Protection of melatonin in experimental models of newborn hypoxic‐ischemic brain injury through <scp>MT</scp>1 receptor

Sinha, Bharati; Wu, Qiaofeng; Li, Wei; Tu, Yanyang; Sirianni, Ana C.; Chen, Yanchun; Jiang, Jiying; Zhang, Xinmu; Wu, Chen; Zhou, Shuanhu; Reíter, Russel J.; Manning, Simon M.; Patel, Nirav J.; Aziz-Sultan, Ali; Inder, Terrie E.; Friedlander, Robert M.; Fu, Jianfang; Wang, Xin

doi:10.1111/jpi.12443

Cited by 70 publications

(77 citation statements)

References 74 publications

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“…As shown in Figure G‐H, compared to the control group, HR injury promoted the migration of cyt‐c from cytoplasm into the nucleus, and this effect could be impaired by resveratrol treatment at high dose. Further, cyt‐c translocation was highly dependent on mitochondrial permeability transition pore (mPTP) opening . Interestingly, mPTP opening rate could be augmented by HR injury and was inhibited by resveratrol in the setting of HR injury (Figure I).…”

Section: Resultsmentioning

confidence: 99%

“…Further, cyt-c translocation was highly dependent on mitochondrial permeability transition pore (mPTP) opening. 57,58 Interestingly, mPTP opening rate could be augmented by HR injury and was inhibited by resveratrol in the setting of HR injury ( Figure 2I). Altogether, these data inform us that mitochondrial apoptosis is activated by HR injury in N2a cells whereas resveratrol treatment sends F I G U R E 3 Resveratrol improves mitochondrial energy metabolism in hypoxia-reoxygenation (HR)-treated N2a cells.…”

Section: F I G U R Ementioning

confidence: 97%

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Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Gao

Wang

et al. 2019

Int J Experimental Path

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Summary The pathogenesis of cerebral ischaemia reperfusion injury (IRI) has not been fully described. Accordingly, there is little effective drug available for the treatment of cerebral IRI. The aim of our study was to explore the exact role played by Mfn1‐mediated mitochondrial protection in cerebral IRI and evaluate the beneficial action of resveratrol on reperfused brain. Our study demonstrated that hypoxia‐reoxygenation (HR) injury caused N2a cell apoptosis and this process was highly affected by mitochondrial dysfunction. Decreased mitochondrial membrane potential, increased mitochondrial oxidative stress, and an activated mitochondrial apoptosis pathway were noted in HR‐treated N2a cells. Interestingly, resveratrol treatment could attenuate N2a cell apoptosis via sustaining mitochondrial homeostasis. Further, we found that resveratrol modulated mitochondrial performance via activating the Mfn1‐related mitochondrial protective system. Knockdown of Mfn1 could abolish the beneficial effects of resveratrol on HR‐treated N2a cells. Besides, we also report that resveratrol regulated Mfn1 expression via the AMPK pathway; inhibition of AMPK pathway also neutralized the anti‐apoptotic effect of resveratrol on N2a cells in the setting of cerebral IRI. Taken together our results show that mitochondrial damage is closely associated with the progression of cerebral IRI. In addition we also demonstrate the protective action played by resveratrol on reperfused brain and show that this effect is achieved via activating the AMPK‐Mfn1 pathway.

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Section: Resultsmentioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 97%

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Gao

Wang

et al. 2019

Int J Experimental Path

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“…The results reported here are the first data obtained in an FDA‐approved clinical study that use the dose‐escalation approach to identify a safe and potentially effective dose of melatonin for neonates with HIE undergoing hypothermia. In preclinical experiments, the most effective melatonin dose was 10‐15 mg/kg, although efficacy was also demonstrated at lower doses . When preclinical studies are translated into clinical experimentation, researchers must consider allometry when extrapolating the dosing .…”

