Animal Models Of Temporal Lobe Epilepsy Research Articles

NLRP1 inflammasome is activated in patients with medial temporal lobe epilepsy and contributes to neuronal pyroptosis in amygdala kindling-induced rat model.

BackgroundTemporal lobe epilepsy (TLE) is often characterized pathologically by severe neuronal loss in the hippocampus. Understanding the mechanisms of neuron death is key to preventing the neurodegeneration associated with TLE. However, the involvement of neuronal loss to the epileptogenic process has yet to be fully determined. Recent studies have shown that the activation of NLRP1 can generate a functional caspase-1-containing inflammasome in vivo to drive the proinflammatory programmed cell death termed ‘pyroptosis’, which has a key role in the pathogenesis of neurological disorders. To the best of our knowledge, there are no reported studies that performed detailed identification and validation of NLRP1 inflammasome during the epileptogenic process.MethodsWe first compared expression of NLRP1 and caspase-1 in resected hippocampus from patients with intractable mesial temporal lobe epilepsy (mTLE) with that of matched control samples. To further examine whether the activation of NLRP1 inflammasome contributes to neuronal pyroptosis, we employed a nonviral strategy to knock down the expression of NLRP1 and caspase-1 in the amygdala kindling-induced rat model. Proinflammatory cytokines levels and hippocampal neuronal loss were evaluated after 6 weeks of treatment in these NLRP1 or caspase-1 deficiency TLE rats.ResultsWestern blotting detected upregulated NLRP1 levels and active caspase-1 in mTLE patients in comparison to those levels seen in the controls, suggesting a role for this inflammasome in mTLE. Moreover, we employed direct in vivo infusion of nonviral small interfering RNA to knockdown NLRP1 or caspase-1 in the amygdala kindling-induced rat model, and discovered that these NLRP1 or caspase-1 silencing rats resulted in significantly reduced neuronal pyroptosis.ConclusionsOur data suggest that NLRP1/caspase-1 signaling participates in the seizure-induced degenerative process in humans and in the animal model of TLE and points to the silencing of NLRP1 inflammasome as a promising strategy for TLE therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0233-0) contains supplementary material, which is available to authorized users.

Upregulation and Diverse Roles of TRPC3 and TRPC6 in Synaptic Reorganization of the Mossy Fiber Pathway in Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is the most common form of intractable epilepsy and is always accompanied with hippocampal sclerosis. The molecular mechanism of this pathological phenomenon has been extensively explored, yet remains unclear. Previous studies suggest that ion channels, especially calcium channels, might play important roles. Transient receptor potential canonical channel (TRPC) is a novel cation channel dominantly permeable to Ca(2+) and widely expressed in the human brain. We measured the expression of two subtypes of TRPC channels, TRPC3 and TRPC6, in temporal lobe epileptic foci excised from patients with intractable epilepsy and in hippocampus of mice with pilocarpine-induced status epilepticus (SE), an animal model of TLE. Cortical TRPC3 and TRPC6 protein expressions were significantly higher in TLE patients compared with those in controls. Expression of TRPC3 and TRPC6 protein also increased significantly in the CA3 region of the hippocampus of SE mice. Inhibition of TRPC3 by intracerebroventricular injection of anti-TRPC3 antibody prevented aberrant-sprouted mossy fiber collaterals in the CA3 region, while inhibition of TRPC6 by anti-TRPC6 antibody reduced dendritic arborization and spine density of CA3 pyramidal neurons. Our results indicate that TRPC3 and TRPC6 participate diversely in synaptic reorganization in the mossy fiber pathway in TLE.

Role(s) of the 5-HT2C receptor in the development of maximal dentate activation in the hippocampus of anesthetized rats.

Substantial evidence indicates that 5-HT2C receptors are involved in the control of neuronal network excitability and in seizure pathophysiology. Here, we have addressed the relatively unexplored relationship between temporal lobe epilepsy (TLE), the most frequent type of intractable epilepsy, and 5-HT2CRs. In this study, we investigated this issue using a model of partial complex (limbic) seizures in urethane-anesthetized rat, based on the phenomenon of maximal dentate activation (MDA) using 5-HT2C compounds, electrophysiology, immunohistochemistry, and western blotting techniques. The 5-HT2C agonists mCPP (1 mg/kg, i.p) and lorcaserin (3 mg/kg, i.p), but not RO60-0175 (1-3 mg/kg i.p.), were antiepileptogenic reducing the MDA response duration. The selective 5-HT2C antagonist SB242084 (2 mg/kg, i.p) unveiled antiepileptogenic effects of RO60-0175 (3 mg/kg, i.p) but did not alter those induced by mCPP and lorcaserin. Compared with control rats, electrically stimulated rats showed an increase in glutamic acid decarboxylase levels and a heterogeneous decrease in 5-HT2CR immunoreactivity in different hippocampal areas. In our animal model of TLE, mCPP and lorcaserin were anticonvulsant; likely acting on receptor subtypes other than 5-HT2C. Epileptogenesis induced early adaptive changes and reorganization in the 5-HT2CR and GABA systems.

Specific Impairment of “What-Where-When” Episodic-Like Memory in Experimental Models of Temporal Lobe Epilepsy

Episodic memory deficit is a common cognitive disorder in human temporal lobe epilepsy (TLE). However, no animal model of TLE has been shown to specifically replicate this cognitive dysfunction, which has limited its translational appeal. Here, using a task that tests for nonverbal correlates of episodic-like memory in rats, we show that kainate-treated TLE rats exhibit a selective impairment of the "what-where-when" memory while preserving other forms of hippocampal-dependent memories. Assisted by multisite silicon probes, we recorded from the dorsal hippocampus of behaving animals to control for seizure-related factors and to look for electrophysiological signatures of cognitive impairment. Analyses of hippocampal local field potentials showed that both the power of theta rhythm and its coordination across CA1 and the DG-measured as theta coherence and phase locking-were selectively disrupted. This disruption represented a basal condition of the chronic epileptic hippocampus that was linked to different features of memory impairment. Theta power was more correlated with the spatial than with the temporal component of the task, while measures of theta coordination correlated with the temporal component. We conclude that episodic-like memory, as tested in the what-where-when task, is specifically affected in experimental TLE and that the impairment of hippocampal theta activity might be central to this dysfunction.

Electrographic seizures are significantly reduced by in vivo inhibition of neuronal uptake of extracellular glutamine in rat hippocampus

Rats were given unilateral kainate injection into hippocampal CA3 region, and the effect of chronic electrographic seizures on extracellular glutamine (GLNECF) was examined in those with low and steady levels of extracellular glutamate (GLUECF). GLNECF, collected by microdialysis in awake rats for 5h, decreased to 62±4.4% of the initial concentration (n=6). This change correlated with the frequency and magnitude of seizure activity, and occurred in the ipsilateral but not in contralateral hippocampus, nor in kainate-injected rats that did not undergo seizure (n=6). Hippocampal intracellular GLN did not differ between the Seizure and No-Seizure Groups. These results suggested an intriguing possibility that seizure-induced decrease of GLNECF reflects not decreased GLN efflux into the extracellular fluid, but increased uptake into neurons. To examine this possibility, neuronal uptake of GLNECF was inhibited in vivo by intrahippocampal perfusion of 2-(methylamino)isobutyrate, a competitive and reversible inhibitor of the sodium-coupled neutral amino acid transporter (SNAT) subtypes 1 and 2, as demonstrated by 1.8±0.17 fold elevation of GLNECF (n=7). The frequency of electrographic seizures during uptake inhibition was reduced to 35±7% (n=7) of the frequency in pre-perfusion period, and returned to 88±9% in the post-perfusion period. These novel in vivo results strongly suggest that, in this well-established animal model of temporal-lobe epilepsy, the observed seizure-induced decrease of GLNECF reflects its increased uptake into neurons to sustain enhanced glutamatergic epileptiform activity, thereby demonstrating a possible new target for anti-seizure therapies.

Septal nuclei enlargement in human temporal lobe epilepsy without mesial temporal sclerosis

To measure the volume of basal forebrain septal nuclei in patients with temporal lobe epilepsy (TLE) as compared to patients with extratemporal epilepsy and controls. In animal models of TLE, septal lesions facilitate epileptogenesis, while septal stimulation is antiepileptic. Subjects were recruited from 2 sites and consisted of patients with pharmacoresistant focal epilepsy (20 with TLE and mesial temporal sclerosis [MTS], 24 with TLE without MTS, 23 with extratemporal epilepsy) and 114 controls. Septal volume was measured using high-resolution MRI in association with newly developed probabilistic septal nuclei maps. Septal volume was compared between subject groups while controlling for relevant factors. Patients with TLE without MTS had significantly larger septal nuclei than patients with extratemporal epilepsy and controls. This was not true for patients with MTS. These results are interpreted with reference to prior studies demonstrating expansion of the septo-hippocampal cholinergic system in animal models of TLE and human TLE surgical specimens. Septal nuclei are enlarged in patients with TLE without MTS. Further investigation of septal nuclei and antiepileptic septo-hippocampal neurocircuitry could be relevant to development of new therapeutic interventions such as septal stimulation for refractory TLE.

Relationship between genetic variant in pre-microRNA-146a and genetic predisposition to temporal lobe epilepsy: A case–control study

There is evidence that inflammatory mechanisms play a role in the pathogenesis of temporal lobe epilepsy (TLE). MicroRNAs (miRNAs), a class of small non-coding endogenous RNAs, which negatively regulate target gene expression, have shown different expression patterns in immune diseases. Recently, several miRNAs have been found to be differentially expressed in animal models of TLE. To understand the role of miRNAs in the molecular mechanisms of TLE, we sought to determine whether genetic variant rs2910164 in the pre-miR-146a gene could influence susceptibility to TLE in an Italian population sample. A cohort of 357 TLE patients and 543 healthy controls were genotyped for detection of this SNP using TaqMan Allelic Discrimination assays, on an Applied Biosystems PCR platform. Analysis of genotype or allelic frequencies between patients and controls showed no statistically significant differences (p=0.536 and p=0.361 respectively). Moreover, such variant did not influence the main clinical characteristics of TLE. In conclusion, our data suggest that the rs2910164 variant in the pre-miR-146a gene is unlikely to influence significantly the risk of developing TLE or its severity.

Mapping the Spatio-Temporal Pattern of the Mammalian Target of Rapamycin (mTOR) Activation in Temporal Lobe Epilepsy

Growing evidence from rodent models of temporal lobe epilepsy (TLE) indicates that dysregulation of the mammalian target of rapamycin (mTOR) pathway is involved in seizures and epileptogenesis. However, the role of the mTOR pathway in the epileptogenic process remains poorly understood. Here, we used an animal model of TLE and sclerotic hippocampus from patients with refractory TLE to determine whether cell-type specific activation of mTOR signaling occurs during each stage of epileptogenesis. In the TLE mouse model, we found that hyperactivation of the mTOR pathway is present in distinct hippocampal subfields at three different stages after kainate-induced seizures, and occurs in neurons of the granular and pyramidal cell layers, in reactive astrocytes, and in dispersed granule cells, respectively. In agreement with the findings in TLE mice, upregulated mTOR was observed in the sclerotic hippocampus of TLE patients. All sclerotic hippocampus (n = 13) exhibited widespread reactive astrocytes with overactivated mTOR, some of which invaded the dispersed granular layer. Moreover, two sclerotic hippocampus exhibited mTOR activation in some of the granule cells, which was accompanied by cell body hypertrophy. Taken together, our results indicate that mTOR activation is most prominent in reactive astrocytes in both an animal model of TLE and the sclerotic hippocampus from patients with drug resistant TLE.

Alzheimer's disease and epilepsy: insight from animal models.

Alzheimer's disease (AD) and epilepsy are separated in the medical community, but seizures occur in some patients with AD, and AD is a risk factor for epilepsy. Furthermore, memory impairment is common in patients with epilepsy. The relationship between AD and epilepsy remains an important question because ideas for therapeutic approaches could be shared between AD and epilepsy research laboratories if AD and epilepsy were related. Here we focus on one of the many types of epilepsy, temporal lobe epilepsy (TLE), because patients with TLE often exhibit memory impairment, depression and other comorbidities that occur in AD. Moreover, the seizures that occur in patients with AD may be nonconvulsive, which occur in patients with TLE. Here we first compare neuropathology in TLE and AD with an emphasis on the hippocampus, which is central to both AD and TLE research. Then we compare animal models of AD pathology with animal models of TLE. Although many aspects of the comparisons are still controversial, there is one conclusion that we suggest is clear: some animal models of TLE could be used to help address questions in AD research, and some animal models of AD pathology are bona fide animal models of epilepsy.

Pilocarpine-induced temporal lobe epilepsy in the rat is associated with increased dopamine neuron activity

Temporal lobe epilepsy (TLE) is defined as the occurrence of spontaneous seizures that involve the limbic system, with the hippocampal formation and associated structures being central to the most prevalent refractory form of adult focal epilepsy. TLE is often associated with psychotic features resembling the hallucinations and delusions that occur with schizophrenia. Given evidence that the ventral hippocampus plays an important role in the maintenance of temporal lobe seizures, we investigated whether an animal model of TLE using intrahippocampal injection of pilocarpine induces alterations in mesolimbic dopamine neuron activity. We found that in 60% of rats in which pilocarpine induced seizure activity, there was a significant increase in the number of dopamine neurons firing per electrode track. Furthermore, this occurred in concert with an increase in amphetamine-stimulated locomotor activity. Both observations are similar to those observed in a rodent developmental model of psychosis. Therefore, as in animal models of schizophrenia, TLE-associated psychosis is probably due to abnormal hippocampal overdrive of dopamine neuron activity.

Selective changes in inhibition as determinants for limited hyperexcitability in the insular cortex of epileptic rats

The insular cortex (IC) is involved in the generalization of epileptic discharges in temporal lobe epilepsy (TLE), whereas seizures originating in the IC can mimic the epileptic phenotype seen in some patients with TLE. However, few studies have addressed the changes occurring in the IC in TLE animal models. Here, we analyzed the immunohistochemical and electrophysiological properties of IC networks in non-epileptic control and pilocarpine-treated epileptic rats. Neurons identified with a neuron-specific nuclear protein antibody showed similar counts in the two types of tissue but parvalbumin- and neuropeptide Y-positive interneurons were significantly decreased (parvalbumin, approximately -35%; neuropeptide Y, approximately -38%; P < 0.01) in the epileptic IC. Non-adapting neurons were seen more frequently in the epileptic IC during intracellular injection of depolarizing current pulses. In addition, single-shock electrical stimuli elicited network-driven epileptiform responses in 87% of epileptic and 22% of non-epileptic control neurons (P < 0.01) but spontaneous postsynaptic potentials had similar amplitude, duration and intervals of occurrence in the two groups. Finally, pharmacologically isolated, GABA(A) receptor-mediated inhibitory postsynaptic potentials had more negative reversal potential (P < 0.01) and higher peak conductance (P < 0.05) in epileptic tissue. These data reveal moderate increased network excitability in the IC of pilocarpine-treated epileptic rats. We propose that this limited degree of hyperexcitability originates from the loss of parvalbumin- and neuropeptide Y-positive interneurons that is compensated by an increased drive for GABA(A) receptor-mediated inhibition.

