Intravenous administration of melatonin reduces the intracerebral cellular inflammatory response following transient focal cerebral ischemia in rats

Lee, Ming-Yang; Kuan, Yu‐Hsiang; Chen, Hung-Yi; Chen, Tsung-Ying; Chen, Shur-Tzu; Huang, Chien-Chih; Yang, I‐Ping; Hsu, Yun-Shang; Wu, Tong; Lee, E-Jian

doi:10.1111/j.1600-079x.2007.00420.x

Cited by 128 publications

(127 citation statements)

References 58 publications

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“…The quality of these studies, however, has been suboptimal and the evidence is not yet compelling enough to suggest that antidepressants be prescribed to all patients with PSD [106]. Non-SSRI antidepressants have not been widely studied in stroke, but drugs like agomelatine may be particularly attractive given that melatonin decreases central nervous system inflammation [107] and improves outcome in experimental models of cerebral ischemia [108,109]. Additional evidence for the role of inflammation in the genesis of PSD and as a viable target for the treatment of PSD includes the fact that treatment with pioglitazone, as opposed to metformin, decreases PSD in patients with diabetes [110].…”

Section: Therapeutic Approaches To the Treatment Of Depression: A Focmentioning

confidence: 99%

Inflammation and the Silent Sequelae of Stroke

Becker

2016

Neurotherapeutics

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Depression and fatigue are common after stroke and negatively impact the quality of life of stroke survivors. The biological bases of these symptoms are unknown, but an abundance of data point to a role for inflammation. This review highlights evidence supporting the contribution of inflammation to poststroke depression and poststroke fatigue. Potential treatments for poststroke depression and poststroke fatigue are explored, with a special emphasis on those that modulate the immune response.

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Section: Therapeutic Approaches To the Treatment Of Depression: A Focmentioning

confidence: 99%

Inflammation and the Silent Sequelae of Stroke

Becker

2016

Neurotherapeutics

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“…4 Melatonin given before and immediately after hypoxia-ischemia is neuroprotective in postnatal rodents. [5][6][7][8][9] Postnatally, high-dose (5 mg/kg per hour over 6 hours) melatonin given immediately after hypoxia-ischemia in term piglets augmented protection from therapeutic hypothermia on both magnetic resonance spectroscopy markers of anaerobic stress, and histopathology. 10 In contrast, there have been few studies of antenatal treatment and relatively limited large-animal evidence that prophylactic lowdose melatonin can protect against hypoxic-ischemic injury in the preterm fetus.…”

Section: Introductionmentioning

confidence: 99%

Partial Neural Protection with Prophylactic Low-Dose Melatonin after Asphyxia in Preterm Fetal Sheep

Drury

Davidson

Bennet

et al. 2013

J Cereb Blood Flow Metab

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Melatonin is a naturally occurring indolamine with mild antioxidant properties that is neuroprotective in perinatal animals. There is limited information on its effects on preterm brain injury. In this study, 23 chronically instrumented fetal sheep received 25 minutes of complete umbilical cord occlusion at 101 to 104 days gestation (term is 147 days). Melatonin was administered to the ewe 15 minutes before occlusion (0.1 mg/kg bolus followed by 0.1 mg/kg per hour for 6 hours, n ¼ 8), or the equivalent volume of vehicle (2% ethanol, n ¼ 7), or saline (n ¼ 8), or maternal saline plus sham occlusion (n ¼ 8). Sheep were killed after 7 days recovery in utero. Fetal blood pressure, heart rate, nuchal activity, and temperature were similar between groups. Vehicle infusion was associated with improved neuronal survival in the caudate nucleus, but greater neuronal loss in the regions of the hippocampus, with reduced proliferation and increased ameboid microglia in the white matter (Po0.05). Maternal melatonin infusion was associated with faster recovery of fetal EEG, prolonged reduction in carotid blood flow, similar neuronal survival to vehicle, improved numbers of mature oligodendrocytes, and reduced microglial activation in the white matter (Po0.05). Prophylactic maternal melatonin treatment is partially protective but its effects may be partly confounded by ethanol used to dissolve melatonin. Keywords: asphyxia; brain; ethanol; melatonin; neuroprotection; preterm fetus INTRODUCTION Birth asphyxia is relatively common with preterm birth, and remains a significant cause of neonatal death and neurodevelopmental delay. 1 Excess free radical production during asphyxia and early reperfusion are associated with lipid peroxidation, nucleic acid damage, and mitochondrial dysfunction that promote cell death. 2 Melatonin is a naturally occurring indolamine involved in circadian rhythm, which also has antioxidant properties. 3,4 It readily crosses the human and ovine placentae making it an attractive option for prophylactic treatment of fetuses at high risk of perinatal hypoxia. 4 Melatonin given before and immediately after hypoxia-ischemia is neuroprotective in postnatal rodents. [5][6][7][8][9] Postnatally, high-dose (5 mg/kg per hour over 6 hours) melatonin given immediately after hypoxia-ischemia in term piglets augmented protection from therapeutic hypothermia on both magnetic resonance spectroscopy markers of anaerobic stress, and histopathology. 10 In contrast, there have been few studies of antenatal treatment and relatively limited large-animal evidence that prophylactic lowdose melatonin can protect against hypoxic-ischemic injury in the preterm fetus. In fetal sheep, Miller et al 11 showed that maternal prophylactic melatonin (1 mg total) given before 10-minute umbilical cord occlusion at term-equivalent was associated with reduced brain lipid peroxidation, neuronal death, microglial activation, and astrogliosis. 11,12 In preterm fetal sheep at 0.6 gestation (Term ¼ 147 days) fetal infusion of high-dose (20 mg/kg) J...

