Prophylactic treatment with melatonin after status epilepticus: Effects on epileptogenesis, neuronal damage, and behavioral changes in a kainate model of temporal lobe epilepsy Jana Tchekalarova a, ⁎, Zlatina Petkova a , Daniela Pechlivanova a , Slavianka Moyanova a , Lidia Kortenska a , Rumiana Mitreva a , Valentin Lozanov b , Dimitrina Atanasova a , Nikolai Lazarov a, c , Alexander Stoynev d a Institute of Neurobiology, Acad. G. Bonchev Str., Bl. 23, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria b Department of Medical Chemistry and Biochemistry, Medical Faculty, Medical University—Sofia, Bulgaria c Department of Anatomy and Histology, Medical Faculty, Medical University—Sofia, Bulgaria d Department of Pathophysiology, Medical Faculty, Medical University—Sofia, Bulgaria abstract article info Article history: Received 23 December 2012 Revised 7 January 2013 Accepted 10 January 2013 Available online xxxx Keywords: Melatonin Circadian Kainic acid Depression Monoamines Neuronal damage Melatonin is a potent antioxidant which showed anticonvulsant activities both in experimental and clinical studies. In the present study, we examined the effect of melatonin treatment (10 mg/kg/day, diluted in drinking water, 8 weeks) during epileptogenesis on the consequences of a kainate (KA)-induced status epilepticus (SE) in rats. Melatonin increased the latency in the appearance of spontaneous recurrent seizures (SRSs) and decreased their frequency only during the treatment period. The behavioral alterations associated with hyperactivity, depression-like behavior during the light phase, and deficits in hippocampus-dependent working memory were positively affected by melatonin treatment in rats with epilepsy. Melatonin reduced the neuronal damage in the CA1 area of the hippocampus and piriform cortex and recovered the decrease of hippocampal serotonin (5-HT) level in rats with epilepsy. Taken together, long-term melatonin treatment after SE was unable to suppress the development of epileptogenesis. However, it showed a potential in reduc- ing some of the deleterious alterations that develop during the chronic epileptic state in a diurnal phase- dependent mode. © 2013 Elsevier Inc. All rights reserved. 1. Introduction Melatonin plays a modulatory role in the circadian rhythms of body temperature, mood, and behavioral performance [1]. This hor- mone exerts an inhibitory function in the central nervous system (CNS) and exhibits anticonvulsant, sedative, hypnotic, and anxiolytic activities in rodents [2–5]. Melatonin is effective against memory def- icit, oxidative stress, and neuronal damage in streptozotocin-induced diabetes [6], cerebral hemorrhage [7], an Alzheimer disease model [8], and age-associated brain dysfunction [9]. Melatonin is a powerful an- tioxidant that can easily cross cell membranes and the blood-brain barrier. Clinical and experimental data raise the point of the potential therapeutic role of melatonin in epilepsy. Epilepsy is characterized by a circadian periodicity of interictal epileptiform EEG activity [10], which is associated with disturbed rhythms of melatonin synthesis in untreated patients with active epilepsy [11]. Clinical evidence has revealed that melatonin is characterized by a low toxicity and may be used for seizure control in conjunction with antiseizure medications [12]. This hormone is also able to reduce the spiking ac- tivity and seizure frequency in patients with intractable epilepsy [13,14]. In patients with temporal lobe epilepsy (TLE), high levels of salivary melatonin have been observed during the postictal period [15]. Experimental data revealed that melatonin acts as an anticonvul- sant against chemically-induced seizures [16–18], maximal electro- shock [19], and electrical kindling of the amygdala [20,21]. Besides being an effective chronobiotic agent and synchronizer of the biologi- cal clock, melatonin acts as a neuroprotective agent able to prevent excitotoxic neuronal damage in animal models of neurotoxicity, stroke, and traumatic brain injury [22]. A single injection of melatonin in rats before and during kainic acid (KA)- or pilocarpine-induced status epilepticus (SE) has neuroprotective effects by reducing neuro- nal death, supragranular mossy fiber sprouting, lipid peroxidation, and microglial activation [4,22,23]. In line with this, Guisti et al. [24] reported that a single 10-mg/kg dose of melatonin prevented KA-induced neuronal death as well as behavioral and biochemical dis- turbances in rats. It is tempting to speculate that the antioxidant action of melatonin may be one of the possible mechanisms of its neuroprotective effect. Melatonin has been shown to have neuro- protective effects against toxic quinones and oxidative stress pro- duced by catecholamines [25]. In addition to protecting several brain Epilepsy & Behavior 27 (2013) 174–187 ⁎ Corresponding author. E-mail address: janetchekalarova@gmail.com (J. Tchekalarova). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.01.009 Contents lists available at SciVerse ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh