lithium-chloride and Epilepsy

Cardiac dysfunction is one of the leading causes of death in epilepsy. The anti-arrhythmic drug, amiodarone, is under investigation for its therapeutic effects in epilepsy. We aimed to evaluate the possible effects of amiodarone on cardiac injury during status epilepticus, as it can cause prolongation of the QT interval. Five rat groups were enrolled in the study; three control groups (1) Control, (2) Control-lithium and (3) Control-Amio, treated with 150 mg/kg/intraperitoneal amiodarone, (4) Epilepsy model, induced by sequential lithium/pilocarpine administration, and (5) the epilepsy-Amio group. The model group expressed a typical clinical picture of epileptiform activity confirmed by the augmented electroencephalogram alpha and beta spikes. The anticonvulsive effect of amiodarone was prominent, it diminished (p < 0.001) the severity of seizures and hence, deaths and reduced serum noradrenaline levels. In the model group, the electrocardiogram findings revealed tachycardia, prolongation of the corrected QT (QTc) interval, depressed ST segments and increased myocardial oxidative stress. The in-vitro myocardial performance (contraction force and - (df/dt)

Topics: Adjuvants, Immunologic; Amiodarone; Animals; Anti-Arrhythmia Agents; Biomarkers; Epilepsy; Glutathione; Heart Diseases; Interleukin-1; Lithium Chloride; Male; Malondialdehyde; Muscarinic Agonists; Myocardial Contraction; Pilocarpine; Rats; Rats, Wistar; Superoxide Dismutase; Troponin I

An increasing number of observations have indicated that the activation of inflammatory processes is involved in the pathogenesis of epilepsy. As an effective adjunctive therapy for medically intractable seizures, vagus nerve stimulation (VNS) is thought to interact with the inflammatory process to play an antiepileptic role. In this study, we examined the levels of multiple cytokine in focal brain tissue and peripheral blood to determine whether the antiepileptic effect of chronic VNS is related to the expression of cytokines. We observed that the frequency and duration of seizures significantly decreased in epileptic rats after two weeks of chronic VNS treatment. Pathological staining showed that the number of neural cells in the hippocampus was higher in the Epi + VNS group than in the Epi group, indicating that chronic VNS had a significant neuroprotective effect on epileptic rats. After comparing the expression of 9 cytokines, we found that the levels of the proinflammatory cytokines IL-6, IL-1β and CXCL-1 in the hippocampus were significantly increased in the Epi group, while these cytokines were significantly decreased in the Epi + VNS group. Moreover, the level of the anti-inflammatory cytokine IL-13 was found to be reduced in Epi rats, while its levels were increased after VNS treatment. However, these changes in cytokine expression were not found in the hypothalamus or peripheral blood. These results suggest that the antiepileptic mechanism of VNS may work by inhibiting the activation of inflammatory processes in the epileptogenic focus.

Topics: Animals; Chemokine CXCL1; Epilepsy; Hippocampus; Interleukin-13; Interleukin-1beta; Interleukin-6; Lithium Chloride; Male; Pilocarpine; Rats; Rats, Sprague-Dawley; Vagus Nerve Stimulation

Abnormal neurogenesis in the hippocampus after status epilepticus (SE) has been suggested as a key pathogeny of temporal lobe epilepsy. This study aimed to investigate the effect of deep brain stimulation of the anterior thalamic nucleus (ANT-DBS) on hippocampal neurogenesis in LiCl-pilocarpine-induced epileptic rats and to analyze its relationship with postoperative spontaneous recurrent seizures (SRS) and anxiety.. SE was induced by a systemic LiCl-pilocarpine injection in adult male rats. Rats in the DBS group underwent ANT-DBS immediately after successful SE induction. SRS was only recorded during the chronic stage. An elevated plus maze was used to evaluate the level of anxiety in rats 7, 28, and 60 days after SE onset. After the elevated plus-maze experiment, rats were sacrificed under anesthesia in order to evaluate hippocampal neurogenesis. Doublecortin (DCX) was used as a marker for neurogenesis.. During the chronic stage, SRS in rats in the DBS group were significantly decreased. The level of anxiety was increased significantly in rats in the DBS group 28 days after SE, while no significant differences in anxiety levels were found 7 and 60 days after SE. The number of DCX-positive cells in the hippocampus was significantly increased 7 days after SE and was significantly decreased 60 days after SE in all rats in which SE was induced. However, the number of DCX-positive cells in the DBS group was significantly lower than that in the other groups 28 days after SE.. ANT-DBS may suppress SRS and increase the postoperative anxiety of epileptic rats by influencing hippocampal neurogenesis.

Topics: Animals; Anterior Thalamic Nuclei; Deep Brain Stimulation; Doublecortin Protein; Epilepsy; Hippocampus; Lithium Chloride; Male; Neurogenesis; Pilocarpine; Rats; Rats, Sprague-Dawley

Sudden unexpected death in epilepsy (SUDEP) is a major outcome of cardiac dysfunction in patients with epilepsy. In continuation of our previous work, the present study was envisaged to explore the key regulators responsible for cardiac damage associated with chronic seizures using whole transcriptome and proteome analysis in a rat model of temporal lobe epilepsy.. A standard lithium-pilocarpine protocol was used to induce recurrent seizures in rats. The isolated rat heart tissue was subjected to transcriptomic and proteomic analysis. An integrated approach of RNA-Seq, proteomics, and system biology analysis was used to identify key regulators involved in seizure-linked cardiac changes. The analyzed differential expression patterns and network interactions were supported by gene and protein expression studies.. Altogether, 1157 differentially expressed genes and 1264 proteins were identified in the cardiac tissue of epileptic animals through RNA-Seq and liquid chromatography with tandem mass spectrometry-based proteomic analysis, respectively. The network analysis revealed seven critical genes-STAT3, Myc, Fos, Erbb2, Erbb3, Notch1, and Mapk8-that could play a role in seizure-mediated cardiac changes. The LC-MS/MS analysis supported the activation of the transforming growth factor β (TGF-β) pathway in the heart of epileptic animals. Furthermore, our gene and protein expression studies established a key role of STAT3, Erbb, and Mapk8 to develop cardiac changes linked with recurrent seizures.. The present multi-omics study identified STAT3, Mapk8, and Erbb as key regulators involved in seizure-associated cardiac changes. It provided a deeper understanding of molecular, cellular, and network-level operations of the identified regulators that lead to cardiac changes in epilepsy.

