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1.
Int J Mol Sci ; 25(12)2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38928281

ABSTRACT

The pivotal role of the basolateral amygdala (BLA) in the emotional modulation of hippocampal plasticity and memory consolidation is well-established. Specifically, multiple studies have demonstrated that the activation of the noradrenergic (NA) system within the BLA governs these modulatory effects. However, most current evidence has been obtained by direct infusion of synthetic NA or beta-adrenergic agonists. In the present study, we aimed to investigate the effect of endogenous NA release in the BLA, induced by a natural aversive stimulus (coyote urine), on memory consolidation for a low-arousing, hippocampal-dependent task. Our experiments combined a weak object location task (OLT) version with subsequent mild predator odor exposure (POE). To investigate the role of endogenous NA in the BLA in memory modulation, a subset of the animals (Wistar rats) was treated with the non-selective beta-blocker propranolol at the end of the behavioral procedures. Hippocampal tissue was collected 90 min after drug infusion or after the OLT test, which was performed 24 h later. We used the obtained samples to estimate the levels of phosphorylated CREB (pCREB) and activity-regulated cytoskeleton-associated protein (Arc)-two molecular markers of experience-dependent changes in neuronal activity. The result suggests that POE has the potential to become a valuable behavioral paradigm for studying the interaction between BLA and the hippocampus in memory prioritization and selectivity.


Subject(s)
Basolateral Nuclear Complex , Emotions , Hippocampus , Memory Consolidation , Norepinephrine , Odorants , Rats, Wistar , Animals , Memory Consolidation/physiology , Memory Consolidation/drug effects , Basolateral Nuclear Complex/metabolism , Basolateral Nuclear Complex/physiology , Basolateral Nuclear Complex/drug effects , Male , Rats , Norepinephrine/metabolism , Hippocampus/metabolism , Hippocampus/physiology , Hippocampus/drug effects , Emotions/physiology , Emotions/drug effects , Cyclic AMP Response Element-Binding Protein/metabolism , Propranolol/pharmacology
2.
Int J Mol Sci ; 25(3)2024 Feb 03.
Article in English | MEDLINE | ID: mdl-38339146

ABSTRACT

A reduction in melatonin function contributes to the acceleration of Alzheimer's disease (AD), and understanding the molecular processes of melatonin-related signaling is critical for intervention in AD progression. Recently, we synthesized a series of melatonin analogues with donepezil fragments and tested them in silico and in vitro. In this study, one of the most potent compounds, 3c, was evaluated in a rat model of pinealectomy (pin) followed by icvAß1-42 infusion. Melatonin was used as the reference drug. Treatment with melatonin and 3c (10 mg/kg, i.p. for 14 days) had a beneficial effect on memory decline and the concomitant increase in hippocampal Aß1-42 and pTAU in the pin+icvAß1-42 rats. Melatonin supplementation facilitated non-amyloidogenic signaling via non-receptor (histone deacetylase sirtuin 1, SIRT1) and receptor-related signaling (MT/ERK/CREB). The hybrid 3c analogue up-regulated the MT1A and MT2B receptors, pERK and pCREB. Our results strongly support the hypothesis that melatonin-related analogues may become a promising drug candidate for Alzheimer's disease therapy.


Subject(s)
Alzheimer Disease , Melatonin , Peptide Fragments , Rats , Animals , Melatonin/pharmacology , Melatonin/therapeutic use , Alzheimer Disease/drug therapy , Donepezil/pharmacology , Pinealectomy , Hippocampus/metabolism , Amyloid beta-Peptides/metabolism , Memory Disorders/drug therapy , Memory Disorders/etiology
3.
Physiol Behav ; 269: 114268, 2023 10 01.
Article in English | MEDLINE | ID: mdl-37308045