Section: Discussionmentioning

confidence: 99%

Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia

Balduini

Weiss

Carloni

et al. 2019

Journal of Pineal Research

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Introduction Neonates with hypoxic‐ischemic encephalopathy (HIE) undergoing hypothermia may benefit from adjunctive therapy with melatonin. However, melatonin safety, pharmacokinetics (PK), and dosage in this sensitive population are still unknown. Methods and results This study assessed the PK and safety of melatonin enteral administration to neonates with HIE undergoing hypothermia. Melatonin was infused at 0.5 mg/kg in five neonates with HIE undergoing hypothermia. Infusion started 1 hour after the neonates reached the target temperature of 33.5°C. Blood samples were collected before and at selective times after melatonin infusion. Abdominal complications or clinically significant changes in patients’ vital signs were not found during or after melatonin. The peak plasma concentration reached 0.25 µg/mL. The area under the curve in 24 hours was 4.35 µg/mL*h. Discussion Melatonin half‐life and clearance were prolonged, and the distribution volume decreased compared to adults. In silico simulation estimated that the steady state can be reached after four infusions. Hypothermia does not affect melatonin PK. In humans high blood concentrations with lower doses can be achieved compared to animal experimentation, although intravenous administration is advised in the neonate population. Our study is a preparatory step for future clinical studies aimed at assessing melatonin efficacy in HIE.

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“…Our fourth set of experiments examined changes in sleep after pharmacological blockade of melatonin receptor in the PFH at light onset. We used “within”‐group design and the extensively used competitive melatonin receptor antagonist, luzindole (10 pmol/50 nL/side), to block MT1 receptors . Luzindole infusion at light onset increased wakefulness, while reducing NREM and REM sleep.…”

Section: Discussionmentioning

confidence: 99%

Melatonin promotes sleep in mice by inhibiting orexin neurons in the perifornical lateral hypothalamus

Sharma

Sahota

Thakkar

2018

Journal of Pineal Research

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Melatonin promotes sleep. However, the underlying mechanisms are unknown. Orexin neurons in the perifornical lateral hypothalamus (PFH) are pivotal for wake promotion. Does melatonin promote sleep by inhibiting orexin neurons? We used C57BL/6J mice and designed 4 experiments to address this question. Experiment 1 used double-labeled immunofluorescence and examined the presence of melatonin receptors on orexin neurons. Second, mice, implanted with bilateral guides targeted toward PFH and sleep-recording electrodes, were infused with melatonin (500 pmole/50 nL/side) at dark onset (onset of active period), and spontaneous bouts of sleep-wakefulness were examined. Third, mice, implanted with bilateral guides into the PFH, were infused with melatonin (500 pmole/50 nL/side) at dark onset and euthanized 2 hours later, to examine the activation of orexin neurons using c-Fos expression in orexin neurons. Fourth, mice, implanted with PFH bilateral guides and sleep-recording electrodes, were infused with melatonin receptor antagonist, luzindole (10 pmol/50 nL/side), at light onset (onset of sleep period), and spontaneous bouts of sleep-wakefulness were examined. Our results suggest that orexin neurons express MT1, but not MT2 receptors. Melatonin infusion into the PFH, at dark onset, site-specifically and significantly increased NREM sleep (43.7%, P = .003) and reduced wakefulness (12.3%, P = .013). Local melatonin infusion at dark onset inhibited orexin neurons as evident by a significant reduction (66%, P = .0004) in the number of orexin neurons expressing c-Fos. Finally, luzindole infusion-induced blockade of melatonin receptors in PFH at sleep onset significantly increased wakefulness (44.1%, P = .015). Based on these results, we suggest that melatonin may act via the MT1 receptors to inhibit orexin neurons and promote sleep.

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Protection of melatonin in experimental models of newborn hypoxic‐ischemic brain injury through MT1 receptor

Cited by 70 publications

References 74 publications

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia

Melatonin promotes sleep in mice by inhibiting orexin neurons in the perifornical lateral hypothalamus

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