Transplanting GABAergic Neurons Differentiated from Neural Stem Cells into Hippocampus Inhibits Seizures and Epileptiform Discharges in Pilocarpine-Induced Temporal Lobe Epilepsy Model

Xu, Kaya; Liu, Feng; Xu, Wei; Liu, Jian; Chen, Shuxuan; Wu, Guofeng

doi:10.1016/j.wneu.2019.01.245

Cited by 11 publications

(7 citation statements)

References 59 publications

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“…Furthermore, many TLE models investigated in therapeutic studies have also been reported to have much lower (1-2 seizures/day) and inconsistent frequency of seizures, or clusters of SRS occurring one or more times a month [84][85][86][87][88][89]. The use of chronic epilepsy models with irregular frequency for SRS may lead to confounding results and interpretation of the therapeutic efficacy of drugs or biologics unless the study employs continuous video-EEG recordings for several months.…”

Section: Discussionmentioning

confidence: 99%

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

Upadhya¹,

Kodali²,

Gitaí³

et al. 2019

Aging and disease

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Many animal prototypes illustrating the various attributes of human temporal lobe epilepsy (TLE) are available. These models have been invaluable for comprehending multiple epileptogenic processes, modifications in electrophysiological properties, neuronal hyperexcitability, neurodegeneration, neural plasticity, and chronic neuroinflammation in TLE. Some models have also uncovered the efficacy of new antiepileptic drugs or biologics for alleviating epileptogenesis, cognitive impairments, or spontaneous recurrent seizures (SRS). Nonetheless, the suitability of these models for testing candidate therapeutics in conditions such as chronic TLE is debatable because of a lower frequency of SRS and an inconsistent pattern of SRS activity over days, weeks or months. An ideal prototype of chronic TLE for investigating novel therapeutics would need to display a large number of SRS with a dependable frequency and severity and related co-morbidities. This study presents a new kainic acid (KA) model of chronic TLE generated through induction of status epilepticus (SE) in 6-8 weeks old male F344 rats. A rigorous characterization in the chronic epilepsy period validated that the animal prototype mimicked the most salient features of robust chronic TLE. Animals displayed a constant frequency and intensity of SRS across weeks and months in the 5th and 6th month after SE, as well as cognitive and mood impairments. Moreover, SRS frequency displayed a rhythmic pattern with 24-hour periodicity and a consistently higher number of SRS in the daylight period. Besides, the model showed many neuropathological features of chronic TLE, which include a partial loss of inhibitory interneurons, reduced neurogenesis with persistent aberrant migration of newly born neurons, chronic neuroinflammation typified by hypertrophied astrocytes and rod-shaped microglia, and a significant aberrant mossy fiber sprouting in the hippocampus. This consistent chronic seizure model is ideal for investigating the efficacy of various antiepileptic drugs and biologics as well as understanding multiple pathophysiological mechanisms underlying chronic epilepsy.

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Section: Discussionmentioning

confidence: 99%

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

Upadhya¹,

Kodali²,

Gitaí³

et al. 2019

Aging and disease

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“…Six ColIV alpha chains (ColIV4a1 to ColIV4a6) have been identified. We studied specifically ColIVa1 and ColIVa3 that are involved in brain vascular integrity [8]. Increased ColIV has been shown in brain blood vessels in mouse, rat and sheep animal models and human stroke tissue [53].…”

Section: Discussionmentioning

confidence: 99%

“…Other major constitutive cells of the BBB are astrocytes, which interact with and surround endothelial cells and pericytes, in particular via specialized structures known as astrocytic end-feet. In the BBB, ColIV is the most abundant component of the basement membrane, and is produced predominantly by endothelial cells, pericytes and astrocytes [8].…”

Section: Introductionmentioning

confidence: 99%

Pilocarpine-Induced Status Epilepticus in the Rat Hippocampus is Associated with Reactive Glia and Concomitant Increased Expression of CD31, PDGFRβ and Collagen IV in Endothelial Cells and Pericytes of the Blood Brain Barrier

