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1.
Behav Brain Res ; 302: 11-28, 2016 Apr 01.
Article in English | MEDLINE | ID: mdl-26779670

ABSTRACT

Previous data have shown that the rat model of melatonin deficit can cause a number of neurobiological aberrations. The aim of the present study was to determine whether the antidepressant drug agomelatine, a MT1/MT2 melatoninergic receptor agonist/5-HT2C receptor antagonist is able to prevent some of the behavioral, biochemical and cellular abnormalities induced by pinealectomy. The injection of agomelatine (40 mg/kg, i.p. for 5 weeks)/vehicle started after pinealectomy/sham procedure in Wistar rats. Animals were tested in different behavioral tests for anxiety and depression during the period of agomelatine treatment (chronic effect) and two months later (plastic effect). The effect of agomelatine on KCl-evoked serotonin (5-HT) release from the hippocampus, the activity of the hypothalamic-pituitary-adrenal (HPA) axis and neuronal loss in pinealectomized rats were assessed. Our results showed that agomelatine not only did not prevent the disturbed emotional arousal/anxiety behavior in pinealectomized rats during the treatment but the enhanced motor activity and decreased anxiety state was still observed two months after the discontinuation of treatment. However, the drug corrected a depressive-like behavior (chronic and plastic effect), alleviated the enhanced KCl-evoked 5-HT release in the hippocampus, recovered the suppressed negative feedback inhibition of HPA axis and exerted a neuroprotection in pinealectomized rats. Our findings suggest that pinealectomy can model melancholic depression disorder while the antidepressant action of agomelatine is associated with a correction of 5-HT release in the hippocampus, dysregulated HPA system and neuroprotection in limbic structures.


Subject(s)
Acetamides/therapeutic use , Depressive Disorder/etiology , Depressive Disorder/prevention & control , Hypnotics and Sedatives/therapeutic use , Pineal Gland/injuries , Pineal Gland/physiology , Adaptation, Ocular/drug effects , Analysis of Variance , Animals , Body Weight/drug effects , Depressive Disorder/pathology , Drug Administration Schedule , Exploratory Behavior/drug effects , Food Preferences/drug effects , Hippocampus/drug effects , Hippocampus/metabolism , Male , Maze Learning/drug effects , Rats , Rats, Wistar , Serotonin/metabolism , Swimming/psychology , Time Factors , Tritium/metabolism
2.
Cell Mol Neurobiol ; 36(6): 927-941, 2016 Aug.
Article in English | MEDLINE | ID: mdl-26464042

ABSTRACT

Over the last 10 years, accumulated experimental and clinical evidence has supported the idea that AT1 receptor subtype is involved in epilepsy. Recently, we have shown that the selective AT1 receptor antagonist losartan attenuates epileptogenesis and exerts neuroprotection in the CA1 area of the hippocampus in epileptic Wistar rats. This study aimed to verify the efficacy of long-term treatment with losartan (10 mg/kg) after kainate-induced status epilepticus (SE) on seizure activity, behavioral and biochemical changes, and neuronal damage in a model of co-morbid hypertension and epilepsy. Spontaneous seizures were video- and EEG-monitored in spontaneously hypertensive rats (SHRs) for a 16-week period after SE. The behavior was analyzed by open field, elevated plus maze, sugar preference test, and forced swim test. The levels of serotonin in the hippocampus and neuronal loss were estimated by HPLC and hematoxylin and eosin staining, respectively. The AT1 receptor antagonism delayed the onset of seizures and alleviated their frequency and duration during and after discontinuation of treatment. Losartan showed neuroprotection mostly in the CA3 area of the hippocampus and the septo-temporal hilus of the dentate gyrus in SHRs. However, the AT1 receptor antagonist did not exert a substantial influence on concomitant with epilepsy behavioral changes and decreased 5-HT levels in the hippocampus. Our results suggest that the antihypertensive therapy with an AT1 receptor blocker might be effective against seizure activity and neuronal damage in a co-morbid hypertension and epilepsy.


Subject(s)
Behavior, Animal/drug effects , Hippocampus/drug effects , Hypertension/physiopathology , Losartan/pharmacology , Neurons/drug effects , Seizures/drug therapy , Animals , Disease Models, Animal , Hypertension/complications , Losartan/administration & dosage , Male , Rats , Rats, Inbred SHR , Seizures/complications , Seizures/physiopathology , Status Epilepticus/chemically induced
3.
Epilepsy Behav ; 51: 1-12, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26245156

ABSTRACT

Our previous studies revealed that Angiotensin (Ang) II has anticonvulsant effects in acute seizure models. However, data on its role in experimental models of epilepsy are missing. In the present study, we tested whether posttreatment with Ang II after kainate (KA)-induced status epilepticus (SE) can affect epileptogenesis, concomitant behavioral changes, and brain damage. The Wistar rats were intracerebroventricularly infused via osmotic mini-pumps with Ang II (1.52µg/µl/day for 28days) after SE. Spontaneous motor seizures (SMS) were video-recorded for up to three months. Locomotor activity, anxiety, and depression-like behavior were evaluated during the last week of drug infusion, while spatial memory was assessed during the 3rd month after SE. Angiotensin II decreased the latency for onset of the first SMS and increased the frequency of SMS two months after SE. The continuous peptide infusion exacerbated the KA-induced hyperactivity and caused depression-like behavior. The reduced anxiety of KA-treated rats was alleviated by Ang II exposure. The KA-induced deficit in the hippocampal-dependent spatial memory was not influenced by Ang II. However, Ang II partially prevented the neuronal damage in the hippocampus, specifically in the CA1 area. The role of AT1 and AT2 receptor activation in the effects of the octapeptide is discussed.