ABSTRACT

Spontaneously hypertensive rats (SHRs) are widely accepted for modeling essential hypertension and Attention deficit hyperactivity disorder (ADHD). However, data concerning central nervous system changes associated with behavioral responses of this strain and usage of Wistar Kyoto (WKY) rats as controls are confounding. The objective of the present study was to assess the impact of anxiety and motor activity on the cognitive responses of SHRs compared to Wistar and WKY rats. In addition, the role of brain-derived neurotrophic factor (BDNF) in the hippocampus on cognitive behavior and seizure susceptibility in the three strains was evaluated. In Experiment#1, SHR demonstrated impulsive responses in the novelty suppression feeding test accompanied by impaired spatial working and associative memory in the Y maze and object recognition test compared with the Wistar rat but not WKY rats. In addition, the WKY rats exhibited diminished activity compared to Wistar rats in an actimeter. In Experiment#2, the seizure susceptibility was assessed by 3-min electroencephalographic (EEG) recording after two consecutive injections of pentylenetetrazol (PTZ) (20+40 mg/kg). The WKY rats were more vulnerable to rhythmic metrazol activity (RMA) than the Wistar rats. In contrast, Wistar rats were more prone to generalized tonic-clonic seizures (GTCS) than WKY rats and SHRs. Control SHR had lower BDNF expression in the hippocampus compared to Wistar rats. However, while the BDNF levels were elevated in the Wistar and WKY rats after PTZ injection, no change in this signaling molecule was observed in the SHR in the seizure condition. The results suggest Wistar rats as a more appropriate control of SHR than WKY rats for studying memory responses mediated by BDNF in the hippocampus. The higher vulnerability to seizures in Wistar and WKY rats compared to SHR might be linked to PTZ-induced decreased expression of BDNF in the hippocampus.


Subject(s)
Attention Deficit Disorder with Hyperactivity , Brain-Derived Neurotrophic Factor , Rats , Animals , Rats, Inbred SHR , Rats, Inbred WKY , Rats, Wistar , Anxiety/psychology , Attention Deficit Disorder with Hyperactivity/metabolism , Attention Deficit Disorder with Hyperactivity/psychology , Cognition , Seizures/chemically induced , Motor Activity , Disease Models, Animal
4.
Int J Mol Sci ; 23(18)2022 Sep 08.
Article in English | MEDLINE | ID: mdl-36142262

ABSTRACT

Prenatal stress (PNS) impairs the circadian rhythm of the sleep/wake cycle. The melatonin (MT) analogue Piromelatine (Pir) was designed for the treatment of insomnia. The present study aimed to explore effects of Pir on circadian rhythmicity, motor activity, and sleep structure in male and female rats with a history of prenatal stress (PNS). In addition, we elucidated the role of MT receptors and brain-derived neurotrophic factor (BDNF) to ascertain the underlying mechanism of the drug. Pregnant rats were exposed to different stressors from day seven until birth. Piromelatine (20 mg/kg/day/14 days) was administered to young adult offspring. Home-cage locomotion, electroencephalographic (EEG) and electromyographic (EMG) recordings were conducted for 24 h. Offspring treated with vehicle showed sex-and phase-dependent disturbed circadian rhythm of motor activity and sleep/wake cycle accompanied by elevated rapid eye movement (REM) pattern and theta power and diminished non-rapid eye movement (NREM) sleep and delta power. While Pir corrected the PNS-induced impaired sleep patterns, the MT receptor antagonist luzindol suppressed its effects in male and female offspring. In addition, Pir increased the BDNF expression in the hippocampus in male and female offspring with PNS. Our findings suggest that the beneficial effect of Pir on PNS-induced impairment of sleep/wake cycle circadian rhythm and sleep structure is exerted via activation of MT receptors and enhanced BDNF expression in the hippocampus in male and female offspring.


Subject(s)
Brain-Derived Neurotrophic Factor , Melatonin , Animals , Brain-Derived Neurotrophic Factor/pharmacology , Circadian Rhythm/physiology , Electroencephalography , Female , Indoles , Male , Melatonin/pharmacology , Melatonin/therapeutic use , Pregnancy , Pyrans/pharmacology , Rats , Receptors, Melatonin , Sleep/physiology
5.
Int J Mol Sci ; 23(5)2022 Mar 04.
Article in English | MEDLINE | ID: mdl-35269951

