Lobe Epilepsy In Rats Research Articles

Spatiotemporal expression and inhibition of prolyl oligopeptidase contradict its involvement in key pathologic mechanisms of kainic acid-induced temporal lobe epilepsy in rats.

SummaryObjectiveProlyl oligopeptidase (PREP) has been implicated in neuroinflammatory processes and neuroplasticity and has been suggested as a target for the treatment of neurodegenerative disease. The aim of this investigation was to explore the involvement of PREP in the neuropathologic mechanisms relevant to temporal lobe epilepsy (TLE) using a PREP inhibitor in a well‐established rat model.Methods PREP activity and expression was studied in Sprague‐Dawley rats 2 and 12 weeks following kainic acid–induced status epilepticus (KASE). Continuous video‐electroencephalography monitoring was performed for 2 weeks in the 12‐week cohort to identify a relationship of PREP expression/activity with epileptic seizures. In addition, the animals included in the 2‐week time point were treated with a specific inhibitor of PREP, KYP‐2047, or saline continuously, starting immediately after SE. PREP activity and its expression were analyzed in rat brain by using enzyme kinetics and western blot. In addition, markers for microglial activation, astrogliosis, cell loss, and cell proliferation were evaluated.ResultsEnzymatic activity of PREP was unchanged following induction of SE after 2 and 12 weeks in rats. PREP activity in epileptic rats did not relate to the number of seizures/day at the 12‐week time point. Moreover, continuous inhibition of PREP for 2 weeks after KASE did not alter the SE‐mediated neuroinflammatory response, cell loss, or cell proliferation in the hippocampal subgranule zone measured at the 2‐week time point.Significance PREP inhibition does not affect key pathologic mechanisms, including activation of glial cells, cell loss, and neural progenitor cell proliferation, in this KASE model of TLE. The results do not support a direct role of PREP in seizure burden during the chronic epilepsy period in this model.

Sub-Convulsing Dose Administration of Pilocarpine Reduces Glycemia, Increases Anxiety-Like Behavior and Decelerates Cortical Spreading Depression in Rats Suckled on Various Litter Sizes.

Epilepsy and malnutrition constitute two worldwide health problems affecting behavior and brain function. The cholinergic agonist pilocarpine (300–380 mg/kg; single administration) reproduces the human type of temporal lobe epilepsy in rats. Pilocarpine-induced epilepsy in rodents has been associated with glycemia, learning and memory and anxiety disturbances. Cortical spreading depression (CSD) is a neural response that has been linked to brain excitability disorders and its diseases, and has been shown to be antagonized by acute pilocarpine. This study aimed to further investigate the effect of chronic pilocarpine at a sub-convulsing dose on weight gain, blood glucose levels, anxiety-like behavior and CSD. In addition, we tested whether unfavorable lactation-induced malnutrition could modulate the pilocarpine effects. Wistar rats were suckled under normal size and large size litters (litters with 9 and 15 pups; groups L9 and L15, respectively). From postnatal days (PND) 35–55, these young animals received a daily intraperitoneal injection of pilocarpine (45 mg/kg/day), or vehicle (saline), or no treatment (naïve). On PND58, the animals were behaviorally tested in an open field apparatus. This was immediately followed by 6 h fasting and blood glucose measurement. At PND60–65, CSD was recorded, and its parameters (velocity of propagation, amplitude, and duration) were calculated. Compared to the control groups, pilocarpine-treated animals presented with reduced weight gain and lower glycemia, increased anxiety-like behavior and decelerated CSD propagation. CSD velocity was higher (p < 0.001) in the L15 groups in comparison to the corresponding groups in the L9 condition. The results demonstrate an influence of chronic (21-day) administration of a sub-convulsing, very low dose (45 mg/kg) of pilocarpine on CSD propagation, anxiety-like behavior, glycemia and body weight. Furthermore, data reinforce the hypothesis of a relationship between CSD and brain excitability. The lactation condition seems to differentially modulate these effects.

