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在临床相关时间段内靶向诱导癫痫发生导致的是短暂而非持久的癫痫发作减少。

Targeting Seizure-Induced Neurogenesis in a Clinically Relevant Time Period Leads to Transient But Not Persistent Seizure Reduction.

机构信息

Department of Biology and Brain Health Consortium, University of Texas at San Antonio, San Antonio, Texas 78249, and.

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.

出版信息

J Neurosci. 2019 Aug 28;39(35):7019-7028. doi: 10.1523/JNEUROSCI.0920-19.2019. Epub 2019 Jul 15.


DOI:10.1523/JNEUROSCI.0920-19.2019
PMID:31308098
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6733567/
Abstract

Mesial temporal lobe epilepsy (mTLE), the most common form of medically refractory epilepsy in adults, is usually associated with hippocampal pathophysiology. Using rodent models of mTLE, many studies including work from our laboratory have shown that new neurons born around the onset of severe acute seizures known as status epilepticus (SE) are crucial for the process of epileptogenesis and targeting seizure-induced neurogenesis either genetically or pharmacologically can impact the frequency of chronic seizures. However, these studies are limited in their clinical relevance as none of them determines the potential of blocking new neurons generated after the epileptogenic insult to alleviate the development of chronic seizures. Therefore, using a pilocarpine-induced SE model of mTLE in mice of either sex, we show that >4 weeks of continuous and concurrent ablation of seizure-induced neurogenesis after SE can reduce the formation of spontaneous recurrent seizures by 65%. We also found that blocking post-SE neurogenesis does not lead to long-term seizure reduction as the effect was observed only transiently for 10 d with >4 weeks of continuous and concurrent ablation of seizure-induced neurogenesis. Thus, these findings provide evidence that seizure-induced neurogenesis when adequately reduced in a clinically relevant time period has the potential to transiently suppress recurrent seizures, but additional mechanisms need to be targeted to permanently prevent epilepsy development. Consistent with morphological and electrophysiological studies suggesting aberrant adult-generated neurons contribute to epilepsy development, ablation of seizure-induced new neurons at the time of the initial insult reduces the frequency of recurrent seizures. In this study, we show that continuous targeting of post-insult new neurons in a therapeutically relevant time period reduces chronic seizures; however, this effect does not persist suggesting possible additional mechanisms.

摘要

内侧颞叶癫痫(MTLE)是成人中最常见的药物难治性癫痫形式,通常与海马生理学有关。使用 MTLE 的啮齿动物模型,包括我们实验室的许多研究表明,在称为癫痫持续状态(SE)的严重急性发作开始时产生的新神经元对于癫痫发生过程至关重要,并且通过遗传或药理学靶向诱导的神经发生可以影响慢性发作的频率。然而,由于这些研究都没有确定阻止癫痫发作后产生的新神经元的潜力以减轻慢性发作的发展,因此它们在临床相关性方面存在局限性。因此,我们使用匹鲁卡品诱导的 MTLE 雄性和雌性小鼠 SE 模型表明,SE 后持续和同时消融诱导的神经发生>4 周可以将自发性复发性癫痫发作的形成减少 65%。我们还发现,阻断 SE 后神经发生不会导致长期的癫痫发作减少,因为这种效果仅在 10 天内短暂观察到,而持续和同时消融诱导的神经发生>4 周。因此,这些发现提供了证据表明,在临床相关时间段内适当减少诱导的神经发生具有暂时抑制复发性癫痫发作的潜力,但需要针对其他机制来永久预防癫痫发作。与形态学和电生理学研究一致,这些研究表明异常的成年产生的神经元有助于癫痫发作的发展,在初始损伤时消融诱导的新神经元可降低复发性癫痫发作的频率。在这项研究中,我们表明在治疗相关时间内持续靶向新神经元可减少慢性癫痫发作;然而,这种效果并不持久,这表明可能存在其他机制。

相似文献

[1]
Targeting Seizure-Induced Neurogenesis in a Clinically Relevant Time Period Leads to Transient But Not Persistent Seizure Reduction.

J Neurosci. 2019-7-15

[2]
Circadian clustering of spontaneous epileptic seizures emerges after pilocarpine-induced status epilepticus.

Epilepsia. 2017-5-24

[3]
Roles of astrocytes and microglia in seizure-induced aberrant neurogenesis in the hippocampus of adult rats.

J Neurosci Res. 2010-2-15

[4]
The polarity and properties of radial glia-like neural stem cells are altered by seizures with status epilepticus: Study using an improved mouse pilocarpine model of epilepsy.

Hippocampus. 2020-3

[5]
Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline.

Nat Commun. 2015-3-26

[6]
Calcium Channel Subunit α2δ4 Is Regulated by Early Growth Response 1 and Facilitates Epileptogenesis.

J Neurosci. 2019-2-21

[7]
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[8]
Seizure-induced neuroinflammation contributes to ectopic neurogenesis and aggressive behavior in pilocarpine-induced status epilepticus mice.

Neuropharmacology. 2020-6-15

[9]
Pilocarpine-induced status epilepticus and subsequent spontaneous seizures: lack of effect on the number of gonadotropin-releasing hormone-positive neurons in a mouse model of temporal lobe epilepsy.

Neuroscience. 2011-12-22

[10]
Cyclicity of spontaneous recurrent seizures in pilocarpine model of temporal lobe epilepsy in rat.

Exp Neurol. 2007-6

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[2]
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Epilepsia. 2025-5

[3]
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Int J Mol Sci. 2023-4-1

[4]
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Neurobiol Dis. 2022-11

[5]
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Front Neurosci. 2022-9-8

[6]
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J Physiol. 2023-8

[7]
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Nat Neurosci. 2022-4

[8]
HOP protein expression in the hippocampal dentate gyrus is acutely downregulated in a status epilepticus mouse model.

IBRO Neurosci Rep. 2021-10-23

[9]
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Neuron. 2021-8-18

[10]
Multipronged Attack of Stem Cell Therapy in Treating the Neurological and Neuropsychiatric Symptoms of Epilepsy.

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本文引用的文献

[1]
Adult neurogenesis in mammals.

Science. 2019-5-31

[2]
Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer's disease.

Nat Med. 2019-3-25

[3]
Human Adult Neurogenesis: Evidence and Remaining Questions.

Cell Stem Cell. 2018-4-19

[4]
Human Hippocampal Neurogenesis Persists throughout Aging.

Cell Stem Cell. 2018-4-5

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Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.

Nature. 2018-3-7

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Ablation of peri-insult generated granule cells after epilepsy onset halts disease progression.

Sci Rep. 2017-12-21

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Mice with conditional NeuroD1 knockout display reduced aberrant hippocampal neurogenesis but no change in epileptic seizures.

Exp Neurol. 2017-7

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Stress as a seizure precipitant: Identification, associated factors, and treatment options.

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[9]
Ablation of Newly Generated Hippocampal Granule Cells Has Disease-Modifying Effects in Epilepsy.

J Neurosci. 2016-10-26

[10]
Neurogenesis-mediated forgetting minimizes proactive interference.

Nat Commun. 2016-2-26

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