ABSTRACT

The pineal gland regulates the aging process via the hormone melatonin. The present report aims to evaluate the effect of pinealectomy (pin) on behavioral and oxidative stress-induced alterations in cholesterol and sphingomyelin (SM) levels in young adult, mature and aging rats. Sham and pin rats aged 3, 14 and 18 months were tested in behavioral tests for motor activity, anxiety, and depression. The ELISA test explored oxidative stress parameters and SM in the hippocampus, while total cholesterol was measured in serum via a commercial autoanalyzer. Mature and aged sham rats showed low motor activity and increased anxiety compared to the youngest rats. Pinealectomy affected emotional responses, induced depressive-like behavior, and elevated cholesterol levels in the youngest rats. However, removal of the pineal gland enhanced oxidative stress by diminishing antioxidant capacity and increasing the MDA level, and decreased SM level in the hippocampus of 14-month-old rats. Our findings suggest that young adult rats are vulnerable to emotional disturbance and changes in cholesterol levels resulting from melatonin deficiency. In contrast, mature rats with pinealectomy are exposed to an oxidative stress-induced decrease in SM levels in the hippocampus.


Subject(s)
Melatonin , Pineal Gland , Animals , Emotions , Melatonin/pharmacology , Oxidative Stress , Pineal Gland/physiology , Pineal Gland/surgery , Rats , Sphingomyelins
6.
Physiol Behav ; 239: 113525, 2021 10 01.
Article in English | MEDLINE | ID: mdl-34242671

ABSTRACT

Recently, we reported that the atypical antidepressant agomelatine (Ago) exerted a beneficial impact on behavioral changes and concomitant neuropathological events in icvSTZ rat model of sporadic Alzheimer diseases (AD). In the present study, we aimed to explore the effect of Ago (40 mg/kg, i.p. for 30 days) on beta-amyloid (Aß) metabolism in icvAß1-42 rat model of AD. The melatonin analogue was administered either simultaneously with Aß1-42 (AßAgo1) or 30 days later during the late stage of the progression of AD (AßAgo2). Treatment with Ago in the early stage of AD attenuated anxiety and depressive-like responses but was inefficient against Aß-induced impairment of hippocampus-dependent spatial memory. The melatonin analogue, administered both during the early and the late stage of AD, corrected to control level the elevated Aß1-42 in the frontal cortex (FC) and the hippocampus. The concentration of α-secretase was enhanced by AßAgo1 compared to the sham- and Aß-veh groups in the hippocampus. No changes in the concentration of ß-secretase in the FC and the hippocampus as well as of γ-secretase in the FC were observed among groups. Both the AßAgo1 and AßAgo2 attenuated to control level the Aß-induced increased concentration of γ-secretase in the hippocampus. AßAgo1 exerted also structure-specific neuroprotection observed mainly in the CA1, septal CA3b subfield of the dorsal hippocampus and septo-temporal piriform cortex (Pir) and partially in the temporal CA3c, septal and temporal Pir. These findings suggest that Ago treatment in the early stage of AD can exert beneficial effects on concomitant behavioral impairments and neuroprotection in associated brain structures. The antidepressant administration both in the early stage and after the progression of AD affected Aß metabolism via decreasing of γ-secretase concentration in the hippocampus.


Subject(s)
Alzheimer Disease , Acetamides , Alzheimer Disease/chemically induced , Alzheimer Disease/complications , Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Animals , Anxiety , Disease Models, Animal , Hippocampus/metabolism , Rats
7.
Psychopharmacology (Berl) ; 237(2): 503-518, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31720718

ABSTRACT

RATIONALE: Exposure to chronic constant light (CCL) has a detrimental impact on circadian rhythms of motor activity and sleep/wake cycles. Agomelatine is an atypical antidepressant showing a chronotropic activity. OBJECTIVES: In this study, we explored the role of melatonin (MT) receptors and brain-derived neurotrophic factor (BDNF) in the brain in the mechanism underlying the effects of agomelatine on diurnal variations of motor activity, sleep/wake cycle, and sleep architecture in a rat model of CCL. METHODS: In Experiment #1, home cage activity was monitored automatically with cameras for a period of 24 h. The diurnal rhythm of MT1, MT2 receptors, and BDNF expression in the hippocampus and frontal cortex (FC), was tested using the ELISA test. In Experiment #2, rats were equipped with electroencephalographic (EEG) and electromyographic (EMG) electrodes and recordings were made under basal conditions (12:12 LD cycle + vehicle), LL + vehicle and LL + agomelatine (40 mg/kg/day for 21 days). RESULTS: The rats exposed to CCL showed an impaired diurnal rhythm of motor activity and sleep/wake cycle with reduced NREM sleep and delta power and increased REM sleep and theta power. The duration and number of episodes of the wake were diminished during the subjective dark phase in this group. The circadian rhythm of MT1 and MT2 receptors and their expression did not change in the hippocampus and FC under CCL exposure, while the BDNF levels in the hippocampus decreased during the subjective light phase. Agomelatine restored the diurnal rhythm of motor activity, disturbed sleep/wake cycle, and sleep architecture, which effect was accompanied by an increase in MT1 receptor and BDNF expression in the hippocampus at 10:00 in CCL rats. CONCLUSIONS: These findings support the value of agomelatine as an antidepressant that can adjust circadian homeostasis of motor activity and sleep/wake cycle in a CCL model.


