Role of Astrocytes in Post-traumatic Epilepsy

Xu, Shaohua; Sun, Qihan; Fan, Jie; Jiang, Yuanyuan; Yang, Wei; Cui, Yifeng; Yu, Ziyou; Jiang, Hao-Bo; Li, Bingjin

doi:10.3389/fneur.2019.01149

Cited by 28 publications

(26 citation statements)

References 136 publications

(142 reference statements)

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“…This includes the release of proinflammatory molecules (eg, IL1β, IL6, or TNFα) and excitatory gliotransmitters (eg, ATP, glutamate), altered expression of ion channels (eg, inwardly rectifying potassium channel K ir 4.1), leading to perturbation in spatial K + buffering, changes in expression of Ca 2+ and Cltransporters, uncoupling of gap junctions, and promotion of Ca 2+ waves, which in turn are thought to modulate the release of a number of gliotransmitters that may influence synaptic function. [23][24][25][26] Moreover, astrocytes express the enzyme adenosine kinase (ADK), which catalyzes the conversion of adenosine into adenosine monophosphate, removing anticonvulsant adenosine from the extracellular space and thereby lowering seizure threshold. 27 Further support for a proepileptic function of activated astrocytes stems from a study showing that the activation of astrocytes in the absence of other pathologies is sufficient to cause epileptic seizures.…”

Section: Epilepsy and Inflammationmentioning

confidence: 99%

Targeting Neuroinflammation via Purinergic P2 Receptors for Disease Modification in Drug-Refractory Epilepsy

Engel¹,

Smith²,

Alves³

2021

JIR

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Treatment of epilepsy remains a clinical challenge, with >30% of patients not responding to current antiseizure drugs (ASDs). Moreover, currently available ASDs are merely symptomatic without altering significantly the progression of the disease. Inflammation is increasingly recognized as playing an important role during the generation of hyperexcitable networks in the brain. Accordingly, the suppression of chronic inflammation has been suggested as a promising therapeutic strategy to prevent epileptogenesis and to treat drug-refractory epilepsy. As a consequence, a strong focus of ongoing research is identification of the mechanisms that contribute to sustained inflammation in the brain during epilepsy and whether these can be targeted. ATP is released in response to several pathological stimuli, including increased neuronal activity within the central nervous system, where it functions as a neuro-and gliotransmitter. Once released, ATP activates purinergic P2 receptors, which are divided into metabotropic P2Y and ionotropic P2X receptors, driving inflammatory processes. Evidence from experimental models and patients demonstrates widespread expression changes of both P2Y and P2X receptors during epilepsy, and critically, drugs targeting both receptor subtypes, in particular the P2Y 1 and P2X 7 subtypes, have been shown to possess both anticonvulsive and antiepileptic potential. This review provides a detailed summary of the current evidence suggesting ATP-gated receptors as novel drug targets for epilepsy and discusses how P2 receptor-driven inflammation may contribute to the generation of seizures and the development of epilepsy.

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Section: Epilepsy and Inflammationmentioning

confidence: 99%

Targeting Neuroinflammation via Purinergic P2 Receptors for Disease Modification in Drug-Refractory Epilepsy

Engel¹,

Smith²,

Alves³

2021

JIR

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“…Multiple mechanisms have been explained in the past that led to altered brain activity provoking seizures, including increased inflammatory markers, altered blood-brain barrier, changes in astrocytes, and glucose metabolism dysregulation [4][5][6][7].…”

Section: Pathogenesis Of Post-traumatic Seizuresmentioning

confidence: 99%

“…Some studies show that they protect the healthy brain by forming scar and separating the damaged area. On the other hand, some depict the same fibrosis spot as the focus for the seizure's origin [5,9].…”

Section: The Astrocytes Controversymentioning

confidence: 99%

“…Disruption of BBB allows albumin to enter the brain. Astrocytes also uptake that albumin and, as a result, activate the transforming growth factor-β/activin receptor-like kinase 5 (TGF-β/ALK 5 pathway) [5].…”