Kyriatzis,

Bernard,

Bôle

et al. 2023

Preprint

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Temporal lobe epilepsy (TLE) is associated with reorganization of neuronal networks, gliosis, neuroinflammation, loss of integrity of the blood brain barrier (BBB) in the hippocampus in humans and animal models. More than 30% of epilepsies remain intractable and characterization of the molecular mechanisms involved in BBB dysfunction is essential to the identification of new therapeutic strategies. In this work, we induced status epilepticus in rats by injection of the proconvulsant drug pilocarpine that leads to TLE. Using RT-qPCR, double immunohistochemistry and confocal imaging, we studied at different time points of epileptogenesis (latent phase, 3, 7, 14 days; chronic phase, 1 and 3 months) the regulation of reactive glia and vascular markers. In the hippocampus, increased expression of mRNA encoding the glial proteins GFAP and Iba1 confirmed neuroinflammatory status. We report for the first time the concomitant induction in endothelial cells, pericytes and basal membrane of the BBB of specific proteins CD31, PDGFR and ColIV, that peaks at the same time points as inflammation. The altered expression of these proteins occurs early in TLE, during the latent phase, suggesting that they could be associated with early rupture and pathogenicity of the BBB that will contribute to the chronic phase of epilepsy.

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“…NSCs can be harvested from several sources such as fetal, postnatal, and adult brains, and also can be generated from ESCs and iPSCs (Hattiangady and Shetty, 2011 ; Noebels et al, 2012 ). In the animal model of temporal lobe epilepsy, transplanting NSCs into the hippocampus appears responsive effects on seizure remission and has the potential to mitigate and repair epilepsy-induced pathological changes (Hattiangady and Shetty, 2012 ; Noebels et al, 2012 ; Uchida et al, 2012 ; de Gois da Silva et al, 2018 ; Xu et al, 2019 ). While NSCs show promising potential for treating mesial temporal lobe epilepsy, clinical research is paucity and a lack of data to demonstrate the effectiveness of NSC therapy on other forms of epilepsy.…”

Section: Sources and Types Of Stem Cellsmentioning

confidence: 99%

Stem Cell Therapy in Treating Epilepsy

Chang

2022

Front. Neurosci.

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Epilepsy is a common disabling chronic neurological disorder characterized by an enduring propensity for the generation of seizures that result from abnormal hypersynchronous firing of neurons in the brain. Over 20–30% of epilepsy patients fail to achieve seizure control or soon become resistant to currently available therapies. Prolonged seizures or uncontrolled chronic seizures would give rise to neuronal damage or death, astrocyte activation, reactive oxygen species production, and mitochondrial dysfunction. Stem cell therapy is potentially a promising novel therapeutic strategy for epilepsy. The regenerative properties of stem cell-based treatment provide an attractive approach for long-term seizure control, particularly in drug-resistant epilepsy. Embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and adipose-derived regenerative cells (ADRCs) are capable of differentiating into specialized cell types has been applied for epilepsy treatment in preclinical animal research and clinical trials. In this review, we focused on the advances in stem cell therapy for epilepsies. The goals of stem cell transplantation, its mechanisms underlying graft effects, the types of grafts, and their therapeutic effects were discussed. The cell and animal models used for investigating stem cell technology in epilepsy treatment were summarized.

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Transplanting GABAergic Neurons Differentiated from Neural Stem Cells into Hippocampus Inhibits Seizures and Epileptiform Discharges in Pilocarpine-Induced Temporal Lobe Epilepsy Model

Cited by 11 publications

References 59 publications

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

Pilocarpine-Induced Status Epilepticus in the Rat Hippocampus is Associated with Reactive Glia and Concomitant Increased Expression of CD31, PDGFRβ and Collagen IV in Endothelial Cells and Pericytes of the Blood Brain Barrier

Stem Cell Therapy in Treating Epilepsy

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