Topics: Animals; Chromatography, Liquid; Disease Models, Animal; Epilepsy; Gene Expression Profiling; Gene Regulatory Networks; Heart Diseases; Lithium Chloride; Mitogen-Activated Protein Kinase 8; Muscarinic Agonists; Myocardium; Pilocarpine; Proteome; Proteomics; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-myc; Rats; Real-Time Polymerase Chain Reaction; Receptor, ErbB-2; Receptor, ErbB-3; Receptor, Notch1; RNA-Seq; Signal Transduction; STAT3 Transcription Factor; Tandem Mass Spectrometry; Time Factors; Transforming Growth Factor beta

Seizure-induced neurogenesis has a widely recognized pro-epileptogenic function. Given the critical role of Notch signaling during the maintenance and neurogenesis of neural stem cells, we hypothesized that Notch may affect epileptogenesis and its progression through its role in neurogenesis in the adolescent rat brain. We used the lithium-pilocarpine-induced epilepsy model in adolescent Sprague-Dawley rats in order to evaluate hippocampal neurogenesis and epileptogenesis following the onset of status epilepticus (SE). We used western blotting analyses and qPCR to measure levels of Notch signaling at different phases after seizures and immunofluorescence to detect the proliferation and differentiation of neural stem cells after seizure. Following the administration of DAPT, a Notch γ-secretase inhibitor, into the lateral ventricles, we observed a suppression of abnormal neurogenesis in the acute phase and a reduction of gliosis in the chronic phase after SE. Accordingly, the frequency and duration of spontaneous seizures in chronic phase were decreased. Our results clarify the basic concept regarding the involvement of Notch signaling in the regulation of hippocampal neurogenesis and epileptogenesis, thereby potentially offering a novel and alternative treatment for epilepsy.

Topics: Animals; Cell Differentiation; Disease Models, Animal; Epilepsy; Hippocampus; Lithium Chloride; Neural Stem Cells; Neurogenesis; Pilocarpine; Rats; Rats, Sprague-Dawley; Receptor, Notch1; Signal Transduction; Status Epilepticus

Chaihu-Longgu-Muli decoction (CLMD) is a well-known ancient formula in traditional Chinese medicine (TCM) to relieve disorder, clear away heat, tranquilize the mind and allay excitement. It has been used for the therapy of neuropsychiatric disorders such as epilepsy, dementia, insomnia, anxiety, and depression for several centuries in China.. This paper is based on the assumption that the mechanism by which CLMD relieves epileptic symptoms in rats is associated with improving autophagy. Several experimental methods are designed to testify the hypothesis.. The lithium-pilocarpine-induced epilepsy model was established in rats. The seizure frequency was recorded. Morphology and number of autophagosomes in hippocampal dentate gyrus was detected with a transmission electron microscope (TEM). Expression of Beclin-1, microtubule-associated proteins 1A/1B light chain 3 (LC3), and mammalian target of rapamycin (mTOR) in dentate gyrus was measured by immunofluorescence assay, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western-blotting.. CLMD could significantly relieve the seizure frequency and improve autophagy in hippocampal dentate gyrus. Meanwhile, the level of Beclin-1 and LC3B decreased significantly, while mTOR increased remarkably after medical intervention.. CLMD could improve autophagy in hippocampal dentate gyrus due to epilepsy, especially at high dose. The mechanism may be related to upregulated expression of mTOR and downregulated expression of Beclin-1 and LC3B.

Topics: Animals; Anticonvulsants; Autophagosomes; Autophagy; Autophagy-Related Proteins; Behavior, Animal; Disease Models, Animal; Drugs, Chinese Herbal; Epilepsy; Hippocampus; Lithium Chloride; Male; Neurons; Pilocarpine; Rats, Sprague-Dawley; Signal Transduction

 To investigate the expression of brain-derived neurotrophic factor(BDNF) and tyrosine kinase B (TrkB) protein in the hippocampus of model rats of comorbid epilepsy and depression.. A rat model of epilepsy was established using lithium chloride.pilocarpine. Among these epileptic rats, those with comorbid depression were selected by a battery of behavioral tests starting on the 14th day after establishing the epilepsy model. A depression group was established by unpredicted chronic mild stress (UCMS) and separate housing. These treatment groups were compared to an untreated control group. Thirteen rats per group were examined by immunofluorescence staining with optical density quantitation to determine the distribution of BDNF- and TrkB-positive cells in the hippocampus and by western blotting to estimate total protein expression levels during the 4th week after establishing the models. Immunofluorescence staining for NeuN was also conducted in hippocampus to evaluate neuronal survival. Depression-like behaviors were also assessed..  Compared to the untreated control group and the epilepsy alone group, the comorbid group exhibited lower average optical densities of BDNF- and TrkB-immunopositive cells as well as lower total BDNF and TrkB protein expression levels (all P = 0.000). The comorbid group exhibited lower behavioral scores compared to all other groups (all P=0.000). Numbers of NeuN-positive cells were lower in the hippocampus of all three experimental groups compared to the untreated control group (all P = 0.000)..  These results suggest that hypofunctional BDNF-TrkB signaling may contribute to depression in epilepsy.. BDNF: Brain-derived neurotrophic factor; TrkB: tyrosine kinase B; UCMS: unpredicted chronic mild stress; PBS: phosphate-buffered saline; HS: Hippocampal sclerosis.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cell Survival; Comorbidity; Depressive Disorder; Disease Models, Animal; Down-Regulation; Epilepsy; Female; Hippocampus; Lithium Chloride; Neurons; Pilocarpine; Random Allocation; Rats, Sprague-Dawley; Receptor, trkB

Adenosine A1 receptor (AA1R) is widely present in the central nervous system, exerting brain protective antiepileptic effects, mainly by binding corresponding G proteins. We evaluated the neuroprotective effects of AA1R on hippocampal neuronal injury after lithium chloride-pilocarpine-induced epilepsy in rats.. A total of 60 male SD rats were randomly divided into four groups (n = 15/group): normal control, epilepsy, epilepsy + AA1R antagonist (DPCPX), and epilepsy + AA1R agonist (2-CAdo). An epilepsy model was established through kindling by lithium chloride-pilocarpine. The four groups were observed on days 1, 14, and 30. Pathological and morphological changes of hippocampal neurons were observed by HE staining; apoptosis was detected by TUNEL assay. Caspase-3 and GABA receptor expressions were detected by Western blot.. In the hippocampal CA3 area of the epilepsy group, the cellular structure was not neatly arranged, and some neurons were swelling, thick, and incomplete. Compared with the epilepsy group at the same time point, cells in the epilepsy + DPCPX group had an increased distortion, disorganization, edema, cytoplasmic vacuoles, and degeneration. In the epilepsy + 2-CAdo group, cell arrangement was regular and orderly, and structural damages were lessened. Compared with the normal control group at the same time point, the epilepsy group underwent evident neuronal apoptosis, with a significantly higher apoptotic index (AI) (p < 0.05). Compared with the epilepsy group, the neuronal apoptosis of the epilepsy + DPCPX group was boosted, and the AI significantly increased (p < 0.05). The neuronal apoptosis of the epilepsy + 2-CAdo group was inhibited, and the AI significantly decreased (p < 0.05). Compared with the epilepsy group, the caspase-3 expression levels of the epilepsy + DPCPX group on days 14 and 30 were significantly upregulated (p < 0.05), but those of the epilepsy + 2-CAdo group were significantly downregulated (p < 0.05).. AA1R abated cell edema and reduced apoptosis, exerting neuroprotective effects on hippocampal neuronal injury after lithium chloride-pilocarpine-induced epilepsy.

