coriaria-lactone and Disease-Models--Animal

Epilepsy is a chronic disease, while epileptogenesis is a latent period where brain will be transformed into an epileptic one. Mechanisms of epileptogenesis remain unclear.. We aim to provide information of hippocampal lipidomic changes related with epileptogenesis in two kindling models. Combining hippocampal structural imaging indices, our study also attempts to assess biochemical alterations as a function of epileptogenesis in a non-invasive way.. We constructed two kinds of chemical kindling models, which have long been used as models of epileptogenesis. Two kindling and one control groups were all subjected to structural imaging acquisition after successfully kindled. Voxel-based morphometry, a postprocessing method for brain imaging data, was used to segment and extract hippocampal gray matter volume for subsequent integrative analysis. LC-MS based lipidomic analysis was applied to identify distinct hippocampal lipidomic profiles between kindling and control groups. Further, we regress hippocampal structural indices on lipids to identify those associated with both epileptogenesis and brain structural changes.. We report distinct lipidomic profiles between kindling groups and control. A total of 638 lipids were detected in all three groups. Among them were 98 individual lipids, showing significant alterations, in particular lipid class of phosphatidylethanolamine (PE), glucosylceramide and phosphatidylcholine. Hippocampal gray matter volumes were found significant different between groups (P = 0.0223). After combining brain imaging data, we demonstrate several individual PE, namely PE(O-18:1_22:3), PE(O-18:1_22:6) and PE(18:1_18:1), are associated with both epileptogenesis and hippocampal gray matter volume.. This study suggests metabolic pathway of PE might involve in epileptogenesis. Also, for the first time, we link level of PE with structural brain imaging indices, in an attempt to potentiate the futuristic application of noninvasive brain imaging techniques to identify epileptogenesis in its latent period.

Topics: Animals; Brain; Disease Models, Animal; Epilepsy; Hippocampus; Kindling, Neurologic; Lactones; Lipidomics; Male; Neuroimaging; Pentylenetetrazole; Phosphatidylethanolamines; Rats

Epilepsy is a chronic and recurrent disease of the central nervous system, with a complex pathology. Recent studies have demonstrated that the activation of glial cells serve an important role in the development of epilepsy. The objective of the present study was to investigate the role of high‑mobility group box‑1 (HMGB1) in mediating the activation of glial cells through the toll‑like receptor 4 (TLR4)/nuclear factor (NF)‑κB signaling pathway in seizure, and the underlying mechanism. The brain tissue of post‑surgery patients with intractable epilepsy after resection and the normal control brain tissue of patients with craniocerebral trauma induced intracranial hypertension were collected. The expression level and distribution pattern of HMGB1, OX42 and NF‑κB p65 were detected by immunohistochemistry. HMGB1, TLR4, receptor for advanced glycation end products (RAGE), NF‑κB p65 and inducible nitric oxide synthase (iNOS) expression levels were detected by western blotting, and serum cytokine levels of interleukin (IL)‑1, IL‑6, tumor necrosis factor (TNF)‑α, transforming growth factor (TGF)‑β and IL‑10 in patients with epilepsy and craniocerebral trauma were detected by ELISA. And cell model of epilepsy was established by coriaria lactone (CL)‑stimulated HM cell, and the same factors were measured. The potential toxic effect of HMGB1 on HM cells was evaluated by MTT and 5‑ethynyl‑2‑deoxyuridine assays. The results demonstrated that compared with the control group, levels of HMGB1, TLR4, RAGE, NF‑κB p65 and iNOS in the brain of the epilepsy group were significantly increased, and increased cytokine levels of IL‑1, IL‑6, TNF‑α, TGF‑β and IL‑10 in patients with epilepsy were also observed. At the same time, the above results were also observed in HM cells stimulated with CL. Overexpression of HMGB1 enhanced the results, while HMGB1 small interfering RNA blocked the function of CL. There was no significant toxic effect of HMGB1 on HM cells. In conclusion, overexpression of HMGB1 potentially promoted epileptogenesis. CL‑induced activation of glial cells may act via up‑regulation of HMGB1 and TLR4/RAGE receptors, and the downstream transcription factor NF‑κB.

Topics: Animals; Biomarkers; Brain; Cell Survival; Disease Models, Animal; Epilepsy; Gene Expression; HMGB1 Protein; Humans; Immunohistochemistry; Lactones; Microglia; NF-kappa B; Signal Transduction; Toll-Like Receptor 4

To investigate the antiepileptic and protective effects of intravenous levetiracetam (iv LEV) in the rhesus monkey model of acute status epilepticus (SE).. Thirty minutes before intraperitoneal induction of SE by Coriaria lactone (CL), rhesus monkeys were treated with LEV (15 or 150 mg/kg) delivered intravenously as a single bolus. CL dose and epileptic behavior were recorded. Electroencephalography (EEG) was performed before and during the experiment. All rhesus monkeys were killed after 1-month video monitoring and processed for pathological investigation of neuronal injury, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, and glial fibrillary acidic protein (GFAP) staining.. No animal exhibited spontaneous seizures during 1-month video monitoring. Development of acute SE was significantly inhibited in the group given 150 mg/kg LEV, compared with controls and the 15 mg/kg LEV group. Delayed latency, reduction of SE duration, decreased cumulative time of tonic convulsions, slight severity of SE, and a high CL induction dose were observed in the high LEV dose group (p<0.05). The EEG showed less frequent epileptic discharges in the group administered with 150 mg/kg LEV. Hematoxylin and eosin (H&E) staining, ultrastructural examination, TUNEL and GFAP staining revealed serious damage, including neuron loss, swollen mitochondrion, and strong positivity for TUNEL in the hippocampus and thalamus of controls, whereas moderate damage in the group administered with 15 mg/kg LEV, and very mild damage in the 150 mg/kg LEV group. Gliosis was found in the hippocampus of controls, not in the LEV groups and normal rhesus monkey.. The study supports the antiepileptic and protective effect of pretreatment with intravenous LEV in rhesus monkey model with SE.

Topics: Administration, Intravenous; Animals; Anticonvulsants; Disease Models, Animal; Humans; Lactones; Levetiracetam; Macaca mulatta; Male; Neurons; Piracetam; Status Epilepticus

Hypoxia-inducible factor-1α (HIF-1α) is thought to mediate pharmacoresistance in tumor by inducing Pgp overexpression. We aimed to investigate the expression of HIF-1α and MDR1/P-glycoprotein in refractory epilepsy, to explore the correlation of HIF-1α with epilepsy multidrug resistance. We collected hippocampus and mesial temporal lobe (MTL) cortex of refractory mesial temporal lobe epilepsy (mTLE) patients that underwent surgery, and established a pharmacoresistant TLE rat model kindled by coriaria lactone. We used real-time quantitative PCR (RQ-PCR) and western blot to investigate expression of HIF-1α and MDR1 in hippocampus and MTL/entorhinal cortex. We found that the expression of HIF-1α and MDR1, at both mRNA and protein levels, were up-regulated in hippocampus and MTL cortex of mTLE patients compared with the control cortex (all P < 0.05), and increased in hippocampus and entorhinal cortex of kindled rat model versus the control group (all P < 0.05). These results demonstrated the overexpression of HIF-1α and MDR1/Pgp in hippocampus and MTL/entorhinal cortex of mTLE patients and the pharmacoresistant TLE rat model. HIF-1α may have a regulatory effect on MDR1 expression in refractory epilepsy, which is probably consistent with MDR mechanism in tumor.

Topics: Adult; Animals; Anticonvulsants; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Brain Neoplasms; Case-Control Studies; Cerebral Hemorrhage; Convulsants; Disease Models, Animal; Drug Resistance, Multiple; Entorhinal Cortex; Epilepsy, Temporal Lobe; Female; Genes, MDR; Hippocampus; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kindling, Neurologic; Lactones; Male; Middle Aged; Nerve Tissue Proteins; Random Allocation; Rats; Rats, Sprague-Dawley; Up-Regulation; Young Adult

One of the major challenges in developing novel therapeutics for human epileptic disorders derives from the limitation of knowledge of the processes by which epilepsy is generated (epileptogenesis). Furthermore, the inability to obtain human samples at the early stage of epilepsy hinders studies designed to further understand epileptogenesis. Thus, an effective animal model is critical for studies investigating this process. The purpose of this study was to establish a new primate kindling model of temporal lobe epilepsy (TLE) as an animal model of epileptogenesis. Here, repeated injections of Coriaria lactone (CL) at a subthreshold dose elicited partial seizures that culminated in secondarily generalized tonic-clonic seizures. The sequence of events and features of the behaviors observed in this model simulated those observed in human TLE. Electroencephalogram monitoring revealed the temporal lobe origins of the epileptiform potentials, which were consistent with the behavioral changes observed. A total of 7 rhesus monkeys (78%) were kindled with a median of 48 (41 to 60) CL injections. Both the seizure-induction and mortality rates were dose-dependent. A CL injection at 1.50mg/kg showed the lowest animal mortality rate (0%) and the highest seizure-induction rate (100%). Extensive kindling by CL injections with a median of 97 injections (overkindling) subsequently resulted in the recurrence of spontaneous seizures in rhesus monkeys with frequency patterns that were similar to those observed in human TLE. In addition, rhesus monkeys subjected to large numbers of kindling stimuli displayed mitochondrial damage and astrocyte activation in a pattern that was similar to the neuropathological changes characteristic of human TLE. Thus, a kindling TLE model in rhesus monkeys representing a primate animal model of epileptogenesis was established for the first time using repeated intramuscular injections of Coriaria lactone. This model was easily and efficiently performed and resulted in behavioral, electrographical, and anatomical characteristics of human TLE. Thus, this model might be used in future investigations of the mechanisms involved in the epileptogenesis of TLE and in the development of new antiepileptic drugs.

Topics: Analysis of Variance; Animals; Brain; Chi-Square Distribution; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy, Temporal Lobe; Glial Fibrillary Acidic Protein; Kindling, Neurologic; Lactones; Macaca mulatta; Male; Mitochondria

The earliest records of traditional Chinese medicine (TCM) prevention and treatment of epilepsy dated back to famous "Huang Di Nei Jing." TCM "spasmolytic powder" (equal-ratio compatibility of scorpion and centipede) is a famous prescription which was recognized as a useful add-on drug for refractory epilepsy in clinical observations. Multidrug resistance gene (mdr1) product Pgp overexpression in blood-brain barrier and blood-cerebrospinal fluid barrier is well recognized as the drug resistance mechanism of refractory epilepsy. Here, we established the drug-resistant epilepsy Sprague-Dawley rat model induced by Coriaria Lactone and treated these rats with topiramate and verapamil and low dose, middle dose, and high dose of spasmolytic powder by intragastric administration for 1 week. Electroencephalogram, real-time PCR, and immunohistochemistry were respectively used to detect epileptic discharge frequencies and amplitudes and expression of mdrl mRNA and Pgp on hippocampus and temporal lobe of rats. The results showed that the seizure decreases significantly in the high- and middle-dose groups of spasmolytic powder and topiramate group; in addition, mdr1 mRNA and Pgp expressions on hippocampus and temporal lobe of these drug intervention groups were significantly less than the model group (P < 0.05). These findings indicate that inhibition of intracephalic Pgp expression is possibly one of mechanisms of spasmolytic powder treating refractory epilepsy.

Topics: Animals; Anticonvulsants; Arthropods; ATP Binding Cassette Transporter, Subfamily B, Member 1; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Electroencephalography; Epilepsy; Fructose; Hippocampus; Kindling, Neurologic; Lactones; Male; Medicine, Chinese Traditional; Rats; Rats, Sprague-Dawley; Temporal Lobe; Tissue Extracts; Topiramate; Verapamil

Neurophysiological, biochemical and anatomical evidence implicates the thalamus as playing a role in epileptic seizures. Until recently, however, longitudinal characterization of in vivo thalamus dynamics had not been reported. In this study, we investigated the metabolism in the thalamus to identify the changes that occur following Coriaria lactone (CL)-induced status epilepticus (SE) and to observe whether the epileptiform discharges could present a difference between the left and right thalami. Five rhesus monkeys underwent whole-brain MRI and single-voxel MRS on a Siemens Trio Tim 3-T MR scanner with a 12-channel head coil. Spectra were processed using LCModel. Scans were performed in five animals before SE and at 1, 7, 21 and 42  days after the onset of SE. Statistical analysis of the data obtained demonstrated no significant difference in the bilateral thalamus of healthy macaques. Our MRS data showed symmetrical distributions of N-acetylaspartate in the right and left thalami after SE (p = 0.003). In addition, this longitudinal study demonstrated elevated glutamate/glutamine (p < 0.05) and reduced myo-inositol (p < 0.05) in the bilateral thalamus 1  day after SE, and all metabolites approached their baseline levels by the fifth scan. Our results demonstrate that metabolic changes occur in the thalamus during CL-induced SE in rhesus monkeys. The various metabolic changes may indicate that the left thalamus is more vulnerable to epileptic strike.

Topics: Animals; Creatinine; Disease Models, Animal; Glutamic Acid; Inositol; Lactones; Macaca mulatta; Magnetic Resonance Spectroscopy; Metabolome; Protons; Status Epilepticus; Thalamus; Time Factors

Glutamate receptor 5 (GluR5) plays a role as an excitatory regulator of synaptic transmission and plasticity; however, its exact role in the pathological mechanism underlying epilepsy is not fully known. We investigated GluR5 expression in resected brain tissues from humans with temporal lobe epilepsy (TLE) and from a macaque model of Coriaria lactone-induced TLE. GluR5 was upregulated in the hippocampus, but not in the temporal neocortex, of patients with TLE compared to the control group. In contrast, GluR5 expression in the hippocampus of macaques treated with Coriaria lactone was not upregulated compared to the control. In addition, mossy fiber sprouting in the hippocampus of TLE patients was correlated with GluR5 upregulation, whereas mossy fiber sprouting was not observed in the macaque model lacking GluR5 upregulation, suggesting that GluR5 function is mainly associated with mossy fiber sprouting.

Topics: Adolescent; Adult; Animals; Blotting, Western; Disease Models, Animal; Epilepsy, Temporal Lobe; Female; Hippocampus; Humans; Lactones; Macaca; Male; Microscopy, Electron; Middle Aged; Mossy Fibers, Hippocampal; Neurons; Polymerase Chain Reaction; Receptors, Kainic Acid; Temporal Lobe; Up-Regulation; Young Adult

To explore the relationship between merlin and hippocampal sclerosis of temporal epilepsy.. The kindling model of epilepsy induced by corciaria lactone (CL) in rats was used. The expression of merlin in neuron of cortex of temporal lobe and hippocampal CA1 region was observed using immunohistochemistry method. Comparison of the amount of neuron with expression of merlin in the two locations was made between the kindled group, non-kindled group and control group.. The expression of merlin in neuron of cortex of temporal lobe and hippocampal CA1 region of the kindled group was higher than the expression of the other two groups (P < 0.05), and there was no significant difference between the expression in the non-kindled group and that in the control group (P > 0.05). The expression of merlin in glial cell of the same region of all groups was seldom seen.. The super-expression of merlin in neuron of cortex of temporal lobe and hippocampal CA1 region of the kindled rats may be involved in the process of neuronal apoptosis and hippocampal sclerosis.

Topics: Animals; Disease Models, Animal; Epilepsy, Temporal Lobe; Hippocampus; Immunohistochemistry; Kindling, Neurologic; Lactones; Male; Neurofibromin 2; Rats; Rats, Sprague-Dawley; Temporal Lobe

Overexpression of the multiple drug resistance gene 1 (MDR1) was quantified in brain tissue from Coriaria lactone (CL)-kindled Sprague-Dawley (SD) rats after treatment with lamotrigine (LTG) or topiramate (TPM) and compared with that found in rats treated with carbamazepine (CBZ) and valproate (VPA).. Twenty-five CL-kindled SD rats were randomized into five groups (n = 5 for each group) to receive once-daily feeding of CBZ, VPA, TPM, and LTG as the monotherapy equivalent of maximum human adult dosage, or normal saline (NS control) for 1 month. The expression of P-gp in brain tissues of all rats was quantified by using an image analysis and measuring system (Image Pro-plus 4.0). Mean area and mean integrated optical density (mean IOD) of P-gp expression were calculated. In addition, the changes in seizure severity were analyzed via video-camera monitoring.. A significant decrease in the number and duration of seizures with antiepileptic drug (AED) treatment was observed in the TPM and LTG groups. The mean area and mean IOD of P-gp expression were highest in the CBZ group and next highest in the VPA group; much lower values were measured in the TPM and LTG groups, and the lowest in the NS control group (p < 0.05).. TPM and LTG significantly inhibited seizures in this CL model. The expression of P-gp was not significantly increased by TPM or LTG treatment in this study.

Topics: Animals; Anticonvulsants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Brain; Carbamazepine; Disease Models, Animal; Drug Resistance; Epilepsy, Temporal Lobe; Fructose; Gene Expression; Genes, MDR; Humans; Immunohistochemistry; Kindling, Neurologic; Lactones; Lamotrigine; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Topiramate; Triazines; Valproic Acid

The aim of this study was to develop a new animal model of pharmacoresistant temporal lobe epilepsy (TLE) by repeated intramuscular injection of Coriaria lactone (CL) at subthreshold dosages and to explore the mechanisms that might be involved.. Healthy male Sprague-Dawley rats (n = 160) were randomized into four groups during the kindling process: three groups (n = 50 for each group) received CL injection at subthreshold dosages (1.25, 1.5, and 1.75 mg/kg, respectively), and ten received normal saline (NS) injection as a control group. The maximal human adult dosage of carbamazepine (CBZ), valproate (VPA), and phenytoin (PHT) was administered as monotherapy to different groups of kindled rats for 1 month (n = 20 for each group). Changes in EEG recording, seizure number, intensity (expressed as grade 1-5 according to Racine stage), and duration, including spontaneous seizures during different interventions, were compared. The expression of P-170, a multiple drug resistance gene (MDR1) encoding P-glycoprotein, was measured in brain samples from different groups of experimental rats by using an image analysis and measurement system (ImagePro-Plus 4.0).. A total of 70 (46.7%) rats were fully kindled with a median of 15 (seven to 20) CL injections. Electrocorticogram (ECoG) including hippocampal (EHG) monitoring revealed the temporal lobe origins of epileptiform potentials, which were consistent with the behavioral changes observed. Spontaneous seizures occurred with frequency and diurnal patterns similar to those of human TLE. The antiepileptic drugs (AEDs) tested lacked a satisfactory seizure control. The maximal P-170 expression was in the kindled rats with AED treatment; the next highest was in the kindled rats without AED intervention. Nonkindled SD rats with CL injection also had increased P-170 expression compared with control SD rats.. The study provided a simple and stable animal TLE kindling model with pharmacoresistant properties. The pharmacoresistance observed in the kindled rats to CBZ, VPA, and PHT at maximal human adult dosages together with the increased P-170 expression was a distinct feature of this model. This model might be used in further investigations of the mechanisms involved in pharmacoresistant TLE and for developing new AEDs.

Topics: Animals; Anticonvulsants; ATP Binding Cassette Transporter, Subfamily B; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance; Drugs, Chinese Herbal; Electroencephalography; Epilepsy, Temporal Lobe; Gene Expression; Glycoproteins; Hippocampus; Humans; Injections, Intramuscular; Kindling, Neurologic; Lactones; Male; Phytotherapy; Rats; Rats, Sprague-Dawley; Temporal Lobe

In order to create chemical kindling effect model of epilepsy, fifty-six adult male SD rats were used in this experiment, and randomly divided into five groups. An intramuscular injection of various subthreshold dose of CL (0.50, 0.75, 1.00, 1.25 mg/kg) was given repeatedly per 3.5 days in the I-IV groups, V group received injections of normal saline of the same volume as control. ECoG and EHG were recorded by telemetric method through electrodes chronically implanted in the cortex and hippocampus. The behavior of them was observed at the same time. The results of experiments showed that: 1. CL can lead to the typical behavior, ECoG and EHG of epilepsy. So it is an effective chemical kindling agent of causing epilepsy, and hippocampus was more than cortex to CL. 2. The relationship between the seizure stages induced by CL various dose groups and the mean injection times had a linear correlation through linear regressive processing (r value: 0.9276-0.99732). The difference comparison of linear regressive intercept of various groups was significant (P less than 0.05), respectively. It is indicated that the more the dose of CL increase, the less the injection times of reaching seizure stages. 3. 24 rats of the experimental groups 46 rats had reached kindling criterion through 40 times injection of CL. The difference comparison between I, II and III, IV groups of kindling rats was quite significant (P less than 0.01), respectively. 4. The mean persistence time of all kindled rats was 113.42 days. The longest persistence time of them was 224 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Electrophysiology; Epilepsy; Kindling, Neurologic; Lactones; Rats; Rats, Inbred Strains

Fifty adult male Sprague-Dawley rats were divided into five groups. Intraperitoneal injections of various doses of coriaria lactone (CL, 0.75, 1.25, 1.75, and 2.0 mg/kg) and normal saline were given respectively per 2 days. The behavior of the rats was observed and the ECoG was recorded by telemetric method. The results of experiments show that a kindling model of epilepsy can be established by intraperitoneal injection of CL in rats. This chronic experimental model is of value for application because it is easily established and the rate of being kindled is relatively high, but the mortality is low, and the kindling effect can last well. The model can avert the pathological change caused by artificial injury to brain, so it is advantageous to the research on neurochemistry and ultrastructure. In our experimental condition, it is optimal to select 1.25 mg/kg or 1.75 mg/kg as the dosage of CL for establishing kindling model.

Topics: Animals; Disease Models, Animal; Epilepsy; Injections, Intraperitoneal; Kindling, Neurologic; Lactones; Male; Rats; Rats, Inbred Strains

Topics: Animals; Disease Models, Animal; Epilepsies, Partial; Lactones; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Plants, Medicinal; Rats; Rats, Inbred Strains

Topics: Animals; Disease Models, Animal; Lactones; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Plants, Medicinal; Rats; Rats, Inbred Strains; Status Epilepticus

Topics: Animals; Disease Models, Animal; Epilepsy; Injections, Intramuscular; Kindling, Neurologic; Lactones; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Plants, Medicinal; Rats; Rats, Inbred Strains

Topics: Animals; Disease Models, Animal; Epilepsy; Female; Hippocampus; Kindling, Neurologic; Lactones; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Microinjections; Plants, Medicinal; Rabbits