Selective Vulnerability to Transcellular Pathway of Blood-Brain Barrier in Chronic Stage of the Kainate Model of Temporal Lobe Epilepsy in Rats

Selective Vulnerability to Transcellular Pathway of Blood-Brain Barrier in Chronic Stage of the Kainate Model of Temporal Lobe Epilepsy in Rats

The role of rosemary extract in degeneration of hippocampal neurons induced by kainic acid in the rat: Abehavioral and histochemical approach.

Systemic Kainic Acid (KA) administration has been used to induce experimental temporal lobe epilepsy in rats. The aim of this study was to evaluate the neuroprotective effect of rosemary extract (RE, 40% Carnosic acid) against KA-induced neurotoxicity in hippocampus and impaired learning and memory. Animals received a single dose of KA (9.5mg/kg) intraperitoneally (i.p.) (KA group) and were observed for 2h and were scored from 0 (for normal, no convulsion) to 5 (for continuous generalized limbic seizures). RE (100mg/kg, orally) was administered daily for 23 days, starting a week before KA injection (KA+RE group). Neuronal degeneration in hippocampus was demonstrated by using Fluoro-Jade B immunofluorescence. The number of pyramidal cells in hippocampus was evaluated by Nissl staining. Also, the Morris Water Maze and Shuttle box have been used to assess spatial memory and passive avoidance learning, respectively. Our results revealed that, after treatment with RE, neuronal loss in CA1 decreased significantly in the animals in KA+RE group. The Morris water navigation task results revealed that spatial memory impairment decreased in the animals in KA+RE group. Furthermore, results in Shuttle box test showed that passive avoidance learning impairment significantly, upgraded in the animals in KA+RE group. These results suggest that RE may improve the spatial and working memory deficits and also neuronal degeneration induced by toxicity of KA in the rat hippocampus, due to its antioxidant activities.

Selective Vulnerability to Transcellular Pathway of Blood-Brain Barrier in Chronic Stage of the Kainate Model of Temporal Lobe Epilepsy in Rats

1. Abstract 1.1. Background: The blood-brain barrier (BBB) integrity is severely affected in many epilepsy syndromes including temporal lobe epilepsy (TLE). 1.2. Aim: In the present study, we investigated the effects of acute and chronic seizures induced by kainic acid (KA) on the transport pathways of BBB in rats. 1.3. Methods: Electroencephalography (EEG) was recorded to evaluate seizure activity. Immunohistochemistry for claudin-5, a tight junction protein, caveolin-1, and the glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, was performed. Electron microscopy was used to ultrastructurally assess the presence and route of extravasation of horseradish peroxidase (HRP), a permeability marker, in barrier type of brain capillary endothelial cells. 1.4. Results: The immunoreactivity of claudin-5 and caveolin-1 in hippocampus increased by both acute and chronic seizures (p 1.5. Conclusion: This study provides immunohistochemical and ultrastructural evidence of BBB disruption through a selective vulnerability of the transcellular transport via an increase in caveolar vesicles in the endothelial cells brain capillaries rather than activation of paracellular pathway in the KA-induced rat model of TLE. 2. Keywords: Blood-Brain Barrier; Caveolin-1; Claudin-5; Electron Microscopy; Kainic Acid; Temporal Lobe Epilepsy

Altered axon initial segment in hippocampal newborn neurons, associated with recurrence of temporal lobe epilepsy in rats.

Hippocampal neurogenesis in temporal lobe epilepsy (TLE) may result in alteration of the excitability of neurons, which contributes to spontaneous recurrent seizures. Axon initial segment (AIS) structural and functional plasticity is important in the control of neuronal excitability. It remains to be elucidated whether the plasticity of AIS occurs in hippocampal newly-generated neurons that are involved in recurrent seizures following pilocarpine-induced status epilepticus (SE). The present study first established a pilocarpine-induced TLE rat model to assess the features of newborn neurons and AIS plasticity alterations using double immunofluorescence staining of Ankyrin G and doublecortin (DCX). AIS plasticity alterations include length and distance from soma in the hippocampal newly-generated neurons post-SE. The results of the present study demonstrated that pilocarpine-induced epileptic rats exhibited aberrant hippocampal neurogenesis and longer DCX-labeled cell dendrites in the dentate gyrus. Pilocarpine-induced epileptic rats demonstrated shortened lengths of AIS and an increased distance from the soma in hippocampal newborn neurons. Mibefradil, a T/L-type calcium blocker, reversed the alterations in length and position of AIS in hippocampal newborn neurons post-SE, accompanied by decreased long-term seizure activity without increased aberrant neurogenesis. These findings indicate that the plasticity of AIS in hippocampal neurogenesis may have profound consequences in epilepsy, at least in animals.

Various modifications of the intrahippocampal kainate model of mesial temporal lobe epilepsy in rats fail to resolve the marked rat-to-mouse differences in type and frequency of spontaneous seizures in this model.

Temporal lobe epilepsy (TLE) is the most common type of acquired epilepsy in adults. TLE can develop after diverse brain insults, including traumatic brain injury, infections, stroke, or prolonged status epilepticus (SE). Post-SE rodent models of TLE are widely used to understand mechanisms of epileptogenesis and develop treatments for epilepsy prevention. In this respect, the intrahippocampal kainate model of TLE in mice is of interest, because highly frequent spontaneous electrographic seizures develop in the kainate focus, allowing evaluation of both anti-seizure and anti-epileptogenic effects of novel drugs with only short EEG recording periods, which is not possible in any other model of TLE, including the intrahippocampal kainate model in rats. In the present study, we investigated whether the marked mouse-to-rat difference in occurrence and frequency of spontaneous seizures is due to a species difference or to technical variables, such as anesthesia during kainate injection, kainate dose, or location of kainate injection and EEG electrode in the hippocampus. When, as in the mouse model, anesthesia was used during kainate injection, only few rats developed epilepsy, although severity or duration of SE was not affected by isoflurane. In contrast, most rats developed epilepsy when kainate was injected without anesthesia. However, frequent electrographic seizures as observed in mice did not occur in rats, irrespective of location of kainate injection (CA1, CA3) or EEG recording electrode (CA1, CA3, dentate gyrus) or dose of kainate injected. These data indicate marked phenotypic differences between mice and rats in this model. Further studies should explore the mechanisms underlying this species difference.

Vildagliptin suppresses temporal lobe epilepsy by up-regulating glucagon-like peptide-1

To investigate the effect of vildagliptin on pentamethazol (PTZ)-induced epilepsy in rats and explore the molecular mechanism. Samples of temporal cortex from 23 patients with temporal lobe epilepsy were collected as epilepsy group and samples of temporal cortex from 14 patients with brain trauma were used as control group. Ninety male SD rats were randomly divided into control group (group A), PTZ-induced epilepsy group (group B), saline 2 mL/kg group (group C), vildagliptin 2.5 mg/kg group (group D), vildagliptin 5mg/kg group (group D) and vildagliptin 10 mg/kg group (group F). Use chronic model of epilepsy induced by PTZ (35 mg/kg) intraperitoneal injection for 3 consecutive weeks, and changes of behavior were observed. The expression of GLP-1R was detected by Western blotting and immunohistochemical (IHC) staining, and the expression of GLP-1 was detected by enzyme-linked immunosorbent assay (ELISA). The location of GLP-1R was detected by immunofluorescent staining. Immunofluorescent staining showed that the GLP-1R located in the neurons, and GLP-1R expression was obviously decreased both in patients with TLE and in rats with epilepsy. The latency time was prolonged and epilepsy attack time was decreased after vildagliptin treatment (P<0.05). GLP-1R expression was increased after vildagliptin treatment (P<0.05). ELISA showed the change of GLP-1 expression was the same as GLP-1R. Vildagliptin can suppress temporal lobe epilepsy in rats by up-regulating GLP-1 and GLP-1R expressions.

Metabotropic glutamate receptor 2/3 density and its relation to the hippocampal neuropathology in a model of temporal lobe epilepsy in rats

Dysregulation in the glutamatergic function is considered a major contributor to hyperexcitatory neuronal networks in mesial temporal lobe epilepsy (MTLE). Studies in animal models of MTLE have shown positive outcomes of augmenting group 2-metabotropic receptor functions that can regulate neuronal excitability from extrasynaptic locations. To assist in efficient translation of these findings to the clinical settings, we aimed to characterise the expression of mGluR2/3 receptors in the brain areas relevant to MTLE. mGluR2/3 density was determined by autoradiographic techniques using [3H]-LY341495 at various cross-sectional timepoints following kainic acid-induced status epilepticus (KASE) covering the acute, latent and chronic phases of epilepsy pathogenesis. We found a significant reduction in the mGluR density in the CA1 and temporal cortex during the acute (2day) timepoint after SE in KASE rats whereas a reduced receptor density was only found in temporal cortex during the latent period (7day). During the late latent phase (14day), a generalised increase in the receptor density was found in widely distributed brain areas of KASE rats. Finally, in the chronic periods (day 42 and 84) a significant decrease was seen in the stratum lacunosum moleculare in the KASE rats. Moreover, mGluR2/3 density in the CA1 regions strongly correlated with the neuronal cell scores in the hippocampal regions. Our findings suggest a time dependent evolving pattern of mGluR2/3 density during the pathogenesis of MTLE and provide insights for utilising this data for in vivo imaging to predict the specific timepoints and responsiveness to the therapy targeting mGluR2/3.

The effect of Vitamin E on learning and memory deficits in intrahippocampal kainate-induced temporal lobe epilepsy in rats.

Objective:Since temporal lobe epilepsy (TLE) is associated with learning and memory impairment, we investigated the beneficial effect of Vitamin E on the impaired learning and memory in the intrahippocampal kainate model of TLE in rats.Materials and Methods:Rats were divided into sham, Vitamin E-treated sham, kainate, and Vitamin E-treated kainate. Intrahippocampal kainate was used for induction of epilepsy. Vitamin E was injected intraperitoneal (i.p.) at a dose of 200 mg/kg/day started 1 week before surgery until 1 h presurgery. Initial and step-through latencies in the passive avoidance test and alternation behavior percentage in Y-maze were finally determined in addition to measurement of some oxidative stress markers.Results:Kainate injection caused a higher severity and rate of seizures and deteriorated learning and memory performance in passive avoidance paradigm and spontaneous alternation as an index of spatial recognition memory in Y-maze task. Intrahippocampal kainate also led to the elevation of malondialdehyde (MDA) and nitrite and reduced activity of superoxide dismutase (SOD). Vitamin E pretreatment significantly attenuated severity and incidence rate of seizures, significantly improved retrieval and recall in passive avoidance, did not ameliorate spatial memory deficit in Y-maze, and lowered MDA and enhanced SOD activity.Conclusion:Vitamin E improves passive avoidance learning and memory and part of its beneficial effect is due to its potential to mitigate hippocampal oxidative stress.

Novel combinations of phenotypic biomarkers predict development of epilepsy in the lithium-pilocarpine model of temporal lobe epilepsy in rats.

The discovery and validation of biomarkers in neurological and neurodegenerative diseases is an important challenge for early diagnosis of disease and for the development of therapeutics. Epilepsy is often a consequence of brain insults such as traumatic brain injury or stroke, but as yet no biomarker exists to predict the development of epilepsy in patients at risk. Given the complexity of epilepsy, it is unlikely that a single biomarker is sufficient for this purpose, but a combinatorial approach may be needed to overcome the challenge of individual variability and disease heterogeneity. The goal of the present prospective study in the lithium-pilocarpine model of epilepsy in rats was to determine the discriminative utility of combinations of phenotypic biomarkers by examining their ability to predict epilepsy. For this purpose, we used a recent model refinement that allows comparing rats that will or will not develop spontaneous recurrent seizures (SRS) after pilocarpine-induced status epilepticus (SE). Potential biomarkers included in our study were seizure threshold and seizure severity in response to timed i.v. infusion of pentylenetetrazole (PTZ) and behavioral alterations determined by a battery of tests during the three weeks following SE. Three months after SE, video/EEG monitoring was used to determine which rats had developed SRS. To determine whether a biomarker or combination of biomarkers performed better than chance at predicting epilepsy after SE, derived data underwent receiver operating characteristic (ROC) curve analyses. When comparing rats with and without SRS and sham controls, the best intergroup discrimination was obtained by combining all measurements, resulting in a ROC area under curve (AUC) of 0.9592 (P<0.01), indicating an almost perfect discrimination or accuracy to predict development of SRS. These data indicate that a combinatorial biomarker approach may overcome the challenge of individual variability in the prediction of epilepsy.

Injectable phenytoin loaded polymeric microspheres for the control of temporal lobe epilepsy in rats.

Epilepsy is a prevalent neurological disorder with a high frequency of drug resistance. While significant advancements have been made in drug delivery systems to overcome anti-epileptic drug resistance, efficacies of materials in biological systems have been poorly studied. The purpose of the study was to evaluate the anti-epileptic effects of injectable poly(epsilon-caprolactone) (PCL) microspheres for controlled release of an anticonvulsant, phenytoin (PHT), in an animal model of epilepsy. PHT-PCL and Blank-PCL microspheres formulated using an oil-in-water (O/W) emulsion solvent evaporation method were evaluated for particle size, encapsulation efficiency, surface morphology and in-vitro drug release profile. Microspheres with the most suitable morphology and release characteristics weresubsequently injected into the hippocampus of a rat tetanus toxin model of temporal lobe epilepsy. Electrocorticography (ECoG)from the cerebral cortex were recorded for all animals. The number of seizure events, severity of seizures, and seizure duration were then compared between the two treatment groups. We have shown that small injections of drug-loaded microspheres are biologically tolerated and released PHT can control seizures for the expected period of time that is in accord with in-vitro release data. The study demonstrated the feasibility of polymer-based delivery systems incontrolling focal seizures.

Seizure dynamics: a computational model based approach demonstrating variability in seizure mechanisms

Epilepsy is a neurological disorder that affects approximately 1% of the world's population. At present, the underlying mechanisms involved in seizure generation and termination are not fully understood. A computational model-based approach to provide further insights into physiological changes occurring in the brain prior to, during, and post seizure is presented. We demonstrate that an unscented Kalman filter [1] can be used to fit physiological parameters of a neural mass model [2] to recorded EEG. This technique elucidates physiological changes in recorded EEG that cannot be determined with standard EEG analysis methods. Neural mass models consist of interconnected populations of neurons. They describe the interaction between populations by the mean membrane potential generated by synapses and the firing rate produced by populations. To demonstrate the ability of this framework to elucidate mechanism involved in seizures, we make use of an in vivo model of temporal lobe epilepsy in rats. For the in vivo model, tetanus toxin is injected into the rat hippocampus, which results in spontaneously occurring seizures. The effect of the tetanus toxin lasts over a period of 6-8 weeks. We insert a twisted pair electrode into the rat hippocampus to record local field potentials (LFPs). The LFPs are used as the observations for the unscented Kalman filter [3]. The neural mass model considered has been shown to be a good phenomenological model of hippocampal EEG; however it cannot capture high frequency dynamics. We estimated physiological parameters (synaptic gains) that govern dynamics from four seizures in four animals, based upon recorded LFP 150 seconds prior to and post seizure, as well as during the seizure. The estimation results show that, for three of the four animals, the mechanisms involved in their seizures are similar. For the fourth animal, the estimated physiology prior to, during, and post seizure vary drastically. When comparing the physiological dynamics between animals, we found that the estimation results predicted that there are different mechanisms involved in seizure initiation, evolution, and termination in each animal. The common element in all the results, except for a single estimated seizure, was an increase in excitation at seizure initiation and a decrease at seizure termination. In the in vivo model, the similarity between physiological dynamics observed when considering a single animal, demonstrates that there may be a single mechanism involved in the generation and termination of seizures. However, when considering multiple seizures from different animals, the estimation results show clear differences between the mechanisms involved in seizures. Changes in the estimated synaptic gains at seizure transitions differed between ictal events in an individual rat. This is an unexpected result, as the methodology to model epilepsy in the rats was identical. The estimation results show that it is possible for different mechanisms to be involved in seizures. It is possible that this framework could be used to understand why certain patients are refractory to standard epilepsy treatments. It may further be possible to use this framework to also understand why certain patients become unresponsive to treatment over time.

(R)-[11C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance: Evaluation in a rat epilepsy model

Neuroinflammation has been suggested as a key determinant of the intrinsic severity of epilepsy. Glial cell activation and associated inflammatory signaling can influence seizure thresholds as well as the pharmacodynamics and pharmacokinetics of antiepileptic drugs. Based on these data, we hypothesized that molecular imaging of microglia activation might serve as a tool to predict drug refractoriness of epilepsy.Brain uptake of (R)-[11C]PK11195, a ligand of the translocator protein 18 kDa and molecular marker of microglia activation, was studied in a chronic model of temporal lobe epilepsy in rats with selection of phenobarbital responders and non-responders.In rats with drug-sensitive epilepsy, (R)-[11C]PK11195 brain uptake values were comparable to those in non-epileptic controls. Analysis in non-responders revealed enhanced brain uptake of up to 39% in different brain regions. The difference might be related to the fact that non-responders exhibited higher baseline seizure frequencies than responders indicating a more pronounced intrinsic disease severity. In hippocampal sections, ED1 immunostaining argued against a general difference in microglia activation between both groups.Our data suggest that TSPO PET imaging might serve as a biomarker for drug resistance in temporal lobe epilepsy. However, it needs to be considered that our findings indicate that the TSPO PET data might merely reflect seizure frequency. Future experimental and clinical studies should further evaluate the validity of TSPO PET data to predict the response to phenobarbital and other antiepileptic drugs in longitudinal studies with scanning before drug exposure and with a focus on the early phase following an epileptogenic brain insult.

Melatonin protects testes against lithium-pilocarpine-induced temporal lobe epilepsy in rats: a time course study

Male dysfunction is common in patients with temporal lobe epilepsy (TLE). We evaluated whether melatonin, as a supplement, can play a positive role in reducing the epileptogenesis imposing abnormalities of spermatozoa and testes in epileptic rats. Status epilepticus was induced based on the TLE lithium-pilocarpine model. Two patterns of melatonin were administered to the epileptic animals along the mean durations of latent (14days) and chronic (60days) phases. Sperm parameters, different antioxidant enzyme levels, germ cell apoptosis, body and relative sex organ weights were evaluated in all groups 60days following SE induction. Chronic TLE caused a significant reduction in sperm parameters. In the testis, the reduced level of antioxidant enzymes was accompanied by a significant increase in malondialdehyde concentration. The presence of oxidant condition in the testes of epileptic animals caused expanded apoptosis in the germ cell layer. Moreover, the amount of weight gain in epileptic animals was more prominent. Melatonin administration was able to improve sperm motility by increasing the total antioxidant level. There was also a significant reduction in the spermatogenic cell line apoptosis and the extra weight gain of melatonin-treated animals. Melatonin supplementation might be considered as an acceptable cotreatment in epileptic patients.

Changes in the hippocampal extracellular amino acid neurotransmitter of kindled rats by kainic acid