Topics: Adenosine A1 Receptor Agonists; Animals; Apoptosis; Disease Models, Animal; Epilepsy; Hippocampus; Lithium Chloride; Male; Neurons; Neuroprotective Agents; Pilocarpine; Rats; Rats, Sprague-Dawley; Time Factors

This study aimed to investigate whether 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase inhibitor with anti-inflammatory effects, could alleviate spontaneous recurrent seizures (SRS) and epilepsy-associated depressive behaviours in the lithium chloride (LiCl)-pilocarpine-induced post-status epilepticus (SE) rat model.. The rats were intraperitoneally (IP) injected with LiCl (127 mg/kg) and pilocarpine (40 mg/kg) to induce SE. A video surveillance system was used to monitor SRS in the post-SE model for 6 weeks (from the onset of the 2nd week to the end of the 7th week after SE induction). TPPU (0.1 mg/kg/d) was intragastrically given for 4 weeks from the 21st day after SE induction in the SRS + 0.1 TPPU group. The SRS + PEG 400 group was given the vehicle (40% polyethylene glycol 400) instead, and the control group was given LiCl and PEG 400 but not pilocarpine. The sucrose preference test (SPT) and forced swim test (FST) were conducted to evaluate the depression-like behaviours of rats. Immunofluorescent staining, enzyme-linked immunosorbent assay, and western blot analysis were performed to measure astrocytic and microglial gliosis, neuronal loss, and levels of soluble epoxide hydrolase (sEH), cytokines [tumour necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6], and cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB).. The frequency of SRS was significantly decreased at 6 weeks and 7 weeks after SE induction in the 0.1TPP U group compared with the SRS + PEG 400 group. The immobility time (IMT) evaluated by FST was significantly decreased, whereas the climbing time (CMT) was increased, and the sucrose preference rate (SPR) evaluated by SPT was in an increasing trend. The levels of sEH, TNF-α, IL-1β, and IL-6 in the hippocampus (Hip) and prefrontal cortex (PFC) were all significantly increased in the SRS + PEG 400 group compared with the control group; neuronal loss, astrogliosis, and microglial activation were also observed. The astrocytic and microglial activation and levels of the pro-inflammatory cytokines in the Hip and PFC were significantly attenuated in the TPPU group compared with the SRS + PEG 400 group; moreover, neuronal loss and the decreased CREB expression were significantly alleviated as well.. TPPU treatment after SE attenuates SRS and epilepsy-associated depressive behaviours in the LiCl-pilocarpine induced post-SE rat model, and it also exerts anti-inflammatory effects in the brain. Our findings suggest a new therapeutic approach for epilepsy and its comorbidities, especially depression.

Topics: Animals; Astrocytes; Brain; Depression; Depressive Disorder; Disease Models, Animal; Epilepsy; Epoxide Hydrolases; Hippocampus; Lithium Chloride; Male; Microglia; Neurons; Phenylurea Compounds; Pilocarpine; Piperidines; Rats; Rats, Sprague-Dawley; Seizures; Status Epilepticus; Tumor Necrosis Factor-alpha

Comorbid depression is common in patients with epilepsy. However, the epilepsy-associated depression is generally atypical and has not been fully recognized by neurologists. This study aimed to compare the behavioral and pathological changes between the chronic lithium chloride-pilocarpine rat epilepsy model (Licl-pilocarpine model) and the Chronic Unpredictable Mild Stress rat depression model (CUMS model), to evaluate for differences between epilepsy-associated depression and primary depression.. The Licl-pilocarpine model and the CUMS model were established respectively and simultaneously. Spontaneous seizures were recorded by video monitoring. Forced swim test (FST) and sucrose consumption test (SCT) were performed to test depressive behaviors. Immobility time (IMT) and climbing time (CMT) in FST, sucrose preference rate (SPR) in SCT, and weight gain rate (WGR) were adopted to represent severity of depressive behaviors in rats. Immunofluorescent staining was conducted to measure expressions of neuronal specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), and cluster of differentiation molecule 11b (CD11b) in the hippocampus of Licl-pilocarpine model, CUMS model, and Control group.. Significantly, more prolonged IMT was observed in both the Licl-pilocarpine model (p<0.05) and the CUMS model (p<0.01) than Control group. But decreased WGR was only seen in the CUMS model. The percentage of rats with CMT greater than 100s was significantly higher in the Licl-pilocarpine model than the CUMS model (p<0.05). Increased CMT was observed in the Licl-pilocarpine model with mild depression subgroup (EMD, IMT≤100s) even compared with the Control group. Neuronal loss was both found in the Licl-pilocarpine model and the CUMS model when comparing with the Control group (p<0.05). However, the number of GFAP and CD11b staining cells was both greater in the Licl-pilocarpine model than the CUMS model and the Control group (p<0.05).. There were some different depressive behavioral and hippocampal pathological changes between the Licl-pilocarpine and the CUMS models except for some common features. Gliosis and microglial activation might be more involved in the pathophysiology of epilepsy-associated depression than primary depression.

Topics: Animals; Depression; Disease Models, Animal; Epilepsy; Hippocampus; Lithium Chloride; Male; Pilocarpine; Rats; Rats, Sprague-Dawley; Stress, Psychological; Swimming

The study aimed to explore the effects of microRNA-129-5p (miR-129-5p) on the development of autoimmune encephalomyelitis (AE)-related epilepsy by targeting HMGB1 through the TLR4/NF-kB signaling pathway in a rat model. AE-related epilepsy models were established. Sprague-Dawley (SD) rats were randomly divided into control, model, miR-129-5p mimics, miR-129-5p inhibitor, HMGB1 shRNA, TLR4/NF-kB (TLR4/NF-kB signaling pathway was inhibited) and miR-129-5p mimics+HMGB1 shRNA groups respectively. Latency to a first epilepsy seizure attack was recorded. Neuronal injuries in the hippocampus regions were detected using HE, Nissl and FJB staining methods 24h following model establishment. Microglial cells were detected by OX-42 immunohistochemistry. Expressions of miR-129-5p, HMGB1 and TLR4/NF-kB signaling pathway-related proteins were detected by qRT-PCR. Protein expressions of HMGB1 and TLR4/NF-kB signaling pathway-related proteins were detected by Western blotting. Dual luciferase reporter gene assay showed that miR-129-5p was negatively targeting HMGB1. Neurons of hippocampal tissues in rats were heavily injured by an injection of lithium chloride. Compared with the model and control groups, neuronal injury of the hippocampus and AE-related epilepsy decreased and microglial cells increased in the miR-129-5p mimics, HMGB1 shRNA and TLR4/NF-kB groups; however, in the miR-129-5p inhibitor group, miR-129-5p expression decreased, HMGB1 expression increased, TLR4/NF-kB signaling pathway was activated, latency to a first epilepsy seizure attack was shortened, and neuronal injury increased. This study provides evidence that miR-129-5p inhibits the development of AE-related epilepsy by suppressing HMGB1 expression and inhibiting TLR4/NF-kB signaling pathway.

Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Epilepsy; Escherichia coli; Genetic Vectors; Hippocampus; HMGB1 Protein; Lentivirus; Lithium Chloride; Male; MicroRNAs; Neurons; NF-kappa B; Pilocarpine; Random Allocation; Rats, Sprague-Dawley; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Toll-Like Receptor 4

The objective was to determine whether the depression comorbid with epilepsy could be predicted based on inherent premorbid patterns of monoaminergic transmission. In male Wistar rats, despair-like and anhedonia-like behaviors were examined using forced swimming and taste preference tests, respectively. Serotonergic raphe nucleus (RN)-prefrontal cortex (PFC) and dopaminergic ventral tegmental area (VTA)-nucleus accumbens (NAcc) pathways were interrogated by fast scan cyclic voltammetry (FSCV). The assays were performed before and 2 months after pilocarpine status epilepticus. In a subset of naive rats, FSCV, coupled with the intensity-dependent stimulation paradigm, detected specific deviations in each pathway (six rats for RN-PFC and seven rats for VTA-NAcc, with overlap in two, of 19 total subjects) in the absence of behavioral impairments. During epilepsy, animals with preexisting deviations in RN-PFC invariably developed despair, and rats with deviations in VTA-NAcc developed anhedonia. Serotonergic and dopaminergic pathways, respectively, showed signs of explicit deterioration. We suggest that epilepsy triggers decompensations in the already vulnerable depression-relevant neuronal circuits, which culminate in depression. The established connection between the identified specific signatures in monoamine transmission in naive rats and specific symptoms of epilepsy-associated depression may help in understanding causes of comorbidity and in developing its early biomarkers.

Topics: Animals; Anticonvulsants; Biogenic Monoamines; Convulsants; Depression; Disease Models, Animal; Epilepsy; Food Preferences; Lithium Chloride; Male; Neural Pathways; Pilocarpine; Rats; Rats, Wistar; Swimming

We aimed to discuss the mechanism of occurrence and progression of epilepsy through analyzing the expression changes of UCA1 and NF-Kb in temporal hippocampus and UCA1 in peripheral blood in rats with epilepsy induced by lithium chloride-pilocarpine.. The lithium chloride-pilocarpine-induced epilepsy rat model was established; 1, 7, 14, 30, and 60 d after status epilepticus were selected as the time points of research. The expression levels of UCA1 and NF-kB in the hippocampus of rats and UCA1 in peripheral blood were detected and analyzed using quantitative Real-time PCR (qRT-PCR). The differences and correlations between expression levels of UCA1 and NF-kB at each time point of research in experimental group and control group were analyzed statistically.. Results showed that mRNA expression levels of UCA1 and NF-kB in brain tissues in experimental group were higher than those in control group at each time point. The change trend of expression levels of UCA1 and NF-kB with time was consistent. The expression level of UCA1 in peripheral blood in experimental group at each time point was higher than that in control group, and mRNA expression level of UCA1 in peripheral blood in experimental group was positively correlated with that in brain tissue.. The expressions of UCA1 and NF-Kb are in the dynamic change in the formation of epilepsy, suggesting that UCA1 may participate in the pathogenesis of epilepsy, so as to provide a potentially feasible new direction for guiding the clinical diagnosis and treatment of epilepsy.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Disease Progression; Epilepsy; Gene Expression Regulation; Hippocampus; Lithium Chloride; Male; NF-kappa B; Pilocarpine; Rats; Rats, Sprague-Dawley; RNA, Long Noncoding; RNA, Messenger

The mechanisms of epilepsy remain incompletely understood. Rac1 (ras-related C3 botulinum toxin substrate 1) belongs to the Rho family of small GTPases. Rac1 play important roles in cytoskeleton rearrangement and neuronal synaptic plasticity, which had also been implicated in epilepsy. However, little is known regarding the expression of Rac1 in the epileptic brain or whether Rac1-targeted interventions affect the progression of epilepsy. The aim of this study was to investigate the expression profile of Rac1 in brain tissues from patients suffering from temporal lobe epilepsy (TLE) and experimental epileptic rats and determine the possible role of Rac1 in epilepsy. We demonstrated that the expression of Rac1 is significantly increased in TLE patients and in lithium-pilocarpine epilepsy model animals compared to the corresponding controls. Rac1 inhibitor NSC23766 reduced the severity of status epilepticus during the acute stage in a lithium-pilocarpine animal model. Consistent with these results, the latent period of a PTZ kindling animal model also increased. Our results demonstrated that the increased expression of Rac1 may contribute to pathophysiology of epilepsy.

Topics: Adult; Aminoquinolines; Animals; Behavior, Animal; Brain; Case-Control Studies; Disease Models, Animal; Epilepsy; Female; Humans; Kindling, Neurologic; Lithium Chloride; Male; Pilocarpine; Pyrimidines; rac1 GTP-Binding Protein; Rats, Sprague-Dawley

Depression is a common comorbidity in patients with epilepsy with unclear mechanisms. This study is to explore the role of glutamate N-methyl-D-aspartate (NMDA) receptor NR1, NR2A and NR2B subunits in epilepsy-associated depression. Lithium chloride (Licl)-pilocarpine chronic rat epilepsy model was established and rats were divided into epilepsy with depression (EWD) and epilepsy without depression (EWND) subgroups based on forced swim test. Expression of NMDA receptor NR1, NR2A and NR2B subunits was measured by western blot and immunofluorescence methods. The immobility time (IMT) was significantly greater in Licl-pilocarpine model group than in Control group, which was also greater in EWD group than in EWND group. No differences of spontaneous recurrent seizure (SRS) counts over two weeks and latency were found between EWD and EWND groups. The number of NeuN positive cells was significantly less in Licl-pilocarpine model group than in Control group, but had no difference between EWD and EWND groups. The ratios of phosphorylated NR1 (p-NR1)/NR1 and p-NR2B/NR2B were significantly greater in the hippocampus in EWD group than in EWND group. Moreover, the expression of p-NR1 and p-NR2B in the CA1 subfield of hippocampus were both greater in Licl-pilocarpine model group than Control group. Selective blockage of NR2B subunit with ifenprodil could alleviate depression-like behaviours of Licl-pilocarpine rat epilepsy model. In conclusion, glutamate NMDA receptor NR2B subunit was involved in promoting depression-like behaviours in the Licl-pilocarpine chronic rat epilepsy model and might be a target for treating epilepsy-associated depression.

Topics: Animals; Antigens, Nuclear; Chronic Disease; Depressive Disorder; Disease Models, Animal; Epilepsy; Hippocampus; Lithium Chloride; Male; Nerve Tissue Proteins; Neurons; Phosphorylation; Pilocarpine; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

The role of serotonin (5-hydroxytryptamine; 5-HT) in epileptogenesis still remains controversial. In this regard, it has been reported that serotonergic drugs can alter epileptogenesis in opposite ways. The main objective of this work was to investigate the effect of the selective 5-HT selective reuptake inhibitor (SSRI) fluoxetine administered subacutely (10mg/kg/day×7 days) on the eventual metabolic impairment induced by the lithium-pilocarpine model of epilepsy in rats. In vivo 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F] FDG) positron emission tomography (PET) was performed to assess the brain glucose metabolic activity on days 3 and 30 after the insult. In addition, at the end of the experiment (day 33), several histochemical and neurochemical assessments were performed for checking the neuronal functioning and integrity. Three days after the insult, a marked reduction of [(18)F] FDG uptake (about 30% according to the brain region) was found in all brain areas studied. When evaluated on day 30, although a hypometabolism tendency was observed, no statistically significant reduction was present in any region analyzed. In addition, lithium-pilocarpine administration was associated with medium-term hippocampal and cortical damage, since it induced neurodegeneration, glial activation and augmented caspase-9 expression. Regarding the effect of fluoxetine, subacute treatment with this SSRI did not significantly reduce the mortality rate observed after pilocarpine-induced seizures. However, fluoxetine did prevent not only the short-term metabolic impairment, but also the aforementioned signs of neuronal damage in surviving animals to lithium-pilocarpine protocol. Finally, fluoxetine increased the density of GABAA receptor both at the level of the dentate gyrus and CA1-CA2 regions in pilocarpine-treated animals. Overall, our data suggest a protective role for fluoxetine against pilocarpine-induced brain damage. Moreover, this action may be associated with an increase of GABAA receptor expression in hippocampus.

Topics: Animals; Apoptosis; Astrocytes; Brain; Caspase 3; Disease Models, Animal; Epilepsy; Fluoxetine; Glucose; Hippocampus; Lithium Chloride; Male; Pilocarpine; Positron-Emission Tomography; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Selective Serotonin Reuptake Inhibitors; Survival Analysis

Attention deficit/hyperactivity disorder (ADHD) is encountered among patients with epilepsy at a significantly higher rate than in the general population. Mechanisms of epilepsy-ADHD comorbidity remain largely unknown. We investigated whether a model of chronic epilepsy in rats produces signs of ADHD, and thus, whether it can be used for studying mechanisms of this comorbidity. Epilepsy was induced in male Wistar rats via pilocarpine status epilepticus. Half of the animals exhibited chronic ADHD-like abnormalities, particularly increased impulsivity and diminished attention in the lateralized reaction-time task. These impairments correlated with the suppressed noradrenergic transmission in locus coeruleus outputs. The other half of animals exhibited depressive behavior in the forced swimming test congruently with the diminished serotonergic transmission in raphe nucleus outputs. Attention deficit/hyperactivity disorder and depressive behavior appeared mutually exclusive. Therefore, the pilocarpine model of epilepsy affords a system for reproducing and studying mechanisms of comorbidity between epilepsy and both ADHD and/or depression.

Topics: Animals; Attention Deficit Disorder with Hyperactivity; Behavioral Symptoms; Brain; Chronic Disease; Compulsive Behavior; Convulsants; Disease Models, Animal; Epilepsy; Functional Laterality; Immobility Response, Tonic; Lithium Chloride; Male; Photic Stimulation; Pilocarpine; Rats; Rats, Wistar; Reaction Time; Swimming

Cell apoptosis can cause hippocampal neuronal loss after epileptic seizures. Hypoxia inducible factor (HIF)-1α is an important factor mediating apoptosis after brain injuries, such as cerebral ischemia and traumatic brain injures, but little research has been done on its role in the lithium chloride-pilocarpine induced epileptic model. Here, we used a rat model of pilocarpine-induced status epilepticus (SE) to investigate HIF-1α expression and apoptosis in the hippocampus, and to explore their relationship during epileptogenesis. 120 male Sprague Dawley (SD) rats were treated with lithium chloride-pilocarpine injections and divided into an experimental group (administered by MK-801) and a positive control group (administered by saline). Then the HIF-1α expression and hippocampal apoptosis were investigated by histological confirmation and western blotting at 24h, 3d, 7d and 14d, respectively. The results showed that the administration of MK-801 significantly reduced (P<0.05) HIF-1α expression and hippocampal apoptosis during epileptogenesis in comparison with the positive control. Moreover, the expression of HIF-1α and hippocampal apoptosis presented significant time-dependent changes (P<0.01) within 2 weeks, and their positive correlation (P<0.05) analyzed by Pearson׳s correlation analysis. Meanwhile, the HIF-1α immunostained cells were distributed in accord with TUNEL immunostained cells and Caspase-3 immunopositive cells in the hippocampus. These results indicate that the HIF-1α expression is associated with hippocampal apoptosis, and suggest that HIF-1α is an important factor during epileptogenesis.

Topics: Animals; Apoptosis; Convulsants; Dizocilpine Maleate; Electroencephalography; Epilepsy; Excitatory Amino Acid Antagonists; Hippocampus; Hypoxia-Inducible Factor 1, alpha Subunit; Lithium Chloride; Male; Pilocarpine; Rats; Rats, Sprague-Dawley