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“…In addition to mitigating the oxidative stress, melatonin treatment was effective in significantly suppressing the TNF-α and IL-1β levels in the retina of hypoxic rats thus mitigating hypoxiainduced inflammation. Suppression of the inflammatory response in ischemic conditions [143] and apoptosis in the developing hypoxic brain and retina [142,43] by melatonin has been demonstrated. Very interestingly, melatonin was also effective in reducing the production of VEGF and NO and hypoxia-induced enhanced vascular permeability [9].…”

Section: Cellular and Molecular Mechanisms Of Retinal Ganglion Cell Dmentioning

confidence: 99%

Cellular and Molecular Mechanisms of Retinal Ganglion Cell Death in Hypoxic-Ischemic Injuries

Kaur¹,

Rathnasamy²,

Foulds³

et al. 2015

J Neurol Exp Neurosci

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Loss of retinal ganglion cells (RGCs) occurs in retinal degenerative diseases, such as glaucoma, age-related macular degeneration, diabetic retinopathy, central retinal artery occlusion and ischemic central retinal vein thrombosis in adults and in retinopathy of prematurity in infants. A critical role of hypoxia, which underlies most of the above disorders, has been reported in causing RGC death. Disruption of blood-retinal barrier (BRB) occurs due to increased production of vascular endothelial growth factor and nitric oxide in response to hypoxia resulting in extravasation of serum derived substances and retinal edema and this may be one of important factors mediating RGC death. Activation of microglial cells in response to hypoxia and subsequent increased release of proinflammatory cytokines by them such as tumor-necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) target the TNF-receptor 1 and IL-receptor 1 on RGCs. Excess release of glutamate in retinal tissue under hypoxia activates the ionotropic glutamate receptors causing excitotoxicity through increased influx of calcium into the RGCs. Increased production of TNF-α, IL-1β and enhanced intracellular calcium results in RGC death through activating several pathways such as caspase signaling, mitochondrial dysfunction and oxidative stress. In our investigations, melatonin, an antioxidant, was shown to reduce RGC death in the adult and neonatal hypoxic retina, through suppression of TNF-α, IL-1β and glutamate levels as well as oxidative stress. Moreover, the function and structure of BRB was well preserved in these animals along with reduction in retinal edema. In view of our observations, we suggest that melatonin could be considered as a therapeutic agent to reduce RGC death in various retinal pathologies, in addition to other potential drugs/molecules of therapeutic interest that could render protection to RGCs. However, future in-depth research on the effects of melatonin on the retina under hypoxic conditions needs to be undertaken to explore its full potential in preventing/ameliorating RGC death. Factors Mediating RGC DeathSeveral factors induced or upregulated by hypoxia may be involved in causing RGC death. These factors include, among others, disruption of the blood-retinal barrier, activation of microglial cells and the accompanying enhanced release of inflammatory cytokines and excess release and accumulation of glutamate in the retinal tissues. Hypoxia and the blood-retinal barrierThe BRB regulates the passage of molecules from blood into the retina [11,12]. It consists of an inner BRB formed by the tight junctions (TJ) between capillary endothelial cells and an outer barrier formed by TJ between retinal pigment epithelial cells [12][13][14][15][16]. The TJ are made up of transmembrane proteins such as occludin, claudin-5 and cytoplasmic proteins such as zona occludens (ZO)-1 that are structurally and functionally important for maintaining the integrity of the BRB. The proper functioning of the inner BRB also requires the collective co...

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Intravenous administration of melatonin reduces the intracerebral cellular inflammatory response following transient focal cerebral ischemia in rats

Cited by 128 publications

References 58 publications

Inflammation and the Silent Sequelae of Stroke

Inflammation and the Silent Sequelae of Stroke

Partial Neural Protection with Prophylactic Low-Dose Melatonin after Asphyxia in Preterm Fetal Sheep

Cellular and Molecular Mechanisms of Retinal Ganglion Cell Death in Hypoxic-Ischemic Injuries

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