Agomelatine alleviates neuronal loss through BDNF signaling in the post-status epilepticus model induced by kainic acid in rat

• Published in: Brain research bulletin 2019-04, Vol.147, p.22-35
• Main Authors: Tchekalarova, Jana, Atanasova, Dimitrinka, Kortenska, Lidia, Lazarov, Nikolai, Shishmanova-Doseva, Michaela, Galchev, Tzeno, Marinov, Pencho
• Format: Article
• Language: English
• Subjects: Acetamides - metabolism; Acetamides - pharmacology; Agomelatine; Animals; BDNF; Brain-Derived Neurotrophic Factor - metabolism; Disease Models, Animal; EEG; Electroencephalography; Epilepsy, Temporal Lobe - chemically induced; Hippocampus - drug effects; Kainic Acid - pharmacology; Lacosamide; Lacosamide - pharmacology; Male; Neurons - drug effects; Neuroprotective Agents - pharmacology; Power spectrum; Rats; Rats, Wistar; Seizures - chemically induced; Seizures - physiopathology; Signal Transduction; Status epilepticus; Status Epilepticus - chemically induced; Status Epilepticus - physiopathology
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2019.01.017

•Ago was unable to mitigate status epilepticus and spontaneous seizures in rats.•Ago and LCM prevented neuronal loss in the dorsal hippocampal and the piriform cortex.•Ago and LCM inhibited increased expression in the mossy fibers of BDNF in epileptic rats.•LCM decreased relative powers of cortical gamma frequency bands to baseline.•LCM decreased absolute powers of high (HI) (60–120 Hz) frequency bands to baseline. Recently, we have reported that while agomelatine (Ago) is unable to prevent development of epilepsy it exerts a strong neuroprotective and anti-inflammatory response in the KA post-status epilepticus (SE) rat model. In the present study, we aimed to explore whether the brain-derived neurotrophic factor (BDNF) in the hippocampus is involved in the neuroprotective effect of Ago against the KA-induced SE and epileptiform activity four months later in rats. Lacosamide (LCM) was used as a positive control. The EEG-recorded seizure activity was also evaluated in two treatment protocols. In Experiment#1, Ago given repeatedly at a dose of 40 mg/kg during the course of SE was unable neither to modify EEG-recorded epileptiform activity nor the video- and EEG-recorded spontaneous seizures four months later compared to LCM (50 mg/kg). However, both Ago and LCM inhibited the expression of BDNF in the mossy fibers and also prevented neuronal loss in the dorsal hippocampal and the piriform cortex after SE. In Experiment#2, acute injection of Ago and LCM on epileptic rats, characterized by high seizure rates, did not prevent EEG-recorded paroxysmal events while only LCM decreased either absolute or relative powers of gamma (28–60 Hz) and high (HI) (60–120 Hz) frequency bands to baseline in the frontal and parietal cortex, respectively. Our results suggest that the protection against neuronal loss in specific limbic regions and overexpressed BDNF in the mossy fibers resulting from the repeated treatment with Ago and LCM, respectively, during SE is not a prerequisite for alleviation of epileptogenesis and development of epilepsy. In addition, a reduction of gamma and HI bands in the frontal and parietal cortex is not associated with EEG-recorded paroxysmal events after acute injection of LCM.