Subject(s)
Angiotensin II/pharmacology , Anticonvulsants/pharmacology , Behavior, Animal/drug effects , CA1 Region, Hippocampal/drug effects , Circadian Rhythm/drug effects , Kainic Acid/pharmacology , Neuroprotective Agents/pharmacology , Spatial Memory/drug effects , Status Epilepticus/drug therapy , Angiotensin II/administration & dosage , Animals , Anticonvulsants/administration & dosage , CA1 Region, Hippocampal/pathology , Disease Models, Animal , Infusions, Intraventricular , Kainic Acid/toxicity , Male , Neuroprotective Agents/administration & dosage , Rats , Rats, Wistar , Status Epilepticus/chemically induced
4.
Pharmacol Biochem Behav ; 127: 27-36, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25456349

ABSTRACT

Recently, we have shown that the blockade of AT1 receptor might be useful as an adjuvant treatment strategy for the prevention of oxidative stress and neurotoxicity caused by status epilepticus (SE) in rats. The purpose of the present study was to further assess the efficacy of long-term treatment with losartan (10mg/kg), the selective AT1 receptor antagonist, during kainate (KA)-induced epileptogenesis in Wistar rats. Losartan treatment started after onset of SE and continued for 4weeks. The rats were video- and EEG-recorded for 3months. Locomotor activity, anxiety and depressive-like behavior were evaluated 9weeks after SE, when all rats had developed chronic epileptic state. Neuronal damage in hippocampus was analyzed by hematoxylin while serotonin (5-HT) levels in hippocampus by HPLC. AT1 receptor antagonism increased the latent seizure-free period and decreased the frequency of spontaneous motor seizures. Losartan positively affected epilepsy-provoked behavioral changes, including impulsivity, low anxiety level and depression in a phase-dependent manner and restored the changes in diurnal fluctuation of motor activity. Losartan exerted neuroprotection selectively in the CA1 area of the hippocampus in the KA-treated rats and lowered the 5-HT levels both in normal and abnormal conditions. Our findings suggest that the AT1 receptor antagonist exerts disease-modifying effects during KA-induced epileptogenesis and neuronal damage in CA1 hippocampal area, attenuated some of the behavioral changes and restored diurnal variability in locomotor activity.


Subject(s)
Anticonvulsants/therapeutic use , Epilepsy, Temporal Lobe/chemically induced , Epilepsy, Temporal Lobe/drug therapy , Kainic Acid/toxicity , Losartan/therapeutic use , Neuroprotective Agents/therapeutic use , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Animals , Male , Random Allocation , Rats , Rats, Wistar , Treatment Outcome
5.
Epilepsy Behav ; 31: 198-208, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24440891

ABSTRACT

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 accepted 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 melatonin 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 (10mg/kg diluted in drinking water, 8weeks) increased the seizure-latent period, decreased the frequency of SRSs, and attenuated the circadian 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 unable to restore epilepsy-associated behavioral abnormalities in SHRs.


Subject(s)
Antioxidants/therapeutic use , Behavior, Animal/drug effects , Brain/pathology , Epilepsy, Temporal Lobe/drug therapy , Epilepsy, Temporal Lobe/physiopathology , Melatonin/therapeutic use , Animals , Antioxidants/pharmacology , Blood Pressure/drug effects , Body Weight/drug effects , Brain/drug effects , Circadian Rhythm/drug effects , Disease Models, Animal , Epilepsy, Temporal Lobe/chemically induced , Exploratory Behavior/drug effects , Food Preferences/drug effects , Kainic Acid/toxicity , Male , Maze Learning/drug effects , Melatonin/pharmacology , Rats , Rats, Inbred SHR , Serotonin/metabolism , Swimming/psychology , Time Factors
6.
Epilepsy Behav ; 27(1): 174-87, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23435277

ABSTRACT

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 (10mg/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 reducing some of the deleterious alterations that develop during the chronic epileptic state in a diurnal phase-dependent mode.


Subject(s)
Central Nervous System Depressants/therapeutic use , Depression/prevention & control , Hyperkinesis/prevention & control , Melatonin/therapeutic use , Status Epilepticus/complications , Analysis of Variance , Animals , Chromatography, High Pressure Liquid , Depression/etiology , Electroencephalography , Excitatory Amino Acid Agonists/toxicity , Exploratory Behavior/drug effects , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Hyperkinesis/etiology , Kainic Acid/toxicity , Kaplan-Meier Estimate , Male , Maze Learning/drug effects , Neurons/pathology , Rats , Rats, Wistar , Serotonin/metabolism , Status Epilepticus/chemically induced , Status Epilepticus/drug therapy , Sucrose/administration & dosage , Swimming , Time Factors
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