Subject(s)
Acetamides/therapeutic use , Brain-Derived Neurotrophic Factor/biosynthesis , Hippocampus/metabolism , Receptor, Melatonin, MT1/biosynthesis , Sleep Stages/physiology , Sleep Wake Disorders/metabolism , Acetamides/pharmacology , Animals , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Brain-Derived Neurotrophic Factor/genetics , Circadian Rhythm/drug effects , Circadian Rhythm/physiology , Electroencephalography/drug effects , Electroencephalography/methods , Gene Expression , Hippocampus/drug effects , Hypnotics and Sedatives/pharmacology , Hypnotics and Sedatives/therapeutic use , Male , Photic Stimulation/adverse effects , Rats , Rats, Wistar , Receptor, Melatonin, MT1/genetics , Sleep Stages/drug effects , Sleep Wake Disorders/drug therapy
8.
Brain Res Bull ; 147: 22-35, 2019 04.
Article in English | MEDLINE | ID: mdl-30738136

ABSTRACT

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.


Subject(s)
Acetamides/pharmacology , Neurons/drug effects , Status Epilepticus/physiopathology , Acetamides/metabolism , Animals , Brain-Derived Neurotrophic Factor/metabolism , Disease Models, Animal , Electroencephalography , Epilepsy, Temporal Lobe/chemically induced , Hippocampus/drug effects , Kainic Acid/pharmacology , Lacosamide/pharmacology , Male , Neuroprotective Agents/pharmacology , Rats , Rats, Wistar , Seizures/chemically induced , Seizures/physiopathology , Signal Transduction , Status Epilepticus/chemically induced
9.
Horm Behav ; 107: 11-19, 2019 01.
Article in English | MEDLINE | ID: mdl-30452900

ABSTRACT

Experimental findings suggest that the melatonin system has a beneficial role in models of Alzheimer's disease (ADs). The aim of the present study was to explore whether the atypical antidepressant agomelatine (Ago), which is a melatonin MT1 and MT2 agonist and 5-HT2C antagonist, is effective against behavioral, biochemical and histological impairments in streptozotocin (STZ)-induced model of ADs in male rats. Male Sprague Dawley rats were treated intraperitoneally (i.p.) with Ago (40 mg/kg) for 30 days starting three months following the intracerebroventricular (icv) injection of STZ. Chronic Ago treatment reduced anxiety-like behavior of STZ-treated rats in the elevated plus maze, increased the preference to saccharine and corrected the spatial memory impairment in the eight-arm radial arm maze test. This melatonin analogue restored STZ-induced biochemical changes, including an increase of beta amyloid (Aß) protein, and signal markers of inflammation (TNF-alpha and IL-1 beta). Ago exerted partial neuroprotection, specifically in the temporal CA3b subfield of the dorsal hippocampus and temporal piriform cortex. The ability of Ago to alleviate behavioral symptoms and concomitant neuropathological events observed in a model of sporadic ADs suggests that this melatonin alternative can be considered a promising adjuvant in this disease.


Subject(s)
Acetamides/pharmacology , Alzheimer Disease/chemically induced , Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Streptozocin , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Animals , Anxiety/metabolism , Anxiety/pathology , Anxiety/physiopathology , Disease Models, Animal , Exploratory Behavior/drug effects , Hippocampus/drug effects , Male , Maze Learning/drug effects , Melatonin/metabolism , Memory Disorders/chemically induced , Memory Disorders/metabolism , Memory Disorders/pathology , Rats , Rats, Sprague-Dawley
10.
Neurobiol Dis ; 115: 127-144, 2018 07.
Article in English | MEDLINE | ID: mdl-29653194

