Effect of add‐on melatonin on seizure outcomes and quality of sleep in epilepsy with idiopathic generalized tonic‐clonic seizures alone in adult patients: Cross‐sectional, randomized, double‐blind, placebo‐controlled clinical trial

Maghbooli, Mehdi; NajafAbadi, Somayeh Alyan; MalekMahmoudi, Ghazal; Molseghi, Mohammad Hadi

doi:10.1002/brb3.2860

Cited by 9 publications

(6 citation statements)

References 57 publications

(47 reference statements)

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“…29 Moreover, treatment of epileptic rodents and patients with melatonin has shown anticonvulsive effects. [30][31][32] This seems, however, to be dependent on melatonin concentrations, with too high melatonin concentrations also having proconvulsive effects. 33 In patients, despite showing normal rhythmicity, melatonin levels have been reported to be lower when compared to control.…”

Section: Discussionmentioning

confidence: 99%

“…Melatonin is the primary hormone integrating sleep–wake cycle and circadian rhythms 29 . Moreover, treatment of epileptic rodents and patients with melatonin has shown anticonvulsive effects 30–32 . This seems, however, to be dependent on melatonin concentrations, with too high melatonin concentrations also having proconvulsive effects 33 .…”

Section: Discussionmentioning

confidence: 99%

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CPEB4–CLOCK crosstalk during temporal lobe epilepsy

de Diego‐Garcia,

Brennan,

Auer

et al. 2023

Epilepsia

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ObjectivePost‐transcriptional mechanisms are increasingly recognized as important contributors to the formation of hyperexcitable networks in epilepsy. Messenger RNA (mRNA) polyadenylation is a key regulatory mechanism governing protein expression by enhancing mRNA stability and translation. Previous studies have shown large‐scale changes in mRNA polyadenylation in the hippocampus of mice during epilepsy development. The cytoplasmic polyadenylation element‐binding protein CPEB4 was found to drive epilepsy‐induced poly(A) tail changes and mice lacking CPEB4 develop a more severe seizure and epilepsy phenotype. The mechanisms controlling CPEB4 function and the downstream pathways that influence the recurrence of spontaneous seizures in epilepsy remain poorly understood.MethodsStatus epilepticus was induced in wild‐type and CPEB4‐deficient male mice via an intra‐amygdala microinjection of kainic acid. CLOCK binding to the CPEB4 promoter was analyzed via Chromatin immunoprecipitation assay and melatonin levels via High‐Performance Liquid Chromatography in plasma.ResultsHere we show increased binding of CLOCK to recognition sites in the CPEB4 promoter region during status epilepticus in mice and increased Cpeb4 mRNA levels in N2A cells overexpressing CLOCK. Bioinformatic analysis of CPEB4‐dependent genes undergoing changes in their poly(A) tail during epilepsy found that genes involved in the regulation of circadian rhythms are particularly enriched. Clock transcripts displayed a longer poly(A) tail length in the hippocampus of mice post‐status epilepticus and during epilepsy. Moreover, CLOCK expression was increased in the hippocampus in mice post‐status epilepticus and during epilepsy, and in resected hippocampus and cortex of patients with drug‐resistant temporal lobe epilepsy. Further, CPEB4 is required for CLOCK expression after status epilepticus, with lower levels in CPEB4‐deficient compared to wild‐type mice. Last, CPEB4‐deficient mice showed altered circadian function, including altered melatonin blood levels and altered clustering of spontaneous seizures during the day.SignificanceOur results reveal a new positive transcriptional‐translational feedback loop (TTFL) involving CPEB4 and CLOCK, which may contribute to the regulation of the sleep‐wake cycle during epilepsy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CPEB4–CLOCK crosstalk during temporal lobe epilepsy

de Diego‐Garcia,

Brennan,

Auer

et al. 2023

Epilepsia

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“…For instance, melatonin showed beneficial effects in animal models of iron‐induced, 114 penicillin‐induced, 115 pentylenetetrazol‐induced, 116 and kainate‐induced seizures 117 . Recent clinical trials support the use of melatonin as an add‐on to improve seizure frequency or severity 118,119 . However, earlier studies have been deemed of poor methodological quality and did not allow for a univocal conclusion on the subject 120 .…”