Objective To establish and evaluate the animal model for temporal lobe epilepsy kindled by kainic acid (KA)in rats,to observe the changes in glutamic amino acid (Glu),taurine amino acid (Tau),and γ-aminobatyric amino acid (GABA) of the extracellular fluid in the hippocampus of kindled rats,and to analyze the role of neurotransmitters in epileptogenesis.Methods In order to establish an animal model for temporal lobe epilepsy in rats,the characteristics of praxiological changes,electrophysiological changes,and ultrastructural examinations were observed.The contents of Glu,Tau,and GABA were detected in the hypppocampus by microdialysis combined with high performance liquid chromatography (HPLC).Results Typical seizures were observed in the models.Epileptic discharges,such as spike,slow,spike-slow,and sharp waves appeared in the electroencephalogram (EEG).Electron microscopic analysis of the hippocampal tissues revealed an increase of excitatory amino acid levels.The levels of Glu,Tau,and GABA were higher than groups that were injected with normal sodium (P ＜ 0.05).Conclusion Excitatory amino acids and inhibitory amino acids in the presence of epilepsy play important roles and is one of the main causes of seizure. Key words: Epilepsy; Kainic acid; Glutamic amino acid; γ-aminobutyric amino acid ; Taurine amino acid

Levetiracetam-loaded biodegradable polymer implants in the tetanus toxin model of temporal lobe epilepsy in rats

Approximately one-third of people with epilepsy receive insufficient benefit from currently available anticonvulsant medication, and some evidence suggests that this may be due to a lack of effective penetration into brain parenchyma. The current study investigated the ability of biodegradable polymer implants loaded with levetiracetam to ameliorate seizures following implantation above the motor cortex in the tetanus toxin model of temporal lobe epilepsy in rats. The implants led to significantly shorter seizures and a trend towards fewer seizures for up to 1week. The results of this study indicate that drug-eluting polymer implants represent a promising evolving treatment option for intractable epilepsy. Future research is warranted to investigate issues of device longevity and implantation site.

Coenzyme Q10 Ameliorates Neurodegeneration, Mossy Fiber Sprouting, and Oxidative Stress in Intrahippocampal Kainate Model of Temporal Lobe Epilepsy in Rat

Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and the most resistant type to treatment. Novel treatment approaches are strongly required to prevent or even reverse the cellular and molecular mechanisms of epileptogenesis. In this study, we investigated the possible neuroprotective effect of coenzyme Q10 (CoQ10) in an intrahippocampal kainate model of TLE in rat. Kainate injection caused a higher seizure severity during status epilepticus and spontaneous seizure phases, and CoQ10 pretreatment significantly attenuated its severity and incidence rate. Intrahippocampal kainate also led to elevation of malondialdehyde (MDA) and nitrite, and CoQ10 significantly attenuated the increased MDA and nitrite content. In addition, intrahippocampal kainate induced a significant degeneration of neurons in CA1, CA3, and hilar regions of the hippocampus, and CoQ10 significantly attenuated these changes in CA1 and CA3 regions. Timm's staining data showed a robust mossy fiber sprouting (MFS) in dentate gyrus of kainate-lesioned rats and CoQ10 significantly lowered MFS intensity. These data suggest that CoQ10 pretreatment could attenuate spontaneous recurrent seizures and inhibit hippocampal neuronal loss and aberrant MFS in kainate-induced model of TLE in rat, and part of its beneficial effect is due to its potential to mitigate oxidative stress.

Fluoxetine restores spatial learning but not accelerated forgetting in mesial temporal lobe epilepsy

Learning and memory dysfunction is the most common neuropsychological effect of mesial temporal lobe epilepsy, and because the underlying neurobiology is poorly understood, there are no pharmacological strategies to help restore memory function in these patients. We have demonstrated impairments in the acquisition of an allocentric spatial task, in patients with unilateral hippocampal sclerosis. We also show that patients have accelerated forgetting of the learned spatial task and that this is associated with damage to the non-dominant hippocampal formation. We go on to show a very similar pattern of chronic allocentric learning and accelerated forgetting in a status epilepticus model of mesial temporal lobe epilepsy in rats, which is associated with reduced and abnormal hippocampal neurogenesis. Finally, we show that reversal of the neurogenic deficit using fluoxetine is associated with reversal of the learning deficit but not the accelerated forgetting, pointing to a possible dissociation in the underlying mechanisms, as well as a potential therapeutic strategy for improving hippocampal-dependent learning in patients with mesial temporal lobe epilepsy.

Different emotional disturbances in two experimental models of temporal lobe epilepsy in rats.

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.