ABSTRACT

Inflammatory signal molecules are suggested to be involved in the mechanism underlying comorbid depression in epilepsy. In the present study, we tested the hypothesis that the novel antidepressant agomelatine, a potent melatonin MT1 and MT2 receptor agonist and serotonin 5HT2C receptor antagonist, can prevent depressive symptoms developed during the chronic epileptic phase by suppressing an inflammatory response. Chronic treatment with agomelatine (40 mg/kg, i.p.) was initiated an hour after the kainate acid (KA)-induced status epilepticus (SE) and maintained for a period of 10 weeks in Wistar rats. Registration of spontaneous motor seizures was performed through a video (24 h/day) and EEG monitoring. Antidepressant activity of agomelatine was explored in the splash test, sucrose preference test (SPT) and forced swimming test (FST) while anxiolytic effect was observed through the novelty suppression-feeding test (NSFT) during chronic phase in epileptic rats. The frequency of motor seizures detected by video and EEG recording did not differ between vehicle and Ago group. Rats with registered spontaneous motor seizures showed symptoms typical for depressive behavior that included decreased grooming, anhedonia during the dark period and hopeless-like behavior. Epileptic rats exhibited also anxiety with novelty-induced hypophagia. This behavioral deficit correlated with increased signal markers of inflammation (plasma levels of interleukin (IL)-1ß and activated glia in brain), while plasma corticosterone levels were not changed. Agomelatine treatment during epileptogenesis exerted a clear antidepressant effect by suppressing all behavioral hallmarks, reducing plasma IL-1ß levels and preventing microgliosis and astrogliosis in specific limbic regions. The present results suggest that agomelatine treatment starting after SE can provide an effective therapy of comorbid depression in chronic epileptic condition through suppression of inflammatory signaling.


Subject(s)
Acetamides/administration & dosage , Antidepressive Agents/administration & dosage , Depression/prevention & control , Disease Models, Animal , Inflammation Mediators/antagonists & inhibitors , Status Epilepticus/drug therapy , Animals , Comorbidity , Depression/metabolism , Depression/physiopathology , Hypnotics and Sedatives/administration & dosage , Inflammation Mediators/metabolism , Male , Rats , Rats, Wistar , Signal Transduction/drug effects , Signal Transduction/physiology , Status Epilepticus/metabolism , Status Epilepticus/physiopathology , Treatment Outcome
11.
Neurobiol Dis ; 104: 1-14, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28438504

ABSTRACT

Recent studies about the novel antidepressant agomelatine, which is a mixed MT1 and MT2 melatonin receptor agonist and 5HT2C serotonin receptor antagonist possessing an anticonvulsant and neuroprotective action, suggest that it may have potential to contribute against epileptogenesis and epilepsy-induced memory impairment. In order to ascertain whether protection of some brain structures could suppress epileptogenesis, in the present study, we evaluated the effect of chronic post-status treatment with agomelatine on epileptogenesis, behavioral and neuronal damage induced by kainate acid (KA) status epilepticus (SE). Agomelatine/vehicle treatment (40mg/kg, i.p.) started one hour after SE and continued up to 10weeks in Wistar rats. Latency for onset of spontaneous motor seizures (SMS) and their frequency was detected by a 24-h video-recording. Locomotor activity, anxiety and hippocampus-dependent spatial memory in open field (OF), elevated plus maze (EPM), light-dark test (LDT) and radial arm maze (RAM) test, respectively, were evaluated during the last two weeks after SE. Agomelatine significantly decreased the latency for onset of SMS and increased the seizure frequency during the 2nd and the 3rd week of treatment. The MT1 and MT2 receptor agonist and serotonin 5HT2C receptor antagonist exacerbated the KA-induced hyperlocomotion and impulsive behavior and it was unable to prevent spatial memory impairment of epileptic rats. However, agomelatine induced a neuroprotection in the dorsal hippocampus, specifically in the CA1, septal CA2 and partially in the CA3c region, the hilus of the dentate gyrus, piriform cortex and septo-temporal and temporal basolateral amygdala. Our findings suggest that the beneficial impact against SE-induced neuronal loss exerted by agomelatine is not crucial for the suppression of epileptogenesis and its deleterious consequences in KA model of temporal lobe epilepsy.


Subject(s)
Acetamides/therapeutic use , Epilepsy, Temporal Lobe/pathology , Epilepsy, Temporal Lobe/prevention & control , Hippocampus/pathology , Neurons/drug effects , Adaptation, Ocular/drug effects , Analysis of Variance , Animals , Anxiety/drug therapy , Anxiety/etiology , Body Weight/drug effects , Disease Models, Animal , Epilepsy, Temporal Lobe/chemically induced , Epilepsy, Temporal Lobe/drug therapy , Excitatory Amino Acid Agonists/toxicity , Exploratory Behavior/drug effects , Hypnotics and Sedatives/therapeutic use , Kainic Acid/toxicity , Male , Maze Learning/drug effects , Motor Activity/drug effects , Rats , Rats, Wistar , Time Factors
12.
Brain Res Bull ; 124: 62-75, 2016 06.
Article in English | MEDLINE | ID: mdl-27040713

ABSTRACT

Recently, we have reported that spontaneously hypertensive rats (SHRs) exhibit higher susceptibility than Wistar rats in kainate (KA) model of epilepsy. The aim of the present study is to compare the baseline of EEG signals in SHRs and Wistar rats using Discrete Fourier transform (DFT) during the three phases of KA model (acute, latent and chronic). The SHRs showed higher baseline relative power of delta waves in the left frontal cortex and lower gamma-HF waves in the left frontal and left/right parietal cortex, respectively, compared to Wistar rats. During the acute phase, both absolute and relative power of fast EEG bands (gamma-HF) was lower in the left/right frontal and the left/right parietal cortex in SHRs compared to Wistar rats. During the latent phase, no difference in the power of the investigated bands was detected between the two strains. During the chronic epileptic phase, the SHRs were characterized with higher power of HF oscillations than Wistar rats both in the frontal and parietal cortex without brain lateralization while theta, alpha and beta bands were with diminished power in the left parietal cortex of SHRs compared to normotensive Wistar rats. Taken together, the presented results suggest that the increased delta waves and lower gamma-HF waves in the frontal/parietal cortex are associated with a higher seizure susceptibility of SHRs compared to Wistar rats while fastest oscillations has a critical role in seizure generation and propagation of hypertensive rats.


Subject(s)
Brain Waves/physiology , Epilepsy/chemically induced , Epilepsy/physiopathology , Excitatory Amino Acid Agonists/toxicity , Kainic Acid/toxicity , Spectrum Analysis , Animals , Blood Pressure , Brain Mapping , Brain Waves/drug effects , Brain Waves/genetics , Disease Models, Animal , Electroencephalography , Male , Rats , Rats, Inbred SHR , Rats, Wistar
13.
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
14.
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
15.
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
16.
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
17.
Exp Transl Stroke Med ; 5(1): 13, 2013 Nov 19.
Article in English | MEDLINE | ID: mdl-24245542

ABSTRACT

BACKGROUND: The human population mostly affected by stroke is more than 65 years old. This study was designed to meet the recommendation that models of cerebral ischemia in aged animals are more relevant to the clinical setting than young animal models. Until now the majority of the pre-clinical studies examining age effects on stroke outcomes have used rats of old age. Considering the increasing incidence of stroke among younger than old human population, new translational approaches in animal models are needed to match the rejuvenation of stroke. A better knowledge of alterations in stroke outcomes in middle-aged rats has important preventive and management implications providing clues for future investigations on effects of various neuroprotective and neurorestorative drugs against cerebrovascular accidents that may occur before late senescence. METHODS: We evaluated the impact of transient focal ischemia, induced by intracerebral unilateral infusion of endothelin-1 (Et-1) near the middle cerebral artery of conscious rats, on volume of brain damage and asymmetry in behavioral and electroencephalographic (EEG) output measures in middle-aged (11-12 month-old) rats. RESULTS: We did not find any age-dependent difference in the volume of ischemic brain damage three days after Et-1 infusion. However, age was an important determinant of neurological and EEG outcomes after stroke. Middle-aged ischemic rats had more impaired somatosensory functions of the contralateral part of the body than young ischemic rats and thus, had greater left-right reflex/sensorimotor asymmetry. Interhemispheric EEG asymmetry was more evident in middle-aged than in young ischemic rats, and this could tentatively explain the behavioral asymmetry. CONCLUSIONS: With a multiparametric approach, we have validated the endothelin model of ischemia in middle-aged rats. The results provide clues for future studies on mechanisms underlying plasticity after brain damage and motivate investigations of novel neuroprotective strategies against cerebrovascular accidents that may occur before late senescence.

18.
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
19.
J Cereb Blood Flow Metab ; 31(4): 1107-18, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21157475

ABSTRACT

We examined the influence of type 4 metabotropic glutamate (mGlu4) receptors on ischemic brain damage using the permanent middle cerebral artery occlusion (MCAO) model in mice and the endothelin-1 (Et-1) model of transient focal ischemia in rats. Mice lacking mGlu4 receptors showed a 25% to 30% increase in infarct volume after MCAO as compared with wild-type littermates. In normal mice, systemic injection of the selective mGlu4 receptor enhancer, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-caboxamide (PHCCC; 10 mg/kg, subcutaneous, administered once 30 minutes before MCAO), reduced the extent of ischemic brain damage by 35% to 45%. The drug was inactive in mGlu4 receptor knockout mice. In the Et-1 model, PHCCC administered only once 20 minutes after ischemia reduced the infarct volume to a larger extent in the caudate/putamen than in the cerebral cortex. Ischemic rats treated with PHCCC showed a faster recovery of neuronal function, as shown by electrocorticographic recording and by a battery of specific tests, which assess sensorimotor deficits. These data indicate that activation of mGlu4 receptors limit the development of brain damage after permanent or transient focal ischemia. These findings are promising because selective mGlu4 receptor enhancers are under clinical development for the treatment of Parkinson's disease and other central nervous system disorders.


Subject(s)
Ischemic Attack, Transient/genetics , Ischemic Attack, Transient/pathology , Receptors, Metabotropic Glutamate/genetics , Receptors, Metabotropic Glutamate/physiology , Animals , Behavior, Animal/physiology , Brain/pathology , Cerebral Infarction/pathology , Coloring Agents , Electroencephalography , Evans Blue , Female , Forelimb/physiology , Hindlimb/physiology , Infarction, Middle Cerebral Artery/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Postural Balance/physiology , Psychomotor Performance/physiology , Rats , Rats, Wistar , Reflex/physiology
20.
Brain Res ; 1153: 58-67, 2007 Jun 11.
Article in English | MEDLINE | ID: mdl-17466282

ABSTRACT

Transient focal ischemia produced by local infusion of endothelin-1 (ET1) in the territory of the middle cerebral artery has been proposed as a potentially useful model for the screening of drugs developed for the treatment of thrombo-embolic stroke. However, most of the data rely exclusively on the assessment of the infarct volume, which is only a partial predictor of the neurological outcome of stroke. Here, we have validated the model using a multimodal approach for the assessment of neuroprotection, which includes (i) determination of the infarct volume by 2,3,5-triphenyltetrazolium chloride staining; (ii) an in-depth behavioral analysis of the neurological deficit; and (iii) an EEG analysis of electrophysiological abnormalities in the peri-infarct somatosensory forelimb cortical area, S1FL. The non-competitive NMDA receptor antagonist, MK-801 (3 mg/kg, injected i.p. 20 min after ET1 infusion in conscious rats) could reduce the infarct volume, reverse the EEG changes occurring at early times post-ET1, and markedly improve the neurological deficit in ischemic animals. The latter effect, however, was visible at day 3 post-ET1, because the drug itself produced substantial behavioral abnormalities at earlier times. We conclude that a multimodal approach can be applied to the ET1 model of focal ischemia, and that MK-801 can be used as a reference compound to which the activity of safer neuroprotective drugs should be compared.


Subject(s)
Dizocilpine Maleate/therapeutic use , Endothelin-1 , Ischemic Attack, Transient/chemically induced , Ischemic Attack, Transient/prevention & control , Neuroprotective Agents/therapeutic use , Analysis of Variance , Animals , Behavior, Animal , Brain Infarction/drug therapy , Brain Infarction/etiology , Disease Models, Animal , Electroencephalography/drug effects , Functional Laterality , Ischemic Attack, Transient/complications , Ischemic Attack, Transient/pathology , Male , Rats , Rats, Wistar , Severity of Illness Index , Somatosensory Cortex/drug effects , Somatosensory Cortex/physiopathology , Tetrazolium Salts
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