ganglia. These brain regions are not involved in the retina-pineal pathway described in rodents or humans. Thus, our results suggest that brain regions other than the presumptive retina-pineal neural pathway may play an important role in the generation and/or regulation of the diurnal production and/or secretion of pineal melatonin in humans. However, a global functional disturbance caused by cerebral hemorrhage cannot be ruled out in some cases. It should be noted that many of the lesions leading to a change in the nocturnal rise of plasma melatonin were unilateral lesions. The significance of this finding is presently unknown. In addition, patients without a nocturnal rise of plasma melatonin were mostly comatose. They had lesions in the basal ganglion, fronto-parietal lobe, brain stem, and lateral and third ventricles. The latter findings suggest that in the brain, certain regions responsible for the state of consciousness of the individual may also be important to the dirunal rhythm of pineal melatonin secretion.
J Pineal Res 1990
PMID:Acute cerebral hemorrhage changes the nocturnal surge of plasma melatonin in humans. 208 7

The antioxidant and anti-inflammatory effects of melatonin on kainic acid (KA)-induced neurodegeneration in the hippocampus were evaluated in vivo. It has been suggested that the pineal secretory product, melatonin, protects neurons in vitro from excitotoxicity mediated by kainate-sensitive glutamate receptors, and from oxidative stress-induced DNA damage and apoptosis. In this study, we injected 10 mg/kg kainate intraperitoneally (i.p.) into adult male Sprague-Dawley rats. This results in selective neuronal degeneration accompanied by intense microglial activation and triggers DNA damage in the hippocampus. We tested the in vivo efficacy of melatonin in preventing KA-induced neurodegeneration, oxidative stress and neuroinflammation in the hippocampus. Melatonin (2.5 mg/kg, i.p.) was given 20 min before, immediately after, and 1 and 2 hr after KA administration. Rats were killed 72 hr later and their hippocampi were examined for evidence of DNA damage (in situ dUTP end-labeling, i.e. TUNEL staining), cell viability (hematoxylin and eosin staining), and microglial (isolectin-B4 histochemistry) and astroglial responses (glial fibrillary acidic protein immunohistochemistry), as well as lipid peroxidation (4-hydroxynonenal immunohistochemistry). A cumulative dose of 10 mg/kg melatonin attenuates KA-induced neuronal death, lipid peroxidation, and microglial activation, and reduces the number of DNA breaks. A possible mechanism for melatonin-mediated neuroprotection involves its antioxidant and anti-inflammatory actions. The present data suggest that melatonin is potentially useful in the treatment of acute brain pathologies associated with oxidative stress-induced neuronal damage such as epilepsy, stroke, and traumatic brain injury.
J Pineal Res 2003 Mar
PMID:Melatonin attenuates kainic acid-induced hippocampal neurodegeneration and oxidative stress through microglial inhibition. 1256

Melatonin is a potent antioxidant and free radical scavenger. Previously, we showed that a single injection of melatonin before ischemia significantly reduced the infarct volume in both permanent and 3-hr middle cerebral artery occlusion (MCAO) rat stroke models. Nitric oxide (NO) and other free radicals play an important role in the pathogenesis of cerebral ischemia, and they have been postulated to mediate the breakdown of the blood-brain barrier (BBB) during ischemia. In this study, we evaluated the influence of melatonin, given at 30 min before MCAO, on brain NO concentration and BBB breakdown. Brain NO concentration was measured at 15 min of MCAO using electron paramagnetic resonance spectroscopy. BBB breakdown at 3 hr of reperfusion following 3 hr of MCAO was assessed using Evans blue extravasation. The relative brain NO concentration was increased to 141.69 +/- 9.71% (mean +/- S.E.M.; n = 9) at 15 min of MCAO. Treatment with melatonin at 1.5, 5, or 50 mg/kg significantly reduced the brain NO concentration to 104.20 +/- 11.20% (n = 8), 55.67 +/- 5.58% (n = 11), and 104.86 +/- 12.56% (n = 9), respectively. Melatonin at 5 mg/kg did not affect Evans blue extravasation. Our results suggest that a single injection of melatonin protects against focal cerebral ischemia partly via inhibition of ischemia-induced NO production and that this regimen does not prevent BBB breakdown following ischemia-reperfusion.
J Pineal Res 2003 Mar
PMID:Melatonin reduces nitric oxide level during ischemia but not blood-brain barrier breakdown during reperfusion in a rat middle cerebral artery occlusion stroke model. 1256 2

