Anticonvulsant effect of melatonin through ATP‐sensitive channels in mice

Mohammadi, Fatemeh; Shakiba, Saeed; Mehrzadi, Saeed; Afshari, Khashayar; Rahimnia, Amirhossein; Dehpour, Ahmad Reza

doi:10.1111/fcp.12490

Cited by 14 publications

(10 citation statements)

References 54 publications

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“…77 In further support, studies have also suggested that melatonin may enhance the antiseizure effects of morphine through the NO pathway. 78,79 A study conducted in 2020 showed that the anticonvulsant effect of melatonin may also be achieved by increasing the opening of the potassium (K ATP ) channels 80 (Table 1). Potassium channels such as Kir6.1 and Kir6.2 channels have been shown to be involved in the oxidative stress and mitochondrial dysfunction of epilepsy, and thus its relationship with melatonin should be investigated further.…”

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confidence: 99%

Melatonin as an Antiepileptic Molecule: Therapeutic Implications via Neuroprotective and Inflammatory Mechanisms

Akyüz

Küllü

Arulsamy

et al. 2021

ACS Chem. Neurosci.

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Epilepsy is a result of unprovoked, uncontrollable, and repetitive outburst of abnormal and excessive electrical discharges, known as seizures, in the neurons. Epilepsy is a devastating neurological condition that affects 70 million people globally. Unfortunately, only two-thirds of epilepsy patients respond to antiepileptic drugs while others become drug resistant and may be more prone to epilepsy comorbidities such as SUDEP. Oxidative stress, mitochondrial dysfunction, imbalance in the excitatory and inhibitory neurotransmitters, and neuroinflammation are some of the common pathologies of neurological disorders and epilepsy. Studies suggests that melatonin, a pineal hormone that governs sleep−wake cycles, may be neuroprotective against neurological disorders and thus may be translated as an antiepileptic as well. Melatonin has been shown to be an antioxidant, antiexcitotoxic, and anti-inflammatory hormone/ molecule in neurodegenerative diseases, which may contribute to its antiepileptic and neuroprotective properties in epilepsy as well. In addition, melatonin has evidently been shown to play a regulatory role in the cardiorespiratory system and sleep−wake cycles, which may have positive implications toward epilepsy associated comorbidities, such as SUDEP. However, studies investigating the changes in melatonin release due to epilepsy and melatonin's antiepileptic role have been inconclusive and scarce, respectively. Thus, this comprehensive review aims to summarize and elucidate the potential role of melatonin in the pathogenesis of epilepsy and its comorbidities, in hopes to develop new diagnostic and therapeutic approaches that will improve the lives of epileptic patients, particularly those who are drug resistant.

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confidence: 99%

Melatonin as an Antiepileptic Molecule: Therapeutic Implications via Neuroprotective and Inflammatory Mechanisms

Akyüz

Küllü

Arulsamy

et al. 2021

ACS Chem. Neurosci.

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“…Clinical and experimental data in several animal models, including the temporal lobe epilepsy model, confi rm the anticonvulsant role of the pineal hormone melatonin [18]. Its advantages are good safety profi le (being an endogenous compound), potent antioxidant activity, contribution to degeneration protection of neurons against the mutagenic and carcinogenic eff ect of oxidants, and above all, its essential biological function to synchronize natural rhythms.…”

Section: Discussionmentioning

confidence: 98%

Aryl Hydrocarbon Receptors in Indole Derivative Treated Mice: Neuropharmacological Perspectives

Andreeva-Gateva

Tchekalarova

Kamenova

et al. 2021

Acta Medica Bulgarica

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Aim/objective. When applied in pharmacological doses, the indole derivative melatonin exhibits neuroactive and neuroprotective effects. Indoles and their metabolites, such as kynurenine, are ligands of aryl hydrocarbon receptors (AhR). This study aimed to evaluate the antiepileptic and analgesic activity of melatonin and two synthetic melatonin derivatives. The possible involvement of AhR and kynurenine in their neuropharmacological effects were also tested. Methods. The tested substances were: melatonin, two melatonin derivatives bearing aryl hydrocarbon moiety with either furyl or thienyl substitute (3e and 3f), and alpha naphthoflavone (ANF), an antagonist of AhR. After intraperitoneal injection of 30, 100, or 300 mg/kg of the tested agents for seven days, male mice ICR (25-30 g) were subjected to a corneal kindling seizure model. Two tests for analgesia, i.e., the hot plate test and the formalin test, were also applied. AhR and kynurenine concentrations were evaluated in brain homogenates. Results. Substances 3e and 3f demonstrated an antiepileptic activity comparable to that of melatonin. Some analgesic activity was also shown, albeit lower than that of melatonin in equivalent doses. For melatonin and 3f treated mice, dose-dependent increases in AhR and kynurenine levels in brain homogenates were recorded. The antagonist ANF neither blocks the antiseizure activity of the tested indoles, nor demonstrated analgesic activity. Conclusion. Melatonin and the two tested melatonin-aroylhydrazone derivatives bearing either furyl or thienyl substitute exhibit antiepileptic and analgesic activity. Our results did not support the involvement of AhR in the demonstrated neurobiological activity. Further studies are needed to elucidate their exact molecular mechanisms.