  The metabolic and biochemical changes that occur during epileptogenesis remain to be determined. (18) F-Fluorodeoxyglucose positron emission tomography (FDG-PET) and proton magnetic resonance spectroscopy ((1) H MRS) are noninvasive techniques that provide indirect information on ongoing pathologic changes. We, therefore, utilized these methods to assess changes in glucose metabolism and metabolites in the rat lithium-pilocarpine model of epilepsy as markers of epileptogenesis from baseline to chronic spontaneous recurrent seizures (SRS)..   PET and MRS were performed at baseline, and during the acute, subacute, silent, and chronic periods after lithium-pilocarpine induced status epilepticus (SE). Sequential changes in glucose metabolism on (18) F-FDG PET using SPM2 and the ratios of percent injected dose per gram (%ID)/g of regions of interest (ROIs) in the bilateral amygdala, hippocampus, basal ganglia with the thalamus, cortex, and hypothalamus normalized to the pons were determined. Voxels of interest (VOIs) on (1) H MRS were obtained at the right hippocampus and the basal ganglia. NAA/Cr levels and Cho/Cr at various time points were compared to baseline values..   Of 81 male Sprague-Dawley rats, 30 progressed to SRS. (18) F-FDG PET showed widespread global hypometabolism during the acute period, returning to baseline level during the subacute period. Glucose metabolism, however, declined in part of the hippocampus during the silent period, with the hypometabolic area progressively expanding to the entire limbic area during the chronic period. (1) H MRS showed that the NAA/Cr levels in the hippocampus and basal ganglia were reduced during the acute period and were not restored subsequently from the subacute to the chronic period without any significant change in the Cho/Cr ratio throughout the entire experiment..   Serial metabolic and biochemical changes in the lithium-pilocarpine model of epilepsy indirectly represent the process of human epileptogenesis. Following initial irreversible neural damage by SE, global glucose metabolism transiently recovered during the subacute period without neuronal recovery. Progressive glucose hypometabolism in the limbic area during the silent and chronic periods may reflect the important role of the hippocampus in the formation of ongoing epileptic network during epileptogenesis.

Topics: Animals; Aspartic Acid; Brain Mapping; Choline; Creatine; Disease Models, Animal; Epilepsy; Fluorodeoxyglucose F18; Glucose; Hippocampus; Lithium Chloride; Magnetic Resonance Spectroscopy; Male; Pilocarpine; Positron-Emission Tomography; Rats; Rats, Sprague-Dawley; Time Factors; Tritium

Focal epilepsies are often associated with blood-brain barrier disruption. In 4 entorhinal cortex tissue samples and 13 hippocampal samples from patients with pharmacoresistent temporal lobe epilepsy, we observed immunoglobulin G (IgG) leakage in the parenchyma and IgG-positive neurons that had evidence of neurodegeneration, such as shrinkage and eosinophilia. These findings were not present in samples from 12 nonepileptic control subjects. To complement these findings, we used a rat in vivo model that mimics the development of limbic epilepsy with blood-brain barrier disruption. During epileptogenesis, IgG leakage and neuronal IgG uptake increased concomitantly with the occurrence of seizures. Immunoglobulin G accumulation in neurons was selective, particularly for interneurons and pyramidal neurons. Immunohistochemistry and electron microscopy showed that IgG uptake in the rat neurons was associated with eosinophilia, shrinkage, and ultrastructural degenerative changes. Moreover, IgG-positive neurons lost their NeuN immunohistochemical staining. Together, these observations suggest that IgG leakage is related to neuronal impairment and may be a pathogenic mechanism in epileptogenesis and chronic epilepsy.

Topics: Adult; Animals; Blood-Brain Barrier; Brain; Epilepsy; Female; Humans; Immunoglobulin G; Lithium Chloride; Male; Membrane Proteins; Microscopy, Immunoelectron; Middle Aged; Neuroglia; Neurons; Phosphoproteins; Phosphopyruvate Hydratase; Rats; Rats, Sprague-Dawley; Syndecan-1; Time Factors; Young Adult; Zonula Occludens-1 Protein

This study was undertaken to observe the effect of acute stress on seizure occurrence in chronic period of epileptic model rats. Lithium-pilocarpine (LiCl-PILO)-induced epileptic rat model was constructed. At the spontaneous recurrent seizure period, acute stress stimulations such as cat's urine and foot electrical shock were applied to observe the behavioral changes and seizure occurrence. The results showed that after the cat's urine stimulation, the self-directed behaviors of the epileptic model rats decreased significantly, while the risk assessment behaviors increased significantly. The seizure occurrence, however, was not observed during the 45 min after the stimulation. Applying electrical foot shocks also did not evoke seizures in epileptic model rats. On the contrast, intra-peritoneal injection of low dose of pentylenetetrazole (PTZ, 30 mg/kg) evoked seizure more efficiently, and the duration of seizure activity was extensively prolonged in epileptic model rats than that of control rats. Taken together, these results indicate that although applying stress stimulations such as cat's urine and electrical foot shock cause several behavioral changes, they are not severe enough to evoke seizure in epileptic model rats.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Epilepsy; Lithium Chloride; Pentylenetetrazole; Pilocarpine; Rats; Seizures; Stress, Physiological

The purpose of this investigation was to explore the potentiality of a novel animal model to be used for the in vivo evaluation of the ability of a drug delivery system to promote the passage through the blood-brain barrier (BBB) and/or to improve the brain localization of a bioactive compound. A Tween 80-coated poly-L-lactid acid nanoparticles was used as a model of colloidal drug delivery system, able to trespass the BBB. Tacrine, administered in LiCl pre-treated rats, induces electrocorticographic seizures and delayed hippocampal damage. The toxic effects of tacrine-loaded poly-L-lactid acid nanoparticles (5mg/kg), a saline solution of tacrine (5mg/kg) and an empty colloidal nanoparticle suspension were compared following i.p. administration in LiCl-pre-treated Wistar rats. All the animals treated with tacrine-loaded nanoparticles showed an earlier outcome of CNS adverse symptoms, i.e. epileptic onset, with respect to those animals treated with the free compound (10 min vs. 22 min respectively). In addition, tacrine-loaded nanoparticles administration induced damage of neuronal cells in CA1 field of the hippocampus in all treated animals, while the saline solution of tacrine only in 60% of animals. Empty nanoparticles provided similar results to control (saline-treated) group of animals. In conclusion, the evaluation of time-to-onset of symptoms and the severity of neurodegenerative processes induced by the tacrine-lithium model of epilepsy in the rat, could be used to evaluate preliminarily the capability of a drug delivery system to trespass (or not) the BBB in vivo.

Topics: Animals; Biological Transport; Blood-Brain Barrier; CA1 Region, Hippocampal; Capillary Permeability; Central Nervous System Agents; Cholinesterase Inhibitors; Disease Models, Animal; Drug Delivery Systems; Epilepsy; Lithium Chloride; Nanoparticles; Polyesters; Rats; Tacrine

To examine calretinin (CR)-containingObjectives: To examine cairetinin (CR)-containingnterneuronsthatdegenerate inthe hippocampus in post statusinterneurons that dege nera te in the hippocampusepilepticus (SE) ratsatdifferent time in post status epilepticus (SE) rats at different time points.. This study was conducted at the Central South University, Xiangya Hospital, Hunan Province, P.R. China between September 2008 and January 2010. Pilocarpine-induced SE was chosen as a model to generate chronic epileptic rats. To determine whether hippocampal neuronal populations are affected by hippocampal seizures, immunohistochemical assays were performed in brain sections obtained from age-matched control (n=50) and epileptic rats (n=170). Nissl stain was used to observe pathological changes of the hippocampus.. Our results revealed the most dramatic cell loss to be in the hilar, cornu Ammonis (CA)1, and CA3 areas in the epileptic rats. Quantitative analysis revealed significant differences between control and epileptic rats in the number of CR-positive interneurons. These interneurons were distributed in the hilar, CA1, and CA3 areas and in thedentate gyrus of both control and epileptic rats, but was more numerous in the hippocampus of normal rats. However, a transient increase of CR-positive interneurons was observed in the CA1 between 7 and 15 days post SE. The CR interneurons were mostly located in the hilar and CA1 for epileptic rats, and in the hilus for control rats.. Our data suggest that a different proportion of inhibitory interneurons was observed in the epileptic rat hippocampus, as their numbers differ from controls. These results indicate that the inhibitory circuits in the hippocampus may represent a compensatory response with a role to balance the enhanced excitatory input in the region.

