Melatonin Increases Following Convulsive Seizures may be Related to its Anticonvulsant Properties at Physiological Concentrations

Abstract

Melatonin (N-acetyl-5-methoxytryptamine, aMT) is an indoleamine produced by several organs and tissues including the pineal gland. Melatonin (aMT) modulates the activity of the brain, mainly acting on both GABA and glutamate receptors. Previous studies have shown the participation of melatonin in the control of convulsive crises, suggesting that aMT concentration increases during seizures, and that patients with seizures of diverse origins show an alteration of the aMT rhythm. However, what is not known is the duration of the aMT response to seizures, and whether aMT changes during seizures could be a marker of the disease. For this reason, the serum levels of aMT in 54 children with a convulsive crisis, febrile and epileptic, were analyzed during the crisis, as well as at 1 h and 24 hours after the seizure. The results show that aMT significantly increases during the seizure (Day group, 75.64±45.91 and Night group, 90.69±51.85 pg/mL), with normal values being recovered 1 h later (Day group, 26.33±10.15 and Night group, 27.78±7.82 pg/mL) and maintained for up to 24 hours, when the circadian variation of aMT returns to the normal acrophase. Due to the interindividual variation of aMT levels among healthy people, a single determination of the indoleamine concentration is not a suitable marker of the existence of a convulsive crisis unless the circadian profile of aMT secretion in the patient is known. The results obtained also support the view that the stimulation of aMT production by the convulsive crisis may participate in the response of the organism against the seizures.