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“…Melatonin may exert the anticonvulsant effect by GABA receptor modulation (Gunata et al 2020;Wan et al 1999), closure of the voltage-dependent calcium channel (Choi et al 2014), suppression of glutamatergic transmission in the striatum (Escames et al 2004), increasing the opening of K ATP channels (Mohammadi et al 2020), and by attenuation of hippocampal and cerebral cortex hyperexcitability through MT 1 receptor agonism (Ray et al 2004). Melatonin and its metabolites directly scavenge various free radicals in a receptor-independent manner and also stimulate the activity of several antioxidant enzymes and inhibit activities of oxidative enzymes (Reiter et al, 2007(Reiter et al, , 2016.…”

Section: Discussionmentioning

confidence: 99%

“…2004), increasing the opening of K ATP channels (Mohammadi et al. 2020), and by attenuation of hippocampal and cerebral cortex hyperexcitability through MT 1 receptor agonism (Ray et al. 2004).…”

Section: Discussionmentioning

confidence: 99%

Effect of add‐on melatonin on seizure outcome, neuronal damage, oxidative stress, and quality of life in generalized epilepsy with generalized onset motor seizures in adults: A randomized controlled trial

Verma

Maiti

Mishra

et al. 2021

J of Neuroscience Research

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Epilepsy treatment is challenging because of multiple impediments like lack of efficacy of monotherapy, adverse drug reactions, and different comorbidities. Add-on therapy to first-line antiepileptics may be the option to overcome therapeutic hurdles. The present randomized, double-blind, add-on placebo-controlled clinical trial was conducted to evaluate the effect of add-on melatonin in the treatment of generalized epilepsy with generalized onset motor seizure in adults. The control group (n = 52) received add-on placebo, and the test group (n = 52) received add-on melatonin (3 mg/day) with valproate (20 mg/kg in two divided doses). Clinical evaluation of seizure frequency, Chalfont-National Hospital seizure severity scale (NHS3), Pittsburgh sleep quality index (PSQI), quality of life in epilepsy inventory, Epworth sleepiness scale (ESS), and biochemical estimation of serum neuron-specific enolase (NSE) and glutathione reductase were done at baseline and compared with follow-up at 8 weeks. Among 104 patients randomized [mean (SD) age of 27.6 (11.5); 84 (80.8%) male], 88 (84.6%) completed the trial. The responder rate and seizure-free rate in the test group were significantly (p = 0.006 and 0.034) higher than the control group.There was a significantly higher reduction in the frequency of seizures (p = 0.016) and NHS3 (−2.39; 95%CI: −4.56 to −0.21; p = 0.032) in the test group compared to the control group. Similarly, improvement in PSQI (−1.40; 95%CI: −2.64 to −0.15; p = 0.029) was significantly better in the test group. There was no significant difference in the change in ESS (p = 0.621) and quality of life scoring (p = 0.456) between the study groups. The decrease in serum NSE was significantly higher with the test group compared to the control group (−2.01; 95% CI: −3.74 to −0.27; p = 0.024).Add-on melatonin increased serum glutathione reductase significantly (p = 0.038), but there was no significant difference between the groups (p = 0.685). Add-on melatonin with valproate for generalized epilepsy with generalized onset motor seizures | 1619 VERMA Et Al. 1 | INTRODUC TI ON Epilepsy is a chronic disabling disorder with neurobiological, cognitive, psychological, and social comorbidities leading to impaired quality of life (Yogarajah & Mula, 2019). Despite the abundance of antiepileptic drugs (AEDs), even after long-term treatment of 6-8 years, 30% of patients continue having seizures (Brigo et al. 2016). Treatment with valproate for generalized epilepsy is associated with weight gain, gastrointestinal distress, alopecia, dizziness, depression, idiosyncratic toxicities like hepatotoxicity, pancreatitis, thrombocytopenia etc. and hence, therapeutic drug monitoring is required to prevent dose-related toxicities. Moreover, comorbidities like sleep disorders, cognitive impairment, anxiety disorders, and depression make the treatment challenging. Sleep disorders in patients with epilepsy are prevalent, and previous studies proved that seizure and sleep are reciprocally related (Ekizoglu et al. 2011). Sleep architect...

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Anticonvulsant effect of melatonin through ATP‐sensitive channels in mice

Cited by 14 publications

References 54 publications

Melatonin as an Antiepileptic Molecule: Therapeutic Implications via Neuroprotective and Inflammatory Mechanisms

Melatonin as an Antiepileptic Molecule: Therapeutic Implications via Neuroprotective and Inflammatory Mechanisms

Aryl Hydrocarbon Receptors in Indole Derivative Treated Mice: Neuropharmacological Perspectives

Effect of add‐on melatonin on seizure outcome, neuronal damage, oxidative stress, and quality of life in generalized epilepsy with generalized onset motor seizures in adults: A randomized controlled trial

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