Astrocytes in the initiation and progression of epilepsy

One of the most important characteristics of the brain compared to other organs is its elevated metabolic demand. Consequently, neurons consume high quantities of oxygen, generating significant amounts of reactive oxygen species (ROS) as a by-product. These potentially toxic molecules cause oxidative stress (OS) and are associated with many disorders of the nervous system, where pathological processes such as aberrant protein oxidation can ultimately lead to cellular dysfunction and death. Epilepsy, characterized by a long-term predisposition to epileptic seizures, is one of the most common of the neurological disorders associated with OS. Evidence shows that increased neuronal excitability—the hallmark of epilepsy—is accompanied by neuroinflammation and an excessive production of ROS; together, these factors are likely key features of seizure initiation and propagation. This review discusses the role of OS in epilepsy, its connection to neuroinflammation and the impact on synaptic function. Considering that the pharmacological treatment options for epilepsy are limited by the heterogeneity of these disorders, we also introduce the latest advances in anti-epileptic drugs (AEDs) and how they interact with OS. We conclude that OS is intertwined with numerous physiological and molecular mechanisms in epilepsy, although a causal relationship is yet to be established.

/pdf/the-interconnected-mechanisms-of-oxidative-stress-and-1pqbrtdu.pdf

The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy

Astrocytes are specialized non-neuronal glial cells of the central nervous system, contributing to neuronal excitability and synaptic transmission (gliotransmission). Astrocytes play a key roles in epileptogenesis and seizure generation. Epilepsy, as a chronic disorder characterized by neuronal hyperexcitation and hypersynchronization, is accompanied by substantial disturbances of glial cells and impairment of astrocytic functions and neuronal signaling. Anti-seizure drugs that provide symptomatic control of seizures primarily target neural activity. In epileptic patients with inadequate control of seizures with available anti-seizure drugs, novel therapeutic candidates are needed. These candidates should treat epilepsy with anti-epileptogenic and disease-modifying effects. Evidence from human and animal studies shows that astrocytes have value for developing new anti-seizure and anti-epileptogenic drugs. In this review, we present the key functions of astrocytes contributing to neuronal hyperexcitability and synaptic activity following an etiology-based approach. We analyze the role of astrocytes in both development (epileptogenesis) and generation of seizures (ictogenesis). Several promising new strategies that attempted to modify astroglial functions for treating epilepsy are being developed: (1) selective targeting of glia-related molecular mechanisms of glutamate transport; (2) modulation of tonic GABA release from astrocytes; (3) gliotransmission; (4) targeting the astrocytic Kir4.1-BDNF system; (5) astrocytic Na + /K + /ATPase activity; (6) targeting DNA hypo- or hypermethylation of candidate genes in astrocytes; (7) targeting astrocytic gap junction regulators; (8) targeting astrocytic adenosine kinase (the major adenosine-metabolizing enzyme); and (9) targeting microglia-astrocyte communication and inflammatory pathways. Novel disease-modifying therapeutic strategies have now been developed, such as astroglia-targeted gene therapy with a broad spectrum of genetic constructs to target astroglial cells. 

Astrocytes as a target for therapeutic strategies in epilepsy: current insights

Temporal lobe epilepsy (TLE) is a chronic neurological disorder that is often resistant to antiepileptic drugs. The pathogenesis of TLE is extremely complicated and remains elusive. Understanding the molecular mechanisms underlying TLE is crucial for its diagnosis