Section: Post-traumatic Inflammationmentioning

confidence: 99%

“…Anderson et al conducted an interventional study by inhibiting scar formation in rats after spinal cord injury, and thus the cells fail to regenerate. Then they injected some hydrogel depots of growth factors released by astrocytes and documented the scar formation and regeneration of neurons [5,21].…”

Section: Astrocyte Changesmentioning

confidence: 99%

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Post-Traumatic Seizures: A Deep-Dive Into Pathogenesis

Anwer

Oliveri

Fotios

et al. 2021

Cureus

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Post-traumatic seizures (PTS) have become an emerging challenge for neurologists worldwide with the rise of brain injuries. Trauma can lead to various outcomes, ranging from naive spasms to debilitating posttraumatic epilepsy (PTE). In this article, we will explore the pathogenesis of convulsions following a concussion. We will look at multiple studies to explain the various structural, metabolic, and inflammatory changes leading to seizures. Additionally, we will explore the association between severity and location of injury and PTE. PTE's pathophysiology is not entirely implicit, and we are still in the dark as to which antiepileptic drugs will be useful in circumventing these attacks. The purpose of this narrative review is to explain the post-traumatic brain changes in detail so that such attacks can be either thwarted or treated more resourcefully in the future.

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Astrocyte reactivity in a mouse model of SCN8A epileptic encephalopathy

et al. 2022

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Objective SCN8A epileptic encephalopathy is caused predominantly by de novo gain‐of‐function mutations in the voltage‐gated sodium channel Nav1.6. The disorder is characterized by early onset of seizures and developmental delay. Most patients with SCN8A epileptic encephalopathy are refractory to current anti‐seizure medications. Previous studies determining the mechanisms of this disease have focused on neuronal dysfunction as Nav1.6 is expressed by neurons and plays a critical role in controlling neuronal excitability. However, glial dysfunction has been implicated in epilepsy and alterations in glial physiology could contribute to the pathology of SCN8A encephalopathy. In the current study, we examined alterations in astrocyte and microglia physiology in the development of seizures in a mouse model of SCN8A epileptic encephalopathy. Methods Using immunohistochemistry, we assessed microglia and astrocyte reactivity before and after the onset of spontaneous seizures. Expression of glutamine synthetase and Nav1.6, and Kir4.1 channel currents were assessed in astrocytes in wild‐type (WT) mice and mice carrying the N1768D SCN8A mutation (D/+). Results Astrocytes in spontaneously seizing D/+ mice become reactive and increase expression of glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity. These same astrocytes exhibited reduced barium‐sensitive Kir4.1 currents compared to age‐matched WT mice and decreased expression of glutamine synthetase. These alterations were only observed in spontaneously seizing mice and not before the onset of seizures. In contrast, microglial morphology remained unchanged before and after the onset of seizures. Significance Astrocytes, but not microglia, become reactive only after the onset of spontaneous seizures in a mouse model of SCN8A encephalopathy. Reactive astrocytes have reduced Kir4.1‐mediated currents, which would impair their ability to buffer potassium. Reduced expression of glutamine synthetase would modulate the availability of neurotransmitters to excitatory and inhibitory neurons. These deficits in potassium and glutamate handling by astrocytes could exacerbate seizures in SCN8A epileptic encephalopathy. Targeting astrocytes may provide a new therapeutic approach to seizure suppression.

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Role of Astrocytes in Post-traumatic Epilepsy

Cited by 28 publications

References 136 publications

Targeting Neuroinflammation via Purinergic P2 Receptors for Disease Modification in Drug-Refractory Epilepsy

Targeting Neuroinflammation via Purinergic P2 Receptors for Disease Modification in Drug-Refractory Epilepsy

Post-Traumatic Seizures: A Deep-Dive Into Pathogenesis

Astrocyte reactivity in a mouse model of SCN8A epileptic encephalopathy

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