Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats

Kondoh, Takashi; Uneyama, Hisayuki; Nishino, Hitoo; Torii, Kunio

doi:10.1016/s0024-3205(02)02256-7

Cited by 65 publications

(61 citation statements)

References 27 publications

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“…Microvascular damage is reportedly reduced by MLT in response to brain hypoperfusion and reperfusion injury [32] , suggesting that MLT might exert a neuroprotective effect by protecting the microvessels themselves. Indeed there is evidence that MLT acts directly on vasculature to mediate blood flow to various vascular beds including the brain, to stabilize blood brain barrier integrity [33] , prevent endothelial cell dysfunction [34] , decrease nitric oxide and VEGF production, and suppress ischemia-induced cerebral edema [35] . Furthermore, neonatal treatment with oral MLT improves cerebral vascular function in chronically hypoxic newborn lambs by increasing cerebral blood flow and improving vascular function [36] .…”

Section: Discussionmentioning

confidence: 99%

Effects of Antenatal Melatonin Treatment on the Cerebral Vasculature in an Ovine Model of Fetal Growth Restriction

et al. 2017

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Chronic moderate hypoxia, such as occurs in fetal growth restriction (FGR) during gestation, compromises the blood-brain barrier (BBB) and results in structural abnormalities of the cerebral vasculature. We have previously determined the neuroprotective and antioxidant effects of maternal administration of melatonin (MLT) on growth-restricted newborn lambs. The potential of maternal MLT therapy for the treatment of cerebrovascular dysfunction-associated developmental hypoxia has also been demonstrated in newborn lambs. We assessed whether MLT had an effect on the previously reported structural and cerebral vascular abnormalities in chronically hypoxic FGR lambs. Single umbilical-artery ligation surgery was performed in fetuses at approximately 105 days of gestation (term: 147 days) to induce placental insufficiency and FGR, and treatment with either saline or an MLT infusion (0.1 mg/kg) was started 4 h after surgery. Ewes delivered naturally at term and lambs were euthanased 24 h later. We found a significant reduction in the number of laminin-positive blood vessels within the subcortical and periventricular white matter (SCWM and PVWM) and the subventricular zone (SVZ) in FGR (p < 0.0005) and FGR + MLT brains (p < 0.0005 vs. controls), with no difference found between FGR and FGR + MLT animals. This was associated with a significant decrease in VEGF immunoreactivity in FGR and FGR + MLT brains versus controls (p < 0.0005; SCWM and PVWM) and in the SVZ in FGR brains versus controls (p < 0.005) and also with significantly lower levels of proliferating blood vessels versus controls (p < 0.0005). Glucose transporter-1 immunoreactivity (vascular endothelium) was decreased in FGR versus control lambs (p < 0.0005) in SCWM, PVWM, and the SVZ; it was significantly increased in FGR + MLT lambs compared with FGR lambs in SCWM and PVWM (p < 0.005) and even more markedly in the SVZ (p < 0.0005). FGR brains showed a 72% reduction in pericyte coverage versus control lambs and 68% versus FGR + MLT in PVWM. In SCWM, we found a 77 and 73% reduction compared with control and FGR + MLT lambs, respectively, while in the SVZ, we observed a 68% reduction versus controls and a 70% reduction in FGR versus FGR + MLT lambs. Astrocyte end-feet coverage in the SCWM showed a significant 24% reduction in FGR versus control levels, a 42% decrease within the PVWM, and a 35% decrease within the SVZ versus controls. MLT normalized astrocyte attachment to blood vessels, with no difference seen between controls and FGR + MLT animals in any of the brain regions examined. We also observed a decrease in albumin extravasation and microhemorrhage in controls and FGR + MLT brains versus FGR lambs. Our results demonstrate that umbilicoplacental insufficiency is associated with FGR-produced vascular changes in the white matter and SVZ of FGR newborn brains and that maternal MLT prevented disruption of the BBB by protecting perivascular cells essential for the maintenance of vascular homeostasis and stability.

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Section: Discussionmentioning

confidence: 99%

Effects of Antenatal Melatonin Treatment on the Cerebral Vasculature in an Ovine Model of Fetal Growth Restriction

et al. 2017

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“…The brain tissues were removed and sectioned at 2 mm intervals in the coronal plane without olfactory bulb, cerebellum and low-set brain stem (Kondoh et al, 2002). Sections were incubated for 30 min at 37 • C in a solution containing phosphate buffered saline and 2% 2,3,5-triphenyltetrazolium chloride (TTC).…”

Section: Neurological Evaluation Morphometric Measurement Of Infarctmentioning

confidence: 99%

Protective effect of flavonoids from Scutellaria baicalensis Georgi on cerebral ischemia injury