Cannabinoid-Mediated Inhibition of Recurrent Excitatory Circuitry in the Dentate Gyrus in a Mouse Model of Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) is a neurological condition associated with neuron loss, axon sprouting, and hippocampal sclerosis, which results in modified synaptic circuitry. Cannabinoids appear to be anti-convulsive in patients and animal models of TLE, but the mechanisms of this effect are not known. A pilocarpine-induced status epilepticus mouse model of TLE was used to study the effect of cannabinoid agonists on recurrent excitatory circuits of the dentate gyrus using electrophysiological recordings in hippocampal slices isolated from control mice and mice with TLE. Cannabinoid agonists WIN 55,212-2, anandamide (AEA), or 2-arachydonoylglycerol (2-AG) reduced the frequency of spontaneous and tetrodotoxin-resistant excitatory postsynaptic currents (EPSCs) in mice with TLE, but not in controls. WIN 55,212-2 also reduced the frequency of EPSCs evoked by glutamate-photolysis activation of other granule cells in epileptic mice. Secondary population discharges evoked after antidromic electrical stimulation of mossy fibers in the hilus were also attenuated by cannabinoid agonists. Agonist effects were blocked by the cannabinoid type 1 receptor (CB1R) antagonist AM251. No change in glutamate release was observed in slices from mice that did not undergo status epilepticus. Western blot analysis suggested an up-regulation of CB1R in the dentate gyrus of animals with TLE. These findings indicate that activation of CB1R present on nerve terminals can suppress recurrent excitation in the dentate gyrus of mice with TLE. This suggests a mechanism for the anti-convulsive role of cannabinoids aimed at modulating receptors on synaptic terminals expressed de novo after epileptogenesis.

Pilocarpine model of temporal lobe epilepsy shows enhanced response to general anesthetics

Complex partial seizures, commonly arising from temporal lobe epilepsy (TLE), are associated with neuronal loss and post-seizure impairment of consciousness. We tested the hypothesis that TLE subjects, in between seizures, are associated with a decreased level of consciousness that is manifested by an enhanced response to a general anesthetic. Two animal models of TLE – amygdala kindling and pilocarpine-induced status epilepticus (Pilo-SE) – were tested. Pilo-SE rats, but not amygdala-kindled rats, showed a prolonged loss of pain and righting responses after 20 and 40 mg/kg i.p. pentobarbital, 2% halothane, and 5 and 10 mg/kg i.v. propofol as compared to control saline-treated rats. Since the major pathology of Pilo-SE rats was cell loss in the piriform cortex (PC) and the entorhinal cortex (EC), we studied the anesthetic response after inactivation of the EC or PC by locally infusing GABA A receptor agonist muscimol. Muscimol inactivation of the PC or EC, as compared to saline infusion in the same rats, prolonged the duration of loss of righting reflex, typically without changing the duration of loss of tail-pinch response, after 20 mg/kg i.p. pentobarbital, 2% halothane and 5 mg/kg i.v. propofol. Muscimol infusion, as compared to saline infusion, in the PC or EC also tended to decrease 30–100 Hz gamma EEG in the frontal cortex. In conclusion, a TLE model that resulted in neuronal loss, Pilo-SE, enhanced the response to a general anesthetic that could partly be attributed to a loss of neurons in the EC and PC.

Transplantation of GABA-Producing Cells for Seizure Control in Models of Temporal Lobe Epilepsy

A high percentage of patients with temporal lobe epilepsy (TLE) are refractory to conventional pharmacotherapy. The progressive neurodegenerative processes associated with a lifetime of uncontrolled seizures mandate the development of alternative approaches to treat this disease. Transplantation of inhibitory cells has been suggested as a potential therapeutic strategy to achieve seizure suppression in humans with intractable TLE. Preclinical investigations over 20 years have demonstrated that multiple cell types from several sources can produce anticonvulsant, and antiepileptogenic, effects in animal models of TLE. Transplanting GABA-producing cells, in particular, has been shown to reduce seizures in several well-established models. This review addresses experimentation using different sources of transplantable GABAergic cells, highlighting progress with fetal tissue, neural cell lines, and stem cells. Regardless of the source of the GABAergic cells used in seizure studies, common challenges have emerged. Several variables influence the anticonvulsant potential of GABA-producing cells. For example, tissue availability, graft survival, immunogenicity, tumorigenicity, and varying levels of cell migration, differentiation, and integration into functional circuits and the microenvironment provided by sclerotic tissue all contribute to the efficacy of transplanted cells. The challenge of understanding how all of these variables work in concert, in a disease process that has no well-established etiology, suggests that there is still much basic research to be done before rational cell-based therapies can be developed for TLE.

