Treatment with melatonin after status epilepticus attenuates seizure activity and neuronal damage but does not prevent the disturbance in diurnal rhythms and behavioral alterations in spontaneously hypertensive rats in kainate model of temporal lobe epilepsy Zlatina Petkova 1 , Jana Tchekalarova ⁎ ,1 , Daniela Pechlivanova 1 , Slavianka Moyanova, Lidia Kortenska, Rumiana Mitreva, Deyan Popov 2 , Petya Markova 2 , Valentin Lozanov 3 , Dimitrina Atanasova, Nikolai Lazarov 4 , Alexander Stoynev 5 Institute of Neurobiology, Acad. G. Bonchev Str., Bl. 23, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria abstract article info Article history: Received 23 October 2013 Revised 14 November 2013 Accepted 15 December 2013 Available online xxxx Keywords: Spontaneous hypertensive rats Kainate model of temporal lobe epilepsy Melatonin Diurnal rhythms Melatonin is involved in the control of circadian and seasonal rhythmicity, possesses potent antioxidant activity, and exerts a neuroprotective and anticonvulsant effect. Spontaneously hypertensive rats (SHRs) are widely ac- cepted as an experimental model of essential hypertension with hyperactivity, deficient sustained attention, and alterations in circadian autonomic profiles. The purpose of the present study was to determine whether mel- atonin treatment during epileptogenesis can prevent the deleterious consequences of status epilepticus (SE) in SHRs in the kainate (KA) model of temporal lobe of epilepsy (TLE). Spontaneous recurrent seizures (SRSs) were EEG- and video-recorded during and after the treatment protocol. Melatonin (10 mg/kg diluted in drinking water, 8 weeks) increased the seizure-latent period, decreased the frequency of SRSs, and attenuated the circa- dian rhythm of seizure activity in SHRs. However, melatonin was unable to affect the disturbed diurnal rhythms and behavioral changes associated with epilepsy, including the decreased anxiety level, depression, and impaired spatial memory. Melatonin reduced neuronal damage specifically in the CA1 area of the hippocampus and piriform cortex and decreased hippocampal serotonin (5-HT) levels both in control and epileptic SHRs. Although long-term melatonin treatment after SE shows a potential to attenuate seizure activity and neuronal loss, it is un- able to restore epilepsy-associated behavioral abnormalities in SHRs. © 2013 Elsevier Inc. All rights reserved. 1. Introduction Depression is a common comorbid disorder in epilepsy, but it often remains unrecognized and untreated. Recently, we studied the develop- ment of behavioral and neurochemical indices of depressive state in the kainate (KA) model of TLE in two rat strains [1]. The emotional distur- bances in epileptic Wistar and SHRs were accompanied by decreased levels of hippocampal serotonin (5-HT) and dopamine (DA). These re- sults were in agreement with the reported compromised serotoninergic neurotransmission in the raphe-hippocampal serotonergic pathway in the pilocarpine post-status epilepticus (SE) model [2]. One factor, which may contribute to the development of depressive state in TLE is rhythm disturbances and, in particular, phase changes in melatonin syn- thesis. It is widely accepted that mood disorders are related to biological rhythm abnormalities, which can include diurnal mood variation, elevat- ed nocturnal body temperature, lower nocturnal thyroid-stimulating hormone, an overall increased cortisol secretion, and sleep architecture abnormalities as well as an increase in cortisol and melatonin secretion [3]. Products active on circadian rhythms are shown to have chronobiotic effects, and exogenous melatonin is considered one of the best-known Epilepsy & Behavior 31 (2014) 198–208 Abbreviations: ABP, arterial blood pressure; BL, basolateral nucleus; C, control; DA, dopamine; DNA, deoxyribonucleic acid; DWRME, “double” working and reference memo- ry error; EEG, electroencephalography; EPM, elevated plus maze; FST, forced swimming test; 5-HT, serotonin; Hip, hippocampus; HPLC, high-performance liquid chromatography; i.p., intraperitoneally; KA, kainic acid; Mel, melatonin; OF, open field; Pir, piriform cortex; PT, pars tuberalis; RAM, radial arm maze; RME, reference memory error; s.c., subcutane- ously; SCN, suprachiasmatic nucleus; SCT, sucrose consumption test; SE, status epilepti- cus; SHRs, spontaneously hypertensive rats; SRSs, spontaneous recurrent seizures; SWDs, spike–wave discharges; TLE, temporal lobe epilepsy; Veh, vehicle; WM, working memory error. ⁎ Corresponding author. E-mail address: janetchekalarova@gmail.com (J. Tchekalarova). 1 These authors contributed equally to this project and should be considered co-first authors. 2 Present address: Department of Physiology, Medical Faculty, Medical University (MU)-Sofia, Bulgaria. 3 Present address: Department of Medical Chemistry and Biochemistry, Medical Faculty, MU-Sofia, Bulgaria. 4 Present address: Department of Anatomy, Medical Faculty, MU-Sofia, Bulgaria. 5 Present address: Department of Pathophysiology, Medical Faculty, MU-Sofia, Bulgaria. 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.12.013 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh