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1.  Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine 
Brain  2008;131(8):2071-2083.
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioural and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naive animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioural equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
doi:10.1093/brain/awn117
PMCID: PMC2587254  PMID: 18559371
comorbidity; depression; epilepsy; hippocampus; serotonin
2.  Comorbidity between epilepsy and depression: Experimental evidence for the involvement of serotonergic, glucocorticoid and neuroinflammatory mechanisms 
Epilepsia  2010;51(Suppl 3):110-114.
Summary
Depression represents one of the most common comorbidities of temporal lobe epilepsy (TLE), and has profound negative impact on the quality of life of TLE patients. However, causes and mechanisms of depression in TLE remain poorly understood, and its effective therapies are lacking. We examined whether a commonly used model of TLE in rats can be used as a model of comorbidity between epilepsy and depression suitable for both mechanistic studies and for the development mechanism-based antidepressant therapies. We established that animals which had been subjected to LiCl and pilocarpine status epilepticus (SE) and developed spontaneous recurrent seizures, exhibited set of impairments congruent with depressive state: behavioral equivalents of anhedonia and despair; dysregulation of the hypothalamo-pituitary adrenocortical (HPA) axis; compromised raphe-hippocampal serotonergic transmission. Pharmacological studies suggested that depressive impairments following SE develop as a result of the enhanced interleukin-1β signaling in the hippocampus, which leads to depression via inducing perturbations in the HPA axis and subsequent deficit in the raphe-hippocampal serotonergic transmission.
doi:10.1111/j.1528-1167.2010.02623.x
PMCID: PMC2909020  PMID: 20618414
Temporal lobe epilepsy; depression; comorbidity; serotonin; hypothalamo-pituitary-adrenocortical axis; interleukin-1β
3.  Comorbidity between epilepsy and depression: role of hippocampal interleukin-1β 
Neurobiology of disease  2009;37(2):461.
Depression is a frequent comorbidity of temporal lobe epilepsy (TLE); however its mechanisms remain poorly understood and effective therapies are lacking. Augmentation of hippocampal interleukin-1β (IL-1β) signaling may be a mechanistic factor of both TLE and clinical depression. We examined whether pharmacological blockade of hippocampal interleukin-1 receptor exerts antidepressant effects in an animal model of comorbidity between TLE and depression, which developed in Wistar rats following pilocarpine status epilepticus (SE). In post-SE animals, depression-like state was characterized by behavioral equivalents of anhedonia and despair; dysregulation of the hypothalamo-pituitary-adrenocortical axis; compromised raphe-hippocampal serotonergic transmission. Two-week long bilateral intrahippocampal infusion of human recombinant Interleukin-1 Receptor antagonist (IL-1ra) improved all of the examined depressive impairments, without modifying spontaneous seizure frequency and without affecting normal parameters in naïve rats. These findings implicate hippocampal IL-1β in epilepsy-associated depression, and provide a rationale for the introduction of IL-1β blockers in the treatment of depression in TLE.
doi:10.1016/j.nbd.2009.11.001
PMCID: PMC2818460  PMID: 19900553
Temporal lobe epilepsy; depression; comorbidity; brain inflammation; Interleukin-1β; hippocampus
4.  Different Emotional Disturbances in Two Experimental Models of Temporal Lobe Epilepsy in Rats 
PLoS ONE  2012;7(6):e38959.
Affective symptoms such as anxiety and depression are frequently observed in patients with epilepsy. The mechanisms of comorbidity of epilepsy and affective disorders, however, remain unclear. Diverse models are traditionally used in epilepsy research, including the status epilepticus (SE) model in rats, which are aimed at generating chronic epileptic animals; however, the implications of different SE models and rat strains in emotional behaviors has not been reported. To address this issue, we examined the emotional sequelae of two SE models of temporal lobe epilepsy (TLE) – the lithium-pilocarpine (LIP) model and the kainic acid (KA) model – in two different rat strains (Wistar and Sprague-Dawley), which differ significantly in the pattern and extent of TLE-associated brain lesions. We found differences between LIP- and KA-treated animals in tests for depression-like and anxiety-like behaviors, as well as differences in plasma corticosterone levels. Whereas only LIP-treated rats displayed increased motivation to consume saccharin, both SE models led to reduced motivation for social contact, with LIP-treated animals being particularly affected. Evaluation of behavior in the open field test indicated very low levels of anxiety in LIP-treated rats and a mild decrease in KA-treated rats compared to controls. After exposure to a battery of behavioral tests, plasma corticosterone levels were increased only in LIP-treated animals. This hyperactivity in the hypothalamus-pituitary-adrenocortical (HPA) axis was highly correlated with performance in the open field test and the social interaction test, suggesting that comorbidity of epilepsy and emotional behaviors might also be related to other factors such as HPA axis function. Our results indicate that altered emotional behaviors are not inherent to the epileptic condition in experimental TLE; instead, they likely reflect alterations in anxiety levels related to model-dependent dysregulation of the HPA axis.
doi:10.1371/journal.pone.0038959
PMCID: PMC3376131  PMID: 22720001
5.  Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression 
Neurotherapeutics  2012;9(2):477-485.
Depression represents a common comorbidity of epilepsy and is frequently resistant to selective serotonin reuptake inhibitors (SSRI). We tested the hypothesis that the SSRI resistance in epilepsy associated depression may be a result of a pathologically enhanced interleukin-1β (IL1-β) signaling, and consequently that the blockade of IL1-β may restore the effectiveness of SSRI. Epilepsy and concurrent depression-like impairments were induced in Wistar rats by pilocarpine status epilepticus (SE). The effects of the 2-week long treatment with fluoxetine, interleukin-1 receptor antagonist (IL-1ra), and their combination were examined using behavioral, biochemical, neuroendocrine, and autoradiographic assays. In post-SE rats, depression-like impairments included behavioral deficits indicative of hopelessness and anhedonia; the hyperactivity of the hypothalamo-pituitary-adrenocortical axis; the diminished serotonin output from raphe nucleus; and the upregulation of presynaptic serotonin 1-A (5-HT1A) receptors. Fluoxetine monotherapy exerted no antidepressant effects, whereas the treatment with IL-1ra led to the complete reversal of anhedonia and to a partial improvement of all other depressive impairments. Combined administration of fluoxetine and IL-1ra completely abolished all hallmarks of epilepsy-associated depressive abnormalities, with the exception of the hyperactivity of the hypothalamo-pituitary-adrenocortical axis, the latter remaining only partially improved. We propose that in certain forms of depression, including but not limited to depression associated with epilepsy, the resistance to SSRI may be driven by the pathologically enhanced interleukin-1β signaling and by the subsequent upregulation of presynaptic 5-HT1A receptors. In such forms of depression, the use of interleukin-1β blockers in conjunction with SSRI may represent an effective therapeutic approach.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0110-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s13311-012-0110-4
PMCID: PMC3337012  PMID: 22427156
Epilepsy; depression; comorbidity; cytokines; selective serotonin reuptake inhibitors
6.  Kindling epileptogenesis in immature rats leads to persistent depressive behavior 
Epilepsy & behavior : E&B  2007;10(3):377-383.
Depression is a frequent comorbidity in epilepsy patients. A variety of biological factors may underlie epilepsy-associated depression. We examined whether kindling-induced chronic increase in seizure susceptibility is accompanied by behavioral symptoms of depression. Three week-old Wistar rats underwent rapid kindling - 84 initially subconvulsant electrical stimulations of ventral hippocampus delivered every five minutes - followed by depression-specific behavioral tests performed two and four weeks later. Kindled animals exhibited sustained increase in the immobility time in the forced swim test and the loss of taste preference towards calorie-free saccharin, as compared to controls. Initial loss of preference towards the intake of calorie-containing sucrose was followed by the increased consumption at four weeks. At both time points, animals exhibited enhanced seizure susceptibility upon test stimulations of the hippocampus. We conclude that neuronal plastic changes associated with kindling state are accompanied by the development of depressive behavior.
doi:10.1016/j.yebeh.2007.02.001
PMCID: PMC1958957  PMID: 17368107
Epilepsy; depression; kindling; forced swim test; taste preference; rat
7.  Activation of brain indoleamine 2,3-dioxygenase contributes to epilepsy-associated depressive-like behavior in rats with chronic temporal lobe epilepsy 
Background
Depression has most often been diagnosed in patients with temporal lobe epilepsy (TLE), but the mechanism underlying this association remains unclear. In this study, we report that indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in tryptophan metabolism, plays a key role in epilepsy-associated depressive-like behavior.
Methods
Rats which develop chronic epilepsy following pilocarpine status epilepticus exhibited a set of interictal disorders consistent with depressive-like behavior. Changes of depressive behavior were examined by taste preference test and forced swim test; brain IL-1β, IL-6 and IDO1 expression were quantified using real-time reverse transcriptase PCR; brain kynurenine/tryptophan and serotonin/tryptophan ratios were analyzed by liquid chromatography-mass spectrometry. Oral gavage of minocycline or subcutaneous injection of 1-methyltryptophan (1-MT) were used to inhibite IDO1 expression.
Results
We observed the induction of IL-1β and IL-6 expression in rats with chronic TLE, which further induced the upregulation of IDO1 expression in the hippocampus. The upregulation of IDO1 subsequently increased the kynurenine/tryptophan ratio and decreased the serotonin/tryptophan ratio in the hippocampus, which contributed to epilepsy-associated depressive-like behavior. The blockade of IDO1 activation prevented the development of depressive-like behavior but failed to influence spontaneous seizures. This effect was achieved either indirectly, through the anti-inflammatory tetracycline derivative minocycline, or directly, through the IDO antagonist 1-MT, which normalizes kynurenine/tryptophan and serotonin/tryptophan ratios.
Conclusion
Brain IDO1 activity plays a key role in epileptic rats with epilepsy-associated depressive-like behavior.
doi:10.1186/1742-2094-11-41
PMCID: PMC3975854  PMID: 24594021
1-methyltryptophan; Minocycline; Kynurenine; Tryptophan; Serotonin; Interleukin-1β; Interleukin-6; Taste preference test; Forced swim test; Epilepsy; Depression
8.  Differences in the hippocampal frequency of creatine inclusions between the acute and latent phases of pilocarpine model defined using synchrotron radiation-based FTIR microspectroscopy 
Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults. Of the animal models developed to investigate the pathogenesis of TLE, the one with pilocarpine-induced seizures is most often used. After pilocarpine administration in animals, three distinct periods—acute, latent, and chronic—can be distinguished according to their behavior. The present paper is the continuation of our previous study which has shown an increased occurrence of creatine inclusions in rat hippocampal formations from the acute phase of pilocarpine-induced status epilepticus (SE) and positive correlation between their quantity and the total time of seizure activity within the observation period. In this paper, we tried to verify if anomalies in hippocampal creatine accumulation were the temporary or permanent effect of pilocarpine-evoked seizures. To realize this purpose, male Wistar rats in the latent phase (3 days after pilocarpine administration) were examined. The results obtained for the period when stabilization of animal behavior and EEG occurs were afterwards compared with ones obtained for the acute phase of pilocarpine-induced SE and for naive controls. To investigate the frequency of creatine inclusions within the hippocampal formation as well as in its selected areas (sectors 1–3 of Ammon’s horn (CA1–CA3), dentate gyrus (DG), and hilus of DG) and cellular layers (pyramidal, molecular, multiform, and granular cell layers), synchrotron radiation-based Fourier-transform infrared microspectroscopy was used. The applied technique, being a combination of light microscopy and infrared spectroscopy, allowed us to localize microscopic details in the analyzed samples and provided information concerning their chemical composition. Moreover, the use of a synchrotron source of IR radiation allowed us to carry out the research at the diffraction-limited spatial resolution which, because of the typical size of creatine inclusions (from a few to dozens of micrometers), was necessary for our study. The comparison of epileptic animals in the latent phase with controls showed statistically significant increase in the number of creatine inclusions for most of the analyzed hippocampal regions, all examined cellular layers, as well as the whole hippocampal formation. Moreover, for the hilus of the DG and CA3 area, the number of creatine deposits was higher in the latent than in the acute phase after pilocarpine injection. In light of the obtained results, an anomaly in the hippocampal accumulation of creatine is the long-term effect of pilocarpine-evoked seizures, and the intensity of this phenomenon may increase with time passing from the primary injury.
FigureThe comparison of baseline corrected IR spectra recorded in selected creatine inclusion and nervous tissue (A). The microscopic view of the DG hippocampal area from the animal representing the SE72H group; creatine deposits are visible as darker points (B). The distributions of selected creatine bands: 2,800 cm−1 (C), 1,398 cm−1 (D), and 1,304 cm−1 (E) in the rectangular tissue area visible in part (B)
doi:10.1007/s00216-013-7191-8
PMCID: PMC3756859  PMID: 23877175
Pilocarpine model of epilepsy; Creatine; SRFTIR microspectroscopy; Synchrotron radiation
9.  Plasticity of presynaptic and postsynaptic serotonin 1A receptors in an animal model of epilepsy – associated depression 
Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients’ quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo-pituitary-adrenocortical (HPA) axis and/or diminished raphe-hippocampal serotonergic transmission. We examined possible involvement of presynaptic and postsynaptic serotonin-1A (5-HT1A) receptors in epilepsy-associated depression. Based on their performance in the forced swim test (FST), post-SE animals were classified as those with moderate and severe depressive impairments. In moderately impaired rats, the activity of the HPA axis (examined using plasma corticosterone radioimmunoassay) was higher than in naïve subjects, but the functional capacity of presynaptic 5-HT1A receptors (measured in raphe using autoradiography) remained unaltered. In severely depressed animals, both the activity of the HPA axis and the function of presynaptic 5-HT1A receptors were increased as compared with naïve and moderately depressed rats. Pharmacological uncoupling of the HPA axis from raphe nucleus exerted antidepressant effects in severely impaired rats, but did not modify behavior in both naïve and moderately depressed animals. Further, the function of postsynaptic 5-HT1A receptors was diminished in the hippocampus of post-SE rats. Pharmacological activation of postsynaptic 5-HT1A receptors improved depressive deficits in epileptic animals. We suggest that under conditions of chronic epilepsy, excessively hyperactive HPA axis activates presynaptic 5-HT1A receptors, thus shifting the regulation of serotonin release in favor of autoinhibition. Downregulation of postsynaptic 5-HT1A receptors may further exacerbate the severity of epilepsy-associated depression.
doi:10.1038/npp.2011.18
PMCID: PMC3077437  PMID: 21346733
Epilepsy; depression; comorbidity; serotonin 1A receptors; dorsal raphe; hypothalamo-pituitary-adrenocortical axis
10.  Plasticity of Presynaptic and Postsynaptic Serotonin 1A Receptors in an Animal Model of Epilepsy-Associated Depression 
Neuropsychopharmacology  2011;36(6):1305-1316.
Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients' quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo–pituitary–adrenocortical (HPA) axis and/or diminished raphe–hippocampal serotonergic transmission. We examined possible involvement of presynaptic and postsynaptic serotonin 1A (5-HT1A) receptors in epilepsy-associated depression. Based on their performance in the forced swim test (FST), post-SE animals were classified as those with moderate and severe depressive impairments. In moderately impaired rats, the activity of the HPA axis (examined using plasma corticosterone radioimmunoassay) was higher than in naive subjects, but the functional capacity of presynaptic 5-HT1A receptors (measured in raphe using autoradiography) remained unaltered. In severely depressed animals, both the activity of the HPA axis and the function of presynaptic 5-HT1A receptors were increased as compared with naive and moderately depressed rats. Pharmacological uncoupling of the HPA axis from raphe nucleus exerted antidepressant effects in severely impaired rats, but did not modify behavior in both naive and moderately depressed animals. Further, the function of postsynaptic 5-HT1A receptors was diminished in the hippocampus of post-SE rats. Pharmacological activation of postsynaptic 5-HT1A receptors improved depressive deficits in epileptic animals. We suggest that under the conditions of chronic epilepsy, excessively hyperactive HPA axis activates presynaptic 5-HT1A receptors, thus shifting the regulation of serotonin release in favor of autoinhibition. Downregulation of postsynaptic 5-HT1A receptors may further exacerbate the severity of epilepsy-associated depression.
doi:10.1038/npp.2011.18
PMCID: PMC3077437  PMID: 21346733
epilepsy; depression; comorbidity; serotonin 1A receptors; dorsal raphe; hypothalamo–pituitary–adrenocortical axis; mood / anxiety / stress disorders; serotonin; animal models; neurology; epilepsy; comorbidity; dorsal aphe; hippocampus; serotonin 1A receptors
11.  The pilocarpine model of temporal lobe epilepsy 
Journal of Neuroscience Methods  2008;172(2-4):143-157.
Understanding the pathophysiogenesis of temporal lobe epilepsy (TLE) largely rests on the use of models of status epilepticus (SE), as in the case of the pilocarpine model. The main features of TLE are: (i) epileptic foci in the limbic system; (ii) an “initial precipitating injury”; (iii) the so-called “latent period”; and (iv) the presence of hippocampal sclerosis leading to reorganization of neuronal networks. Many of these characteristics can be reproduced in rodents by systemic injection of pilocarpine; in this animal model, SE is followed by a latent period and later by the appearance of spontaneous recurrent seizures (SRSs). These processes are, however, influenced by experimental conditions such as rodent species, strain, gender, age, doses and routes of pilocarpine administration, as well as combinations with other drugs administered before and/or after SE. In the attempt to limit these sources of variability, we evaluated the methodological procedures used by several investigators in the pilocarpine model; in particular, we have focused on the behavioural, electrophysiological and histopathological findings obtained with different protocols. We addressed the various experimental approaches published to date, by comparing mortality rates, onset of SRSs, neuronal damage, and network reorganization. Based on the evidence reviewed here, we propose that the pilocarpine model can be a valuable tool to investigate the mechanisms involved in TLE, and even more so when standardized to reduce mortality at the time of pilocarpine injection, differences in latent period duration, variability in the lesion extent, and SRS frequency.
doi:10.1016/j.jneumeth.2008.04.019
PMCID: PMC2518220  PMID: 18550176
AEDs, antiepileptic drugs; CA, Cornu Ammonis; EEG, electroencephalogram; i.p., intraperitoneal; MRI, magnetic resonance imaging; P, postnatal; s.c., subcutaneous; SE, status epilepticus; SRSs, spontaneous recurrent seizures; TLE, temporal lobe epilepsy; Animal models; Entorhinal cortex; Hippocampus; Pilocarpine; Temporal lobe epilepsy
12.  THE PILOCARPINE MODEL OF TEMPORAL LOBE EPILEPSY 
Journal of neuroscience methods  2008;172(2):143-157.
Understanding the pathophysiogenesis of temporal lobe epilepsy (TLE) largely rests on the use of models of status epilepticus (SE), as in the case of the pilocarpine model. The main features of TLE are: (i) epileptic foci in the limbic system: (ii) an “initial precipitating injury”; (iii) the so-called “latent period”; and (iv) the presence of hippocampal sclerosis leading to reorganization of neuronal networks. Many of these characteristics can be reproduced in rodents by systemic injection of pilocarpine; in this animal model, SE is followed by a latent period and later by the appearance of spontaneous recurrent seizures (SRSs). These processes are, however, influenced by experimental conditions such as rodent species, strain, gender, age, doses and routes of pilocarpine administration, as well as combinations with other drugs administered before and/or after SE. In the attempt to limit these sources of variability, we evaluated the methodological procedures used by several investigators in the pilocarpine model; in particular, we have focused on the behavioural, electrophysiological and histopathological findings obtained with different protocols. We addressed the various experimental approaches published to date, by comparing mortality rates, onset of SRSs, neuronal damage, and network reorganization. Based on the evidence reviewed here, we propose that the pilocarpine model can be a valuable tool to investigate the mechanisms involved in TLE, and even more so when standardized to reduce mortality at the time of pilocarpine injection, differences in latent period duration, variability in the lesion extent, and SRS frequency.
doi:10.1016/j.jneumeth.2008.04.019
PMCID: PMC2518220  PMID: 18550176
Animal models; Entorhinal cortex; Hippocampus; Pilocarpine; Temporal Lobe Epilepsy
13.  Cannabinoid-Mediated Inhibition of Recurrent Excitatory Circuitry in the Dentate Gyrus in a Mouse Model of Temporal Lobe Epilepsy 
PLoS ONE  2010;5(5):e10683.
Temporal lobe epilepsy (TLE) is a neurological condition associated with neuron loss, axon sprouting, and hippocampal sclerosis, which results in modified synaptic circuitry. Cannabinoids appear to be anti-convulsive in patients and animal models of TLE, but the mechanisms of this effect are not known. A pilocarpine-induced status epilepticus mouse model of TLE was used to study the effect of cannabinoid agonists on recurrent excitatory circuits of the dentate gyrus using electrophysiological recordings in hippocampal slices isolated from control mice and mice with TLE. Cannabinoid agonists WIN 55,212-2, anandamide (AEA), or 2-arachydonoylglycerol (2-AG) reduced the frequency of spontaneous and tetrodotoxin-resistant excitatory postsynaptic currents (EPSCs) in mice with TLE, but not in controls. WIN 55,212-2 also reduced the frequency of EPSCs evoked by glutamate-photolysis activation of other granule cells in epileptic mice. Secondary population discharges evoked after antidromic electrical stimulation of mossy fibers in the hilus were also attenuated by cannabinoid agonists. Agonist effects were blocked by the cannabinoid type 1 receptor (CB1R) antagonist AM251. No change in glutamate release was observed in slices from mice that did not undergo status epilepticus. Western blot analysis suggested an up-regulation of CB1R in the dentate gyrus of animals with TLE. These findings indicate that activation of CB1R present on nerve terminals can suppress recurrent excitation in the dentate gyrus of mice with TLE. This suggests a mechanism for the anti-convulsive role of cannabinoids aimed at modulating receptors on synaptic terminals expressed de novo after epileptogenesis.
doi:10.1371/journal.pone.0010683
PMCID: PMC2871782  PMID: 20498848
14.  Progressive, potassium-sensitive epileptiform activity in hippocampal area CA3 of pilocarpine-treated rats with recurrent seizures 
Epilepsy research  2011;97(1-2):92-102.
Rat hippocampal area CA3 pyramidal cells synchronously discharge in rhythmic bursts of action potentials after acute disinhibition or convulsant treatment in vitro. These burst discharges resemble epileptiform activity, and are of interest because they may shed light on mechanisms underlying limbic seizures. However, few studies have examined CA3 burst discharges in an animal model of epilepsy, because a period of prolonged, severe seizures (status epilepticus) is often used to induce the epileptic state, which can lead to extensive neuronal loss in CA3. Therefore, the severity of pilocarpine-induced status epilepticus was decreased with anticonvulsant treatment to reduce damage. Rhythmic burst discharges were recorded in the majority of slices from these animals, between two weeks and nine months after status epilepticus. The incidence and amplitude of bursts progressively increased with time after status, even after spontaneous behavioral seizures had begun. The results suggest that modifying the pilocarpine models of temporal lobe epilepsy to reduce neuronal loss leads to robust network synchronization in area CA3. The finding that these bursts increase long after spontaneous behavioral seizures begin supports previous arguments that temporal lobe epilepsy exhibits progressive pathophysiology.
doi:10.1016/j.eplepsyres.2011.07.008
PMCID: PMC3215800  PMID: 21880468
status epilepticus; hippocampal slice electrophysiology; paroxysmal depolarizing shift; temporal lobe epilepsy
15.  Rapamycin attenuates aggressive behavior in a rat model of pilocarpine-induced epilepsy 
Neuroscience  2012;215:90-97.
Psychiatric disorders are fairly common comorbidities of epilepsy in humans. Following pilocarpine-induced status epilepticus (SE), experimental animals not only developed spontaneous recurrent seizures, but also exhibited significantly elevated levels of aggressive behavior. The cellular and molecular mechanism triggering these behavioral alterations remains unclear. In the present study, we found that aggression is positively correlated with development of spontaneous seizures. Treatment with rapamycin, a potent mTOR pathway inhibitor, markedly diminished aggressive behavior. Therefore, the mTOR pathway may have significance in the underlying molecular mechanism leading to aggression associated with epilepsy.
doi:10.1016/j.neuroscience.2012.04.011
PMCID: PMC3371158  PMID: 22522471
mTOR; epilepsy; psychiatric comorbidities; rapamycin; seizure
16.  Lovastatin Modulates Glycogen Synthase Kinase-3β Pathway and Inhibits Mossy Fiber Sprouting after Pilocarpine-Induced Status Epilepticus 
PLoS ONE  2012;7(6):e38789.
This study was undertaken to assay the effect of lovastatin on the glycogen synthase kinase-3 beta (GSK-3β) and collapsin responsive mediator protein-2 (CRMP-2) signaling pathway and mossy fiber sprouting (MFS) in epileptic rats. MFS in the dentate gyrus (DG) is an important feature of temporal lobe epilepsy (TLE) and is highly related to the severity and the frequency of spontaneous recurrent seizures. However, the molecular mechanism of MFS is mostly unknown. GSK-3β and CRMP-2 are the genes responsible for axonal growth and neuronal polarity in the hippocampus, therefore this pathway is a potential target to investigate MFS. Pilocarpine-induced status epilepticus animal model was taken as our researching material. Western blot, histological and electrophysiological techniques were used as the studying tools. The results showed that the expression level of GSK-3β and CRMP-2 were elevated after seizure induction, and the administration of lovastatin reversed this effect and significantly reduced the extent of MFS in both DG and CA3 region in the hippocampus. The alteration of expression level of GSK-3β and CRMP-2 after seizure induction proposes that GSK-3β and CRMP-2 are crucial for MFS and epiletogenesis. The fact that lovastatin reversed the expression level of GSK-3β and CRMP-2 indicated that GSK-3β and CRMP-2 are possible to be a novel mechanism of lovatstain to suppress MFS and revealed a new therapeutic target and researching direction for studying the mechanism of MFS and epileptogenesis.
doi:10.1371/journal.pone.0038789
PMCID: PMC3383707  PMID: 22761705
17.  Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models 
Molecular psychiatry  2010;17(1):49-61.
The etiology of depression is still poorly understood, but two major causative hypotheses have been put forth: the monoamine deficiency and the stress hypotheses of depression. We evaluate these hypotheses using animal models of endogenous depression and chronic stress. The endogenously depressed rat and its control strain were developed by bidirectional selective breeding from the Wistar–Kyoto (WKY) rat, an accepted model of major depressive disorder (MDD). The WKY More Immobile (WMI) substrain shows high immobility/despair-like behavior in the forced swim test (FST), while the control substrain, WKY Less Immobile (WLI), shows no depressive behavior in the FST. Chronic stress responses were investigated by using Brown Norway, Fischer 344, Lewis and WKY, genetically and behaviorally distinct strains of rats. Animals were either not stressed (NS) or exposed to chronic restraint stress (CRS). Genome-wide microarray analyses identified differentially expressed genes in hippocampi and amygdalae of the endogenous depression and the chronic stress models. No significant difference was observed in the expression of monoaminergic transmission-related genes in either model. Furthermore, very few genes showed overlapping changes in the WMI vs WLI and CRS vs NS comparisons, strongly suggesting divergence between endogenous depressive behavior- and chronic stress-related molecular mechanisms. Taken together, these results posit that although chronic stress may induce depressive behavior, its molecular underpinnings differ from those of endogenous depression in animals and possibly in humans, suggesting the need for different treatments. The identification of novel endogenous depression-related and chronic stress response genes suggests that unexplored molecular mechanisms could be targeted for the development of novel therapeutic agents.
doi:10.1038/mp.2010.119
PMCID: PMC3117129  PMID: 21079605
animal models; depression; microarray; selective breeding; Wistar Kyoto rat
18.  Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models 
Molecular Psychiatry  2010;17(1):49-61.
The etiology of depression is still poorly understood, but two major causative hypotheses have been put forth: the monoamine deficiency and the stress hypotheses of depression. We evaluate these hypotheses using animal models of endogenous depression and chronic stress. The endogenously depressed rat and its control strain were developed by bidirectional selective breeding from the Wistar–Kyoto (WKY) rat, an accepted model of major depressive disorder (MDD). The WKY More Immobile (WMI) substrain shows high immobility/despair-like behavior in the forced swim test (FST), while the control substrain, WKY Less Immobile (WLI), shows no depressive behavior in the FST. Chronic stress responses were investigated by using Brown Norway, Fischer 344, Lewis and WKY, genetically and behaviorally distinct strains of rats. Animals were either not stressed (NS) or exposed to chronic restraint stress (CRS). Genome-wide microarray analyses identified differentially expressed genes in hippocampi and amygdalae of the endogenous depression and the chronic stress models. No significant difference was observed in the expression of monoaminergic transmission-related genes in either model. Furthermore, very few genes showed overlapping changes in the WMI vs WLI and CRS vs NS comparisons, strongly suggesting divergence between endogenous depressive behavior- and chronic stress-related molecular mechanisms. Taken together, these results posit that although chronic stress may induce depressive behavior, its molecular underpinnings differ from those of endogenous depression in animals and possibly in humans, suggesting the need for different treatments. The identification of novel endogenous depression-related and chronic stress response genes suggests that unexplored molecular mechanisms could be targeted for the development of novel therapeutic agents.
doi:10.1038/mp.2010.119
PMCID: PMC3117129  PMID: 21079605
animal models; depression; microarray; selective breeding; Wistar Kyoto rat
19.  Status epilepticus affects the gigantocellular network of the pontine reticular formation 
BMC Neuroscience  2009;10:133.
Background
The impairment of the pontine reticular formation (PRF) has recently been revealed to be histopathologically connected with focal-cortical seizure induced generalized convulsive status epilepticus. To elucidate whether the impairment of the PRF is a general phenomenon during status epilepticus, the focal-cortical 4-aminopyridine (4-AP) application was compared with other epilepsy models. The presence of "dark" neurons in the PRF was investigated by the sensitive silver method of Gallyas in rats sacrificed at 3 h after focal 4-AP crystal or systemic 4-AP, pilocarpine, or kainic acid application. The behavioral signs of the developing epileptic seizures were scored in all rats. The EEG activity was recorded in eight rats.
Results
Regardless of the initiating drug or method of administration, "dark" neurons were consistently found in the PRF of animals entered the later phases of status epilepticus. EEG recordings demonstrated the presence of slow oscillations (1.5-2.5 Hz) simultaneously with the appearance of giant "dark" neurons in the PRF.
Conclusion
We argue that the observed slow oscillation corresponds to the late periodic epileptiform discharge phase of status epilepticus, and that the PRF may be involved in the progression of status epilepticus.
doi:10.1186/1471-2202-10-133
PMCID: PMC2781816  PMID: 19912649
20.  Progress in Neuroprotective Strategies for Preventing Epilepsy 
Progress in neurobiology  2007;84(4):363-404.
Neuroprotection is increasingly considered as a promising therapy for preventing and treating temporal lobe epilepsy (TLE). The development of chronic TLE, also termed as epileptogenesis, is a dynamic process. An initial precipitating injury (IPI) such as the status epilepticus (SE) leads to neurodegeneration, abnormal reorganization of the brain circuitry and a significant loss of functional inhibition. All of these changes likely contribute to the development of chronic epilepsy, characterized by spontaneous recurrent motor seizures (SRMS) and learning and memory deficits. The purpose of this review is to discuss the current state of knowledge pertaining to neuroprotection in epileptic conditions, and to highlight the efficacy of distinct neuroprotective strategies for preventing or treating chronic TLE. Although the administration of certain conventional and new generation antiepileptic drugs is effective for primary neuroprotection such as reduced neurodegeneration after acute seizures or the SE, their competence for preventing the development of chronic epilepsy after an IPI is either unknown or not promising. On the other hand, alternative strategies such as the ketogenic diet therapy, administration of distinct neurotrophic factors, hormones or antioxidants seem useful for preventing and treating chronic TLE. However, long term studies on the efficacy of these approaches introduced at different time-points after the SE or an IPI are lacking. Additionally, grafting of fetal hippocampal cells at early time-points after an IPI holds considerable promise for preventing TLE, though issues regarding availability of donor cells, ethical concerns, timing of grafting after SE, and durability of graft-mediated seizure suppression need to be resolved for further advances with this approach. Overall, from the studies performed so far, there is consensus that neuroprotective strategies need to be employed as quickly as possible after the onset of the SE or an IPI for considerable beneficial effects. Nevertheless, ideal strategies that are capable of facilitating repair and functional recovery of the brain after an IPI and preventing the evolution of IPI into chronic epilepsy are still hard to pin down.
doi:10.1016/j.pneurobio.2007.10.010
PMCID: PMC2441599  PMID: 18207302
aberrant synaptic reorganization; antiepileptic drugs; antioxidants; dentate gyrus; dentate neurogenesis; GABA-ergic interneurons; head injury; hippocampus; hippocampal cell grafts; hormones; ketogenic diet; learning and memory deficits; mossy fiber sprouting; neural cell transplants; neural stem cells; neurodegeneration; neurotrophic factors; spontaneous seizures; status epilepticus; synaptic plasticity; temporal lobe epilepsy
21.  ACUTE AND CHRONIC RESPONSES TO THE CONVULSANT PILOCARPINE IN DBA/2J AND A/J MICE 
Neuroscience  2007;149(2):465-475.
Characterizing the responses of different mouse strains to experimentally-induced seizures can provide clues to the genes that are responsible for seizure susceptibility, and factors that contribute to epilepsy. This approach is optimal when sequenced mouse strains are available. Therefore, we compared two sequenced strains, DBA/2J (DBA) and A/J. These strains were compared using the chemoconvulsant pilocarpine, because pilocarpine induces status epilepticus, a state of severe, prolonged seizures. In addition, pilocarpine-induced status is followed by changes in the brain that are associated with the pathophysiology of temporal lobe epilepsy (TLE). Therefore, pilocarpine can be used to address susceptibility to severe seizures, as well as genes that could be relevant to TLE.
A/J mice had a higher incidence of status, but a longer latency to status than DBA mice. DBA mice exhibited more hippocampal pyramidal cell damage. DBA mice developed more ectopic granule cells in the hilus, a result of aberrant migration of granule cells born after status. DBA mice experienced sudden death in the weeks following status, while A/J mice exhibited the most sudden death in the initial hour after pilocarpine administration.
The results support previous studies of strain differences based on responses to convulsants. They suggest caution in studies of seizure susceptibility that are based only on incidence or latency. In addition, the results provide new insight into the strain-specific characteristics of DBA and A/J mice. A/J mice provide a potential resource to examine the progression to status. The DBA mouse may be valuable to clarify genes regulating other seizure-associated phenomena, such as seizure-induced neurogenesis and sudden death.
doi:10.1016/j.neuroscience.2007.06.009
PMCID: PMC2640947  PMID: 17904758
epilepsy; mossy fiber sprouting; neurogenesis; neuropeptide Y; seizure; status epilepticus
22.  m1 Acetylcholine Receptor Expression is Decreased in Hippocampal CA1 region of Aged Epileptic Animals 
Aging and Disease  2011;2(4):301-307.
In the present study, we investigated the possible additive effects of epilepsy and aging on the expression of m1 muscarinic acetylcholine receptors (AChR) in the rat hippocampus. Young (3 months) and Aged (20 months) male, Wistar rats were treated with pilocarpine to induce status epilepticus (SE). Immunohistochemical procedure for m1 AChR detection was performed 2 months after pilocarpine-induced SE. In the CA1 pyramidal region m1 AChR staining was significantly decreased in aged epileptic animals when compared to young epileptic and aged control rats, indicating that the aging effect is worsened by the epileptic condition. However, the Nissl-stained cell analysis indicated that the number of pyramidal CA1 neurons was similarly reduced in both epileptic groups, young and aged animals. Therefore, our data suggest that the progressive reduction of m1 AChR expression in CA1 pyramidal cells of aged epileptic rats might bear relevance to the associated progressive cognitive impairment.
PMCID: PMC3295068  PMID: 22396882
Epilepsy; m1 ACh receptor; Aging; Hippocampus; Pilocarpine; Epilepsy
23.  The Behavioral Actions of Lithium in Rodent Models 
For nearly as long as lithium has been in clinical use for the treatment of bipolar disorder, depression, and other conditions, investigators have attempted to characterize its effects on behaviors in rodents. Lithium consistently decreases exploratory activity, rearing, aggression, and amphetamine-induced hyperlocomotion; and it increases the sensitivity to pilocarpine-induced seizures, decreases immobility time in the forced swim test, and attenuates reserpine-induced hypolocomotion. Lithium also predictably induces conditioned taste aversion and alterations in circadian rhythms. The modulation of stereotypy, sensitization, and reward behavior are less consistent actions of the drug. These behavioral models may be relevant to human symptoms and to clinical endophenotypes. It is likely that the actions of lithium in a subset of these animal models are related to the therapeutic efficacy, as well the side effects, of the drug. We conclude with a brief discussion of various molecular mechanisms by which these lithium-sensitive behaviors may be mediated, and comment on the ways in which rat and mouse models can be used more effectively in the future to address persistent questions about the therapeutically relevant molecular actions of lithium.
doi:10.1016/j.neubiorev.2007.04.002
PMCID: PMC2150568  PMID: 17532044
mood stabilizer; antidepressant; animal model; endophenotype; bipolar disorder; manic-depressive illness; mania; depression; rat; mouse
24.  Seizures and reproductive function: insights from female rats with epilepsy 
Annals of neurology  2008;64(6):687-697.
OBJECTIVE
Chronic seizures in women can have adverse effects on reproductive function, such as polycystic ovarian syndrome (PCOS), but it has been difficult to dissociate the effects of epilepsy per se from the role of antiepileptic drugs (AEDs). To distinguish the effects of chronic seizures from AEDs, we used the laboratory rat, where an epileptic condition can be induced without concomitant AED treatment.
METHODS
Adult female rats were administered the chemoconvulsant pilocarpine to initiate status epilepticus (SE), which was decreased in severity by the anticonvulsant diazepam. These rats developed spontaneous seizures in the ensuing weeks, and are therefore termed “epileptic.” Controls were saline-treated rats, or animals that were injected with pilocarpine but did not develop SE. Ovarian cyclicity and weight gain were evaluated for 2-3 months. Serum hormone levels were assayed from trunk blood, collected at the time of death. Paraformaldehyde-fixed ovaries were evaluated quantitatively.
RESULTS
Rats that had pilocarpine-induced seizures had an increased incidence of acyclicity by the end of the study, even if SE did not occur. Ovarian cysts and weight gain were significantly greater in epileptic rats than controls, whether rats maintained cyclicity or not. Serum testosterone was elevated in epileptic rats, but estradiol, progesterone and prolactin were not.
INTERPRETATIONS
The results suggest that an epileptic condition in the rat leads to increased body weight, cystic ovaries and elevated testosterone levels. Although caution is required when comparing female rats to women, the data suggest that epilepsy per se may be sufficient to induce abnormalities in the control of the ovary.
doi:10.1002/ana.21518
PMCID: PMC2677522  PMID: 19107990
Estrogen; progesterone; testosterone; prolactin; estrous cycle; ovaries; pilocarpine; status epilepticus; polycystic ovarian syndrome; temporal lobe epilepsy
25.  Expressional analysis of the astrocytic Kir4.1 channel in a pilocarpine–induced temporal lobe epilepsy model 
The inwardly rectifying potassium (Kir) channel Kir4.1 in brain astrocytes mediates spatial K+ buffering and regulates neural activities. Recent studies have shown that loss-of-function mutations in the human gene KCNJ10 encoding Kir4.1 cause epileptic seizures, suggesting a close relationship between the Kir4.1 channel function and epileptogenesis. Here, we performed expressional analysis of Kir4.1 in a pilocarpine-induced rat model of temporal lobe epilepsy (TLE) to explore the role of Kir4.1 channels in modifying TLE epileptogenesis. Treatment of rats with pilocarpine (350 mg/kg, i.p.) induced acute status epilepticus, which subsequently caused spontaneous seizures 7–8 weeks after the pilocarpine treatment. Western blot analysis revealed that TLE rats (interictal condition) showed significantly higher levels of Kir4.1 than the control animals in the cerebral cortex, striatum, and hypothalamus. However, the expression of other Kir subunits, Kir5.1 and Kir2.1, remained unaltered. Immunohistochemical analysis illustrated that Kir4.1-immunoreactivity-positive astrocytes in the pilocarpine-induced TLE model were markedly increased in most of the brain regions examined, concomitant with an increase in the number of glial fibrillary acidic protein (GFAP)-positive astrocytes. In addition, Kir4.1 expression ratios relative to the number of astrocytes (Kir4.1-positive cells/GFAP-positive cells) were region-specifically elevated in the amygdala (i.e., medial and cortical amygdaloid nuclei) and sensory cortex. The present study demonstrated for the first time that the expression of astrocytic Kir4.1 channels was elevated in a pilocarpine-induced TLE model, especially in the amygdala, suggesting that astrocytic Kir4.1 channels play a role in modifying TLE epileptogenesis, possibly by acting as an inhibitory compensatory mechanism.
doi:10.3389/fncel.2013.00104
PMCID: PMC3734973  PMID: 23922547
Kir4.1 channel; astrocytes; temporal lobe epilepsy; status epilepticus; spatial potassium buffering; pilocarpine

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