Section: Discussionmentioning

confidence: 99%

“…117 Recent clinical trials support the use of melatonin as an add-on to improve seizure frequency or severity. 118,119 However, earlier studies have been deemed of poor methodological quality and did not allow for a univocal conclusion on the subject. 120 The findings presented here indicate that the possible benefits of the use of melatonin in epilepsy are worth further research.…”

Section: Kir21 Protein Trafficking To the Plasma Membrane Was Not Alt...mentioning

confidence: 99%

Melatonin protects Kir2.1 function in an oxidative stress‐related model of aging neuroglia

Remigante,

Spinelli,

Zuccolini

et al. 2023

BioFactors

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Melatonin is a pleiotropic biofactor and an effective antioxidant and free radical scavenger and, as such, can be protective in oxidative stress‐related brain conditions including epilepsy and aging. To test the potential protective effect of melatonin on brain homeostasis and identify the corresponding molecular targets, we established a new model of oxidative stress‐related aging neuroglia represented by U‐87 MG cells exposed to D‐galactose (D‐Gal). This model was characterized by a substantial elevation of markers of oxidative stress, lipid peroxidation, and protein oxidation. The function of the inward rectifying K+ channel Kir2.1, which was identified as the main Kir channel endogenously expressed in these cells, was dramatically impaired. Kir2.1 was unlikely a direct target of oxidative stress, but the loss of function resulted from a reduction of protein abundance, with no alterations in transcript levels and trafficking to the cell surface. Importantly, melatonin reverted these changes. All findings, including the melatonin antioxidant effect, were reproduced in heterologous expression systems. We conclude that the glial Kir2.1 can be a target of oxidative stress and further suggest that inhibition of its function might alter the extracellular K+ buffering in the brain, therefore contributing to neuronal hyperexcitability and epileptogenesis during aging. Melatonin can play a protective role in this context.

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“…Another study found a decrease in seizures in children who took exogenous melatonin to improve sleep [ 46 ]. In patients with epilepsy with idiopathic generalized tonic-clonic seizures, Maghbooli et al found that the addition of melatonin to patients’ valproic acid treatment was associated with a significant reduction in the severity of epilepsy and improvement in sleep quality [ 47 ].…”

Section: Melatonin: Usage and Considerationsmentioning

confidence: 99%

Chronic Administration of Melatonin: Physiological and Clinical Considerations

Givler

Luther

et al. 2023

Neurology International

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Background: Exogenous melatonin is commonly used to treat insomnia, other sleep problems, and numerous medical illnesses, including Alzheimer’s disease, autism spectrum disorder, and mild cognitive impairment in adults and children. There is evolving information regarding issues with the use of chronic melatonin. Methods: The present investigation was a narrative review. Results: Melatonin usage has risen dramatically in recent years. Many countries only allow melatonin prescriptions. In the United States (U.S.), it is classified as a dietary supplement accessible over the counter and can be derived from animals, microorganisms, or, most commonly, made synthetically. No regulatory agency oversees its manufacturing or sale in the U.S. melatonin concentration of marketed preparations varies widely between product labels and manufacturers. Melatonin’s ability to induce sleep is detectable. However, it is modest for most people. Sleep length appears to be less important in sustained-release preparations. The optimal dosage is unknown, and routinely used amounts vary substantially. Melatonin’s short-term negative effects are minimal, resolve at medicine cessation, and do not usually prevent usage overall. Much research on long-term melatonin administration has found no difference between exogenous melatonin and placebo in terms of long-term negative effects. Conclusion: Melatonin at low to moderate dosages (approximately 5–6 mg daily or less) appears safe. Long-term usage appears to benefit certain patient populations, such as those with autism spectrum disorder. Studies investigating potential benefits in reducing cognitive decline and increased longevity are ongoing. However, it is widely agreed that the long-term effects of taking exogenous melatonin have been insufficiently studied and warrant additional investigation.

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Effect of add‐on melatonin on seizure outcomes and quality of sleep in epilepsy with idiopathic generalized tonic‐clonic seizures alone in adult patients: Cross‐sectional, randomized, double‐blind, placebo‐controlled clinical trial

Cited by 9 publications

References 57 publications

CPEB4–CLOCK crosstalk during temporal lobe epilepsy

CPEB4–CLOCK crosstalk during temporal lobe epilepsy

Melatonin protects Kir2.1 function in an oxidative stress‐related model of aging neuroglia

Chronic Administration of Melatonin: Physiological and Clinical Considerations

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