Zhang

Wang

et al. 2006

Journal of Ethnopharmacology

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The protective effect of flavonoids extracted from Scutellaria baicalensis Georgi on cerebral ischemia injury has been explored in experimental animals. Scutellaria flavonoid (SF) could significantly prolong gasping time (prolonged ratio, 23.79%) and survival time after carotid artery occlusion, and decrease attenuate malondialdehyde (MDA) content in damaged brain tissues from 118.56+/-47.95 nmol/g in untreated to 199.29+/-24.24 nmol/g. SF could also increase the content of superoxide dismutase (SOD) in brain tissues after ischemic mice from 1486+/-94 NU/g in untreated to 1168+/-76 NU/g, and showed significant protective effect on cerebral hypoxia and reperfusion brain tissues in middle cerebral artery occlusion (MCAO) procedure. Additionally, SF has inhibitory effect on platelet aggregation, with the average inhibition rate of 45.52%, while the aspirin group was 54.96%. These results suggest that SF has a significant protective effect on cerebral ischemia and ischemia-reperfusion induced brain injury.

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“…8,9 Therefore, only a few selective ligands have been reported in the literature, especially with respect to MT 1 receptors; none of these ligands has been tested in vitro in cells or tissues expressing MLT receptors, and their efficacy in the treatment of neuropsychiatric diseases has been poorly evaluated. Other effects of MLT described in the literature include its neuroprotective, [10][11][12] antiinflammatory, 13,14 pain modulatory, 15 retinal, 16 vascular, [17][18][19] antitumour 20 and antioxidant 21 properties.…”

Section: Introductionmentioning

confidence: 99%

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

Comai

Gobbi

2014

J Psychiatry Neurosci

155

126

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IntroductionMelatonin (MLT) is a neurohormone synthesized from serotonin (5-HT) and secreted foremost by the mammalian pineal gland following a distinct circadian rhythm with the acrophase during the dark phase and the nadir during the light phase in both diurnal and nocturnal species.1 A typical human adult's average daytime and nighttime levels of blood MLT are approximately 10 pg/mL and 60 pg/mL, respectively.2 Its production is controlled through the suprachiasmatic nucleus (SCN) by the photoperiod, peaking at night and dropping during the day. Melatonin is involved in numerous physiologic processes, including circadian rhythms, mood regulation, anxiety, sleep, appetite, immune responses and cardiac functions. 3,4 Most of the effects of MLT in the brain result from the activation of 2 high-affinity G-protein coupled receptors (GPCRs), MT 1 and MT 2 .5 Of note, GPCRs have a proven history of being excellent therapeutic targets. Recent market analyses indicate that 40%-50% of modern drugs and almost 25% of the top 200 best-selling drugs target GPCRs. 6 In addition to these high-affinity MLT receptors, another low-affinity MLT binding site, MT 3 , has recently been characterized as an MLT-sensitive form of the human enzyme quinone reductase 2. 7 The functional characterization of MT 1 and MT 2 receptors in target tissues is hampered by the paucity of selective MT 1 and MT 2 receptor ligands. Structural Background: Melatonin (MLT) is a pleiotropic neurohormone controlling many physiological processes and whose dysfunction may contribute to several different diseases, such as neurodegenerative diseases, circadian and mood disorders, insomnia, type 2 diabetes and pain. Melatonin is synthesized by the pineal gland during the night and acts through 2 G-protein coupled receptors (GPCRs), MT 1 (MEL1a) and MT 2 (MEL1b). Although a bulk of research has examined the physiopathological effects of MLT, few studies have investigated the selective role played by MT 1 and MT 2 receptors. Here we have reviewed current knowledge about the implications of MT 2 receptors in brain functions. Methods: We searched PubMed, Web of Science, Scopus, Google Scholar and articles reference lists for studies on MT 2 receptor ligands in sleep, anxiety, neuropsychiatric diseases and psychopharmacology, including genetic studies on the MTNR1B gene, which encodes the melatonin MT 2 receptor. Results: These studies demonstrate that MT 2 receptors are involved in the pathophysiology and pharmacology of sleep disorders, anxiety, depression, Alzheimer disease and pain and that selective MT 2 receptor agonists show hypnotic and anxiolytic properties. Limitations: Studies examining the role of MT 2 receptors in psychopharmacology are still limited. Conclusion: The development of novel selective MT 2 receptor ligands, together with further preclinical in vivo studies, may clarify the role of this receptor in brain function and psychopharmacology. The superfamily of GPCRs has proven to be among the most successful drug targets and, consequently, M...

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Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats

Cited by 65 publications

References 27 publications

Effects of Antenatal Melatonin Treatment on the Cerebral Vasculature in an Ovine Model of Fetal Growth Restriction

Effects of Antenatal Melatonin Treatment on the Cerebral Vasculature in an Ovine Model of Fetal Growth Restriction

Protective effect of flavonoids from Scutellaria baicalensis Georgi on cerebral ischemia injury

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

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