The brain is highly susceptible to focal or global ischemia. Unless ischemia is promptly reversed, reperfusion produces further cerebral damage. Acute thrombolysis or defibrinogenation is effective only in selective patients with ischemic stroke and carries a significant risk of bleeding complications. Whereas numerous neuroprotectants were shown to be effective in experimental studies, none of them have been shown to work in clinical trials. The major pathogenetic mechanisms of ischemia/reperfusion injury include excitotoxicity, disturbed calcium ion homeostasis, overproduction of nitric oxide and other free radicals, inflammation, and apoptosis. Nitric oxide and other free radicals, the key mediators of excitotoxicity and disturbed calcium ion homeostasis, cause direct injury and also indirectly damage via inflammation and apoptosis. Melatonin is a potent free radical scavenger and an indirect antioxidant. This mini review summarizes the in vivo and in vitro evidence that melatonin protects against ischemia/reperfusion injury. There is convincing evidence from the literature that melatonin treatment is highly effective in different in vivo and in vitro models of excitotoxicity or ischemia/reperfusion in multiple animal species. Melatonin is safe and non-toxic in humans, and its administration via the oral route or intravenous injection is convenient. While more experimental studies should be conducted to further explore the neuroprotective mechanisms and to document any synergistic or additive protection from combining melatonin with thrombolysis, defibrinogenation or other neuroprotectants, interested clinical scientists should consider planning phase II and III studies to confirm the benefit of melatonin as an acute stroke treatment or a preventive measure for stroke patients.
J Pineal Res 2003 Apr
PMID:The utility of melatonin in reducing cerebral damage resulting from ischemia and reperfusion. 1261 73

Melatonin, a pineal secretory product synthesized from tryptophan, has been found to be effective against neurotoxicity. The present study was aimed at demonstrating the effectiveness of melatonin in vivo in reducing ischemia-induced cerebral edema using magnetic resonance imaging (MRI). Rats were subjected to middle cerebral artery (MCA) occlusion/reperfusion surgery. Melatonin was administered twice (6.0 mg/kg, p.o.) just prior to 1 hr of MCA occlusion and 1 day after the surgery. T2-weighted multislice spin-echo images were acquired 1 day after the surgery. In the saline-treated control rats, increases in T2-weighted signals (water content) were clearly observed in the striatum and in the cerebral cortex. In the melatonin-treated group, total volume of edema was reduced by 51.6% compared with control group (P < 0.01). The protective effect of melatonin against edema was more clearly observed in the cerebral cortex (reduced by 59.8%, P < 0.01) than in the striatum (reduced by 34.2%, P < 0.05). Edema volume in a coronal slice was the greatest at the level of the bregma. Suppression of cerebral edema by melatonin was more effective posterior than anterior to the bregma. Melatonin appeared to reduce the volume of the edematous sites rather than to shift the signal intensity distribution. The present MRI study clearly demonstrates the effectiveness of melatonin against cerebral edema formation in ischemic animals in vivo, especially in the cerebral cortex. Melatonin may be highly useful in preventing cortical dysfunctions such as motor, sensory, memory, and psychological impairments associated with ischemic stroke.
J Pineal Res 2004 Jan
PMID:Melatonin suppresses cerebral edema caused by middle cerebral artery occlusion/reperfusion in rats assessed by magnetic resonance imaging. 1467 26

Inflammatory response following cerebral ischemia/reperfusion plays a key pathogenic role in ischemic cerebral damage. Nitric oxide (NO), cyclooxygenase-2 (COX-2) and myeloperoxidase (MPO) are important inflammatory mediators. Neuronal NO synthase (nNOS) is a major initial source of excessive NO during ischemia/reperfusion. Induction of COX-2 and infiltration of polymorphonuclear cells expressing MPO are critical factors in delayed inflammatory damage. Previously, we demonstrated that administration of melatonin before ischemia significantly reduced the infarct volume in a rat middle cerebral artery occlusion (MCAO) stroke model. In this study, we examined the effect of pretreatment with melatonin at 5 mg/kg on the immunoreactivity (ir) for nNOS, COX-2, MPO, and glial fibrillary acidic protein (GFAP) at 24, 48, and 72 hr after right-sided endovascular MCAO for 1 hr in adult male Sprague-Dawley rats. Melatonin did not affect the hemodynamic parameters. When compared with rats with sham MCAO, ischemia/reperfusion led to an ipsilateral increase in cells with positive ir for nNOS (similar at all times) and in ir-GFAP (similar at all times). Ischemia/reperfusion led to appearance of cells with positive ir for COX-2 (greatest at 24 hr with a tendency to increase again at 72 hr) or MPO (greatest at 24 hr). A single dose of melatonin significantly lessened the ipsilateral increase in cells with positive ir for nNOS, COX-2 or MPO, but did not influence the ipsilateral change in ir-GFAP. Our results suggest that melatonin treatment mediates neuroprotection against ischemia/reperfusion injury partly via inhibition of the consequential inflammatory response.
J Pineal Res 2004 Sep
PMID:Pretreatment with melatonin exerts anti-inflammatory effects against ischemia/reperfusion injury in a rat middle cerebral artery occlusion stroke model. 1529 66