Key words

Melatonin - epileptic seizures - febrile seizures - children - anticonvulsant

References

• 1 Acuña-Castroviejo D, Castillo JL, Fernández B, Gomar MD, Del Águila CM. Modulation by pineal gland of ouabain high-affinity binding sites in rat cerebral cortex.  Am J Physiol. 1992;  262 R698-R706
• 2 Acuña-Castroviejo D, Del Águila CM, Fernández B, Gomar MD, Castillo JL. Pinealectomy increases ouabain high-affinity binding sites and dissociation constant in rat cerebral cortex.  Neurosci Lett. 1991;  127 227-230
• 3 Acuña-Castroviejo D, Del Águila CM, Fernández B, Gomar MD, Castillo JL. Characterization of ouabain high-affinity binding to rat cerebral cortex. Modulation by melatonin.  Eur J Pharmacol. 1992;  226 59-67
• 4 Acuña-Castroviejo D, Escames Rosa G, Macías M, Muñoz-Hoyos A, Molina-Carballo A, Arauzo M. et al . Cell protective role of melatonin in the brain.  J Pineal Res. 1995;  19 57-63
• 5 Acuna-Castroviejo D, Lowenstein PR, Rosenstein R, Cardinali DP. Diurnal variations of benzodiazepine binding in rat cerebral cortex: disruption by pinealectomy.  J Pineal Res. 1986;  3 101-109
• 6 Acuña-Castroviejo D, Martín M, Macías M, Escames G, León J, Khaldy H. et al . Melatonin, mitochondria, and cellular bioenergetics.  J Pineal Res. 2001;  30 65-74
• 7 Anton-Tay F. Melatonin: Effects on brain function.  Adv Biochem Psychopharmacol. 1974;  11 315-324
• 8 Bauer J, Kaufmann P, Klingmüller D, Elger CE. Serum prolactin response to repetitive epileptic seizures.  J Neurol. 1994;  241 242-245
• 9 Bazil CW, Short D, Crispin D, Zheng W. Patients with intractable epilepsy have low melatonin, which increases following seizures.  Neurology. 2000;  55 1746-1748
• 10 Bikjdaouene L, Escames G, Leon J, Ferrer JM, Khaldy H, Vives F. et al . Changes in brain amino acids and nitric oxide after melatonin administration in rats with pentylenetetrazole-induced seizures.  J Pineal Res. 2003;  35 54-60
• 11 Cardinali DP, Golombek DA. The rhythmic GABAergic system.  Neurochem Res. 1998;  23 607-614
• 12 Cardinali DP, Lowenstein PR, Rosenstein RE, Gonzalez-Solveyra C, Sarmiento MI, Romeo HE. et al . Functional links between benzodiazepine and GABA receptors and pineal activity.  Adv Biochem Psychopharmacol. 1986;  42 155-164
• 13 Carter DS, Goldman BD. Progonadal role of the pineal in the Djungarian hamster (Phodopus sungorus sungorus): mediation by melatonin.  Endocrinology. 1983;  113 1268-1273
• 14 Castillo-Romero JL, Vives-Montero F, Acuna-Castroviejo D. Paradoxical effects of melatonin on spontaneous neuronal activity in the striatum of sham-operated and pinealectomized rats.  J Pineal Res. 1992;  12 149-154
• 15 Datta PC, King MG. Melatonin: Effects on brain and behavior.  Neurosci Biobehav Rev. 1980;  4 451-458
• 16 Dragunow M. Endogenous anticonvulsant substances.  Neurosci Behav Physiol. 1986;  10 229-244
• 17 Fariello RG, Bubenik GA, Brown GM, Grota LJ. Epileptogenic action of intraventricularly injected anti-melatonin antibody.  Neurology. 1977;  27 567-570
• 18 Fauteck J, Schmidt H, Lerchl A, Kurlemann G, Wittkowski W. Melatonin in epilepsy: first results of replacement therapy and first clinical results.  Biol Signals Recept. 1999;  8 105-110
• 19 Fernández B, Malde JL, Montero A, Acuña D. Relationship between adenohypophyseal and steroid hormones and variations in serum and urinary melatonin levels during the ovarian cycle, perimenopause and menopause in healthy women.  J Steroids Biochem. 1990;  33 257-262
• 20 Jan JE, Connolly MB, Hamilton D, Freeman RD, Laudon M. Melatonin treatment of non-epileptic myoclonus in children.  Dev Med Child Neurol. 1999;  41 255-259
• 21 Jan MM. Melatonin for the treatment of handicapped children with severe sleep disorders.  Pediatr Neurol. 2000;  23 229-232
• 22 Kabuto H, Yokoi I, Ogawa N. Melatonin inhibits iron-induced epileptic discharges in rats by suppressing peroxidation.  Epilepsia. 1998;  39 237-243
• 23 Kabuto M, Namura I, Saitoh Y. Nocturnal enhancement of plasma melatonin could be suppressed by benzodiazepines in humans.  Endocrinol Jpn. 1986;  33 405-414
• 24 Klein DC. Photoneural regulation of the mammalian pineal gland. In: Clark S, Evered D, eds. Photoperiodism: melatonin and the pineal. London: Ciba. Found.Symp. 1985: 129-148
• 25 Lapin IP, Mirzaev SM, Ryzov IV, Oxenkrug GF. Anticonvulsant activity of melatonin against seizures induced by quinolinate, kainate, glutamate, NMDA, and pentylenetetrazole in mice.  J Pineal Res. 1998;  24 215-218
• 26 Manev H, Uz T, Kharlamov A, Joo JY. Increased brain damage after stroke or excitotoxic seizures in melatonin deficient rats.  FASEB J. 1996;  10 1546-1551