Predictors of pharmacoresistant epilepsy: Pharmacoresistant rats differ from pharmacoresponsive rats in behavioral and cognitive abnormalities associated with experimentally induced epilepsy

Patients with intractable temporal lobe epilepsy (TLE) exhibit an increased risk of psychiatric comorbidity, including depression, anxiety, psychosis, and learning disorders. Furthermore, a history of psychiatric comorbidity has been suggested as a predictor of lack of response to therapy with antiepileptic drugs (AEDs) in patients with epilepsy. However, clinical studies on predictors of pharmacoresistant epilepsy are affected by several confounding variables, which may complicate conclusions. In the present study, we evaluated whether behavioral alterations in epileptic rats are different in AED nonresponders versus responders. For this purpose, we used an animal model of TLE in which AED responders and nonresponders can be selected by prolonged treatment of epileptic rats with phenobarbital (PB). Behavioral and cognitive abnormalities were compared between responders and nonresponders as well as between epileptic rats and nonepileptic controls in a battery of tests. Fifteen epileptic rats with spontaneous recurrent seizures (SRS) either responding (11 rats) or not responding (4 rats) to PB were used for this study. The nonresponders differed markedly in behavioral and cognitive abnormalities from responders and nonepileptic controls in tests of anxiety (open field, elevated-plus maze test), behavioral hyperexcitability (approach-response, touch-response, pick-up tests), and learning and memory (Morris water maze). Our hypothesis that AED-resistant rats will show more severe behavioral and cognitive changes than AED-responsive rats was confirmed by the present experiments. The data substantiate that rodent models of TLE are useful to delineate predictors of pharmacoresistant epilepsy.

Neurogenesis in the human hippocampus and its relevance to temporal lobe epilepsies

Ample evidence points to the dentate gyrus as anatomical region for persistent neurogenesis in the adult mammalian brain. This has been confirmed in a variety of animal models under physiological as well as pathophysiological conditions. Notwithstanding, similar experiments are difficult to perform in humans. Postmortem studies demonstrated persisting neurogenesis in the elderly human brain. In addition, neural precursor cells can be isolated from surgical specimens obtained from patients with intractable temporal lobe epilepsy (TLE) and propagated or differentiated into neuronal and glial lineages. It remains a controversial issue, whether epileptic seizures have an effect on or even increase hippocampal neurogenesis in humans. Recent data support the notion that seizures induce neurogenesis in young patients, whereas the capacity of neuronal recruitment and proliferation decreases with age. Animal models of TLE further indicate that these newly generated neurons integrate into epileptogenic networks and contribute to increased seizure susceptibility. However, pathomorphological disturbances within the epileptic hippocampus, such as granule cell dispersion (GCD), may not directly result from compromised neurogenesis. Still, the majority of adult TLE patients present with significant dentate granule cell loss at an end stage of the disease, which relates to severe memory and learning disabilities. In conclusion, surgical specimens obtained from TLE patients represent an important tool to study mechanisms of stem cell recruitment, proliferation and differentiation in the human brain. In addition, increasing availability of surgical specimens opens new avenues to systematically explore disease pathomechanisms in chronic epilepsies.

Important role of matrix metalloproteinase 9 in epileptogenesis

Temporal lobe epilepsy (TLE) is a devastating disease in which aberrant synaptic plasticity plays a major role. We identify matrix metalloproteinase (MMP) 9 as a novel synaptic enzyme and a key pathogenic factor in two animal models of TLE: kainate-evoked epilepsy and pentylenetetrazole (PTZ) kindling–induced epilepsy. Notably, we show that the sensitivity to PTZ epileptogenesis is decreased in MMP-9 knockout mice but is increased in a novel line of transgenic rats overexpressing MMP-9. Immunoelectron microscopy reveals that MMP-9 associates with hippocampal dendritic spines bearing asymmetrical (excitatory) synapses, where both the MMP-9 protein levels and enzymatic activity become strongly increased upon seizures. Further, we find that MMP-9 deficiency diminishes seizure-evoked pruning of dendritic spines and decreases aberrant synaptogenesis after mossy fiber sprouting. The latter observation provides a possible mechanistic basis for the effect of MMP-9 on epileptogenesis. Our work suggests that a synaptic pool of MMP-9 is critical for the sequence of events that underlie the development of seizures in animal models of TLE.