Topics: Analysis of Variance; Animals; Calbindin 2; Disease Models, Animal; Epilepsy; Gene Expression Regulation; Hippocampus; Interneurons; Lithium Chloride; Male; Pilocarpine; Rats; Rats, Sprague-Dawley; S100 Calcium Binding Protein G; Time Factors

To test the feasibility that whole body exposure to structurally matched, physiologically patterned magnetic fields could reduce cellular injury within specific regions of the brain, young rats were seized with lithium and pilocarpine and then exposed to a sham field or to one of three computer-generated magnetic field patterns. They were digitized equivalents of the pulsed patterns of electric current known to produce long-term potential (LTP) in slices of hippocampus or entorhinal cortices. Histological analyses of their brains as adults indicated the earlier exposure to the LTP-patterned fields produced a robust reduction of damage within the primary and association areas of the right temporal cortices and the CA1/CA2 hippocampal fields. The results suggest physiologically patterned magnetic fields could be employed to target specific nuclei anywhere within the brain by matching intrinsic activity.

Topics: Animals; Brain Injuries; Dose-Response Relationship, Radiation; Epilepsy; Lithium Chloride; Long-Term Potentiation; Magnetic Field Therapy; Male; Pilocarpine; Rats; Rats, Wistar; Temporal Lobe

The underlying mechanisms of the ketogenic diet (KD) remain unknown. Involvement of peroxisome proliferator-activated receptor-alpha (PPARalpha) has been suggested. The aim of this study was to assess the anticonvulsant properties of fenofibrate, a PPARalpha agonist. Wistar rats were fed at libitum during 14 days by regular diet, KD, regular diet containing 0.2% fenofibrate (F), or KD containing 0.2% fenofibrate (KD + F). Pentylenetetrazol (PTZ) threshold and latencies to the onset of status epilepticus induced by lithium-pilocarpine were used to assess diet treatments with anticonvulsive effects. Myoclonic and generalized seizure PTZ thresholds were increased in F- and KD-treated animals in comparison to control. No difference was observed between KD + F group and the others groups (control, F, KD). Latencies to the onset of status epilepticus were increased in F and KD groups compared to control. Fenofibrate exerts anticonvulsive properties comparable to KD in adult rats using PTZ and lithium-pilocarpine models. The underlying mechanisms such as PPARalpha activation and others should be investigated. These findings may provide insights into future directions to simplify KD protocols.

Topics: 3-Hydroxybutyric Acid; Analysis of Variance; Animals; Body Weight; Diet, Ketogenic; Disease Models, Animal; Electroencephalography; Epilepsy; Fenofibrate; Hypolipidemic Agents; Ketone Bodies; Lithium Chloride; Liver; Male; Organ Size; Pentylenetetrazole; Pilocarpine; PPAR alpha; Rats; Rats, Wistar; Reaction Time

Extreme obesity slowly develops in female rats over the months following seizures induced by a single systemic injection of lithium and pilocarpine if the resulting limbic seizures are treated with the atypical neuroleptic acepromazine (but not with ketamine). To discern the contributions from food consumption, water consumption, and (daytime and nighttime) activity to this weight gain, these behaviors were monitored for 4 months, about 2 months after seizure induction. The results indicated that the rats that underwent the obesity procedure exhibited 50% heavier body weights and consumed 42% more food than the reference group, which included rats that had been induced to seize but treated with ketamine. There were no statistically significant differences between groups with respect to either water consumption or (daytime or nighttime) activity. Factor analyses of data for individual rats verified the dissociation between activity and weight gain for the obese rats. The results suggest that the progressive weight gains are centrally mediated and are not secondary to diminished activity or altered fluid consumption.

Topics: Acepromazine; Analysis of Variance; Animals; Antipsychotic Agents; Body Weight; Disease Models, Animal; Drinking; Eating; Epilepsy; Female; Lithium Chloride; Obesity; Pilocarpine; Rats; Rats, Wistar; Weight Gain

The lithium-pilocarpine model of epilepsy in rat has been used extensively to investigate basic mechanisms of epilepsy and mimics human temporal lobe epilepsy. Our aim was to investigate longitudinal alterations in metabolism after lithium-pilocarpine induced status epilepticus (SE) using [(18)F]FDG microPET. Twenty-eight Wistar rats received lithium chloride followed by pilocarpine (n=19) or saline (n=9) IP. Continuous video-EEG was used to monitor SE and occurrence of spontaneous seizures (SS). FDG microPET imaging was performed at baseline, on day 3 after drug administration (D3), and at the end of the monitoring period (CR). MicroPET images were spatially normalized to Paxinos space and parametric standardized uptake value (SUV)-images were generated. Metabolism was compared between groups of animals and between different time points. Eighteen animals developed SE, 11 had died by D3. SS were recorded in 3 of 7 surviving SE animals. On D3, metabolism was reduced in SE group compared to controls throughout the brain (-49+/-27%), except for the cerebellum: mostly in hippocampus, entorhinal cortex and thalamus bilaterally. Metabolism tended to be different between SS and no SS animals on D3 in striatum and hippocampus. In CR condition, relative metabolism was significantly different in SE group compared to controls in cerebellum and brainstem bilaterally and left striatum and entorhinal cortex. There were no significant differences between SS and no SS animals in CR condition. Pilocarpine-induced SE causes a severe, but transient reduction in overall metabolism on D3 in rat brain. Metabolic differences on D3 between SS and no SS animals need further study to investigate potential use as an early marker of epileptogenesis.