• 27 Márquez de Prado, Castañeda TR, Galindo A, del Arco A, Segovia G, Reiter RJ. et al . Melatonin disrupts circadian rhythms of glutamate and GABA in the neostriatum of the aware rat: a microdialysis study.  J Pineal Res. 2000;  29 209-216
• 28 Molina A, Muñoz A, Rodríguez T, Acuña D, Moreno F, Ruiz C. Interaction between duration of convulsion, refractory postseizure period and melatonin levels.  Neuroendocrinology. 1990;  52 102 , [Abstract]
• 29 Molina-Carballo A, Acuña-Castroviejo D, Rodríguez-Cabezas T, Muñoz-Hoyos A. Effects of febrile and epileptic convulsions on daily variations in plasma melatonin concentration in children.  J Pineal Res. 1994;  16 1-9
• 30 Molina-Carballo A, Muñoz-Hoyos A, Reiter RJ, Sánchez Forte M, Moreno Madrid F, Rufo Campos M. et al . Utility of high doses of melatonin as adjunctive anticonvulsant therapy in a child with severe myoclonic epilepsy: Two years' experience.  J Pineal Res. 1997;  23 97-105
• 31 Molina-Carballo A, Muñoz-Hoyos A, Rodríguez-Cabezas T, Acuña-Castroviejo D. Day night variations in melatonin secretion by the pi-neal gland during febrile and epileptic convulsions in children.  Psychiat Res. 1994;  52 273-283
• 32 Monteleone P, Tortorella A, Borriello R, Natale M, Cassandro P, Maj M. Suppression of nocturnal plasma melatonin levels by evening administration of sodium valproate in healthy humans.  Biol Psychiat. 1997;  41 336-341
• 33 Muñoz-Hoyos A, Jaldo R, Molina-Carballo A, Escames G, Macías M, Fernández-García JM. et al . Characterization of nocturnal ultradian rhythms of melatonin in children with growth hormone-dependent and independent growth delay.  J Clin Endocrinol Metab. 2001;  86 1181-1187
• 34 Muñoz-Hoyos A, Molina-Carballo A, Macías M, Rodríguez-Cabezas T, Martín-Medina E, Narbona-López E. et al . Comparison between tryptophan, methoxyindole and kynurenine metabolic pathways in normal and preterm neonates and in neonates with acute fetal distress.  Eur J Endocrinol. 1998;  139 89-95
• 35 Muñoz-Hoyos A, Molina-Carballo A, Rodríguez-Cabezas T, Uberos-Fernández J, Ruiz-Cosano C, Acuna-Castroviejo D. Relationships between methoxyindole and kynurenine pathway metabolites in plasma and urine in children suffering from febrile and epileptic seizures.  Clin Endocrinol (Oxf). 1997;  47 667-677
• 36 Philo R. Catecholamines and pinealectomy convulsions in the gerbil (Meriones unguiculatus). In: Reiter RJ, ed. The pineal and its hormones. New York: Alan R. Liss 1982: 233-241
• 37 Quigg M. Circadian rhythms: interactions with seizures and epilepsy.  Epilepsy Res. 2000;  42 43-55
• 38 Reiter RJ. Mechanisms of control of reproductive physiology by the pi-neal gland and its hormones. In: Reiter RJ, Fraschini F, eds. Advances in Pineal Research. 2000 London, John Libbey & Co Ltd. 1987: 109-125
• 39 Reiter RJ, Guerrero JM, Escames G, Pappolla MA, Acuña-Castroviejo D. Prophylactic actions of melatonin in oxidative neurotoxicity.  Ann N Y Acad Sci. 1997;  825 70-78
• 40 Renkawek K, Renier WO, Pont JJHHM de, Vogels OJM, Gabreëls FJM. Neonatal status convulsivus, spongiform encephalopathy, and low activity of Na⁺/K⁺-ATPase in the brain.  Epilepsia. 1992;  33 58-64
• 41 Rudeen PK, Philo RC, Symmes SK. Antiepileptic effects of melatonin in the pinealectomized Mongolian gerbil.  Epilepsia. 1980;  21 149-154
• 42 Sánchez-Forte M, Moreno-Madrid F, Muñoz-Hoyos A, Molina-Carballo A, Acuña-Castroviejo D, Molina-Font JA. The effect of melatonin as anti-convulsant and neuronal protector.  Rev Neurol. 1997;  25 1229-1234
• 43 Sandyk R, Tsagas N, Anninos PA. Melatonin as a proconvulsive hormone in humans.  Int J Neurosci. 1992;  63 125-135
• 44 Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children.  Lancet. 1998;  351 1254
• 45 Sugawara T, Tsurubuchi Y, Agarwala KL, Ito M, Fukuma G, Mazaki-Miyazaki E. et al . A missense mutation of the Na+ channel alpha II subunit gene Na(v)12 in a patient with febrile and afebrile seizures causes channel dysfunction.  Proc Natl Acad Sci USA. 2001;  98 6384-6389
• 46 Wassmer E, Quinn E, Whitehouse W, Seri S. Melatonin as a sleep inductor for electroencephalogram recordings in children.  Clin Neurophysiol. 2001;  112 683-685
• 47 Zhdanova IV, Dollins AB, Lynch HJ, Wurtman RJ. Induced melatonin levels comparable to normal nocturnal levels affect human sleep.  Clin Res. 1994;  42 A260
• 48 Zhdanova IV, Lynch HJ, Wurtman RJ. Melatonin: a sleep-promoting hormone.  Sleep. 1997;  20 899-907

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