Could Hippocampal Neurogenesis be a Future Drug Target for Treating Temporal Lobe Epilepsy?

The dentate gyrus, a region of the hippocampal formation, displays the highest level of plasticity in the brain and exhibits neurogenesis all through life. Dentate neurogenesis, believed to be essential for learning and memory function, responds to physiological stimuli as well as pathological situations. The role of dentate neurogenesis in the pathophysiology of temporal lobe epilepsy (TLE) has received increased attention lately because of its disparate response in the early and chronic stages of the disease. Acute seizures or status epilepticus immensely enhance dentate neurogenesis and lead to an aberrant migration of newly born neurons into the dentate hilus and the formation of epileptogenic circuitry in the injured hippocampus. Conversely, spontaneous recurrent seizures that arise during chronic TLE are associated with dramatically reduced dentate neurogenesis. In this review, we discuss the potential significance of enhanced but abnormal neurogenesis taking place shortly after brain injury or the status epilepticus towards the development of chronic epilepsy, and prospective implications of dramatically waned dentate neurogenesis occurring during chronic epilepsy for learning and memory function and depression in TLE. Furthermore, we confer whether hippocampal neurogenesis is a possible drug target for preventing TLE after brain injury or the status epilepticus, and for easing learning and memory impairments during chronic epileptic conditions. Additionally, we discuss some possible drugs and approaches that need to be evaluated in future in animal models of TLE to further understand the role of neurogenesis in the pathogenesis of TLE and whether modulation of neurogenesis is useful for treating TLE.

Concise Review: Prospects of Stem Cell Therapy for Temporal Lobe Epilepsy

Certain regions of the adult brain have the ability for partial self-repair after injury through production of new neurons via activation of neural stem/progenitor cells (NSCs). Nonetheless, there is no evidence yet for pervasive spontaneous replacement of dead neurons by newly formed neurons leading to functional recovery in the injured brain. Consequently, there is enormous interest for stimulating endogenous NSCs in the brain to produce new neurons or for grafting of NSCs isolated and expanded from different brain regions or embryonic stem cells into the injured brain. Temporal lobe epilepsy (TLE), characterized by hyperexcitability in the hippocampus and spontaneous seizures, is a possible clinical target for stem cell-based therapies. This is because these approaches have the potential to curb epileptogenesis and prevent chronic epilepsy development and learning and memory dysfunction after hippocampal damage related to status epilepticus or head injury. Grafting of NSCs may also be useful for restraining seizures during chronic epilepsy. The aim of this review is to evaluate current knowledge and outlook pertaining to stem cell-based therapies for TLE. The first section discusses the behavior of endogenous hippocampal NSCs in human TLE and animal models of TLE and evaluates the role of hippocampal neurogenesis in the pathophysiology and treatment of TLE. The second segment considers the prospects for preventing or suppressing seizures in TLE using exogenously applied stem cells. The final part analyzes problems that remain to be resolved before initiating clinical application of stem cell-based therapies for TLE. Disclosure of potential conflicts of interest is found at the end of this article.

Neuroprotective Strategies to Avert Seizure‐Induced Neurodegeneration in Epilepsy

Neurodegeneration in limbic circuits is a hallmark feature of chronic temporal lobe epilepsy (TLE). Studies in experimental animal models and human patients indicate that seizure-induced neuronal injury involves some active, as well as passive cell death processes. Experimental approaches that inhibit active steps in cell death programs have been shown to reduce neuronal cell death and sclerosis, but not to prevent epileptogenesis in animal models of TLE. These findings suggest that we need additional research using both animal models and brain slices from human patients to understand the pathological mechanisms underlying seizure generation. Such comparative studies will also aid in evaluating the potential therapeutic value of inhibiting cell death in seizure disorders.