Melatonin has previously been shown to be neuroprotective in rodent models of ischemic stroke. Herein, we tested whether this antioxidant may also be suitable for prophylactic use against stroke. To clarify this issue, melatonin was administrated orally for 9 wk (4 mg/kg/day) in mice and its effects on subsequent injury development after 90 min of intraluminal middle cerebral artery (MCA) occlusion were tested. To evaluate its neuroprotective properties, the protective actions of prophylactic melatonin were compared with both acute melatonin (4 mg/kg, i.p.) administration and with a diluent (sham)-treated control condition. MCA occlusion resulted in reproducible ischemia, as revealed by laser Doppler flowmetry; this was followed by a rapid restoration of blood flow immediately after reperfusion onset. Laser Doppler flow values after reperfusion onset were moderately elevated by melatonin, both when the indole was given prophylactically and when acutely administrated after stroke. In control animals, reproducible brain infarcts were observed 24 hr after reperfusion onset. Treatment with melatonin significantly reduced the infarct size by approximately 30-35%, independent of whether the indole was given prophylactically before or acutely after ischemia. To test whether brain protection involved vascular mechanisms, as suggested earlier, the effects of melatonin on endothelin converting enzyme-1 (ECE-1) levels were studied using Western blots. Interestingly, delivery of melatonin was accompanied by a marked inhibition of ECE-1 levels, which was similarly seen after both acute and chronic melatonin treatment. Our data suggest that melatonin, given at pharmacological doses, may be suitable as a prophylaxis against stroke. Tissue protection may involve an inhibition of ECE-1, which improves vasodilation, after ischemia.
J Pineal Res 2004 Nov
PMID:Prophylactic use of melatonin protects against focal cerebral ischemia in mice: role of endothelin converting enzyme-1. 1548 50

Melatonin is a candidate neuroprotective drug for ischaemic stroke. Any decision to proceed to clinical trial for such drugs should be based on an unbiased assessment of all available data. Such an assessment should include not only the efficacy of a drug but also the in vivo characteristics and limits--in terms of time window, dose, species and model of ischaemia used--to that efficacy. Here we use a systematic approach to establish the limits to and characteristics of the neuroprotective efficacy of melatonin in experimental stroke. We have used systematic review and meta-analysis to assess the evidence for a protective effect of melatonin in animal models of focal cerebral ischaemia. Fourteen studies were identified describing procedures involving 432 animals. The point estimate for the effect of melatonin was a 42.8% (95% CI 39.3-46.3%) improvement in outcome. Efficacy was greater when ketamine anaesthesia was used, and melatonin was equally effective in permanent or temporary ischaemia. Study quality was generally poor by clinical trial standards, and no evidence was found regarding the efficacy of melatonin in focal cerebral ischaemia in aged, hypertensive or diabetic animals, in species other than rats, or at time windows beyond 2 hr. These findings demonstrate a marked efficacy of melatonin in animal models of focal cerebral ischaemia, identify priority areas for future animal research, and suggest melatonin as a candidate neuroprotective drug for human stroke.
J Pineal Res 2005 Jan
PMID:Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke. 1561 35

Because of its favorable action profile in humans, melatonin is a particularly interesting candidate as a neuroprotectant in acute ischemic stroke. Until now, the signaling mechanisms mediating melatonin's neuroprotective actions remained essentially uninvestigated. Herein, we examined the effects of melatonin, administered either orally for 9 wk as a stroke prophylactic (4 mg/kg/day) or intraperitoneally immediately after reperfusion onset (4 mg/kg), on the activation of signal transduction pathways in mice submitted to 90 min of intraluminal middle cerebral artery occlusion, followed by 24 hr of reperfusion. In these studies, melatonin significantly reduced ischemic infarct size by approximately 30-35%, as compared with animals receiving diluent (sham) treatment, independent of whether the indole was administered prior to or after ischemia. Under both conditions, animals receiving melatonin exhibited elevated phosphorylated Akt levels in their brains, as determined by Western blots. Additionally, phosphorylation levels of mitogen-activated protein kinase/extracellular-regulated kinase (ERK)-1/-2 and Jun kinase (JNK)-1/-2 were increased following prophylactic, but not acute, melatonin treatment. Our data suggest a role of phosphatidyl inositol-3 kinase/Akt signaling in acute melatonin-induced neuroprotection, while ERK-1/-2 and/or JNK-1/-2 rather appear to be involved in melatonin's long-term effects.
J Pineal Res 2005 Jan
PMID:Signal transduction pathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice. 1561 39


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