Topics: Animals; Brain; Brain Mapping; Disease Models, Animal; Electroencephalography; Epilepsy; Fluorodeoxyglucose F18; Glucose; Lithium Chloride; Male; Pilocarpine; Positron-Emission Tomography; Rats; Rats, Wistar

Enhancement of glucose utilization in the brain has been well known during acute seizure in various kinds of animal model of epilepsy. This enhancement of glucose utilization might be related to neural damage in these animal models. Recently, we found that methyl ethyl ketone (MEK) had both anticonvulsive and neuroprotective effects in lithium-pilocapine (Li-pilo) status epilepticus (SE) rat. In this article, we measured the uptake of [(14)C]2-deoxyglucose ([(14)C]DG) in the Li-pilo SE and Li-pilo SE with MEK rat brain in order to assess whether the glucose utilization was a useful biomarker for the detection of efficacy of anticonvulsive compounds. Significant increase of [(14)C]DG uptake (45 min after the injection) in the cerebral cortex, hippocampus, amygdala and thalamus during acute seizure induced by Li-pilo were observed. On the other hand, the initial uptake of [(14)C]DG (1 min after the injection) in the Li-pilo SE rats was not different from the control rats. Therefore, the enhancement of glucose metabolism during acute seizure was due to the facilitation of the rate of phosphorylation process of [(14)C]DG in the brain. Pretreatment with MEK (8 mmol/kg) completely abolished the enhancement of glucose utilization in the Li-pilo SE rats. The present results indicated that glucose utilization in the brain during acute seizure might be a useful biomarker for the evaluation of efficacy of anticonvulsive compounds.

Topics: Animals; Anticonvulsants; Biomarkers; Brain; Butanones; Drug Evaluation, Preclinical; Epilepsy; Glucose; Lithium Chloride; Male; Pilocarpine; Radionuclide Imaging; Rats; Rats, Wistar

To explore the effects of the ultrastructural features of sprouted mossy fiber synapses in the mechanism of temporal lobe epilepsy. To explore the correlation between axon guidance molecule-netrin-1 gene expression and mossy fiber synaptic reorganization.. Sixty-one SD rats underwent intraperitoneal injection of lithium chloride and pilocarpine to establish models of status epilepticus characterized with temporal lobe epilepsy. Nineteen rats were used as controls. One, 2, and 4 weeks after the injection, a certain numbers of rat were killed with their brains taken out. The sprouted mossy fiber synaptic terminals were labeled by Timm histochemistry and the ultrastructure of new synapses were observed by electron microscopy. By in situ hybridization, the mRNA expression of netrin-1 gene was observed.. The sprouted mossy fiber synapses in epileptic rats most commonly formed asymmetric synapses with dendritic spines and occasionally with granule cell somata. Seven days after the injection, up-regulation of netrin-1 mRNA expression was seen in the dentate granule cell layers of hippocampus and continued to 4 weeks after the injection. The time course of the increase of netrin-1 mRNA in the dentate granule cell layers was correlated with the time course of mossy fiber sprouting and synaptic reorganization in hippocampus.. The ultrastructural features of sprouted mossy fiber synapses support the viewpoint that the reorganization of synapses prominently involves the formation of recurrent excitatory circuits. The axon guidance molecule- netrin-1 plays an important role in the process of mossy fiber axonal outgrowth and synaptogenesis in the hippocampal dentate gyrus.

Topics: Animals; Disease Models, Animal; Epilepsy; Epilepsy, Temporal Lobe; In Situ Hybridization; Lithium Chloride; Male; Microscopy, Electron; Mossy Fibers, Hippocampal; Nerve Growth Factors; Netrin-1; Pilocarpine; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Synapses; Tumor Suppressor Proteins

Conceiving the organization of the brain as a "neuromatrix" could provide significant insights into how different injuries to the nervous system could result in very distinct changes in behavior. The use of different pharmacological treatments to combat the deleterious consequences of such injuries is common practice. However, such treatments may have the capacity to alter the configurations of various neuronal circuits that contribute to the "neuromatrix" by selectively preventing damage to some pathways while facilitating the spread of destruction along others. The choice of pharmacological treatment may have profound consequences on the recovery of normal functioning following injury. We examined the behavior of rats treated with one of two potentially neuroprotective agents, the N-methyl-D-aspartate antagonist ketamine and the atypical neuroleptic acepromazine, on seizures induced by lithium-pilocarpine. Rats treated with ketamine following seizure onset were virtually indistinguishable from nonepileptic controls on a variety of behavioral tasks that included tests on learning, memory, and anxiety. In contrast, acepromazine-treated rats showed marked deficits on all learning and behavioral measures tested. These results suggest that administration of ketamine relatively soon after the emergence of epilepsy can prevent many of the cognitive deficits that are commonly found in rats subjected to lithium-pilocarpine-induced seizures. Further clinical testing investigating ketamine as a potential adjunct treatment for epilepsy may be well warranted.

Topics: Acepromazine; Analysis of Variance; Animals; Antipsychotic Agents; Behavior, Animal; Brain; Chi-Square Distribution; Conditioning, Psychological; Disease Models, Animal; Epilepsy; Escape Reaction; Excitatory Amino Acid Antagonists; Exploratory Behavior; Fear; Ketamine; Lithium Chloride; Male; Maze Learning; Rats; Rats, Wistar; Seizures; Time Factors

Different ratios of normal male rats and male rats in which limbic seizures had been induced by a single systemic injection of lithium and pilocarpine were housed in groups of six. The group ratios ranged along the continuum from all normal rats to all experimental rats. The average numbers of episodes of boxing, biting and mounting--thrusting per rat per hour per group were recorded by direct observation (red light) for 1 h during the midscotophase. Groups that contained less than two normal rats exhibited significantly elevated amounts of agonistic (boxing, biting) behavior but not mounting behavior. Multiple regression analyses showed that combinations of neuronal loss within only two to three areas accommodated at least 50% of the variance in the numbers of these behaviors.

Topics: Agonistic Behavior; Animals; Antimanic Agents; Behavior, Animal; Brain Injuries; Cerebral Cortex; Corpus Striatum; Data Interpretation, Statistical; Epilepsy; Limbic System; Lithium Chloride; Male; Muscarinic Agonists; Nerve Degeneration; Pilocarpine; Rats; Rats, Wistar

In three separate experiments, chronic epileptic male rats (ns = 24, 24, and 4) were exposed to experimental magnetic fields whose intensities were either constant or varied. The ripple frequency was always 7 Hz. Only exposure to a field with a constant intensity (700 nT) appeared to inhibit occurrence of the seizures. Although exposure to a field configuration whose strength increased and decreased by fixed increments during the hour before feeding did not affect the incidence of seizures, exposure to these fields for 5 min, only once per hour (increments of 15 to 20 nT for 30 sec. to a maximum of 70 nT) during the previous night between midnight and 0800 hr. increased the proportion of seizures following the presentation of food. An explanation is given for the persistent antithetical effects of experimental magnetic fields and geomagnetic activity upon seizure phenomena.

Topics: Amygdala; Animals; Electromagnetic Fields; Epilepsy; Gravitation; Lithium Chloride; Male; Rats; Rats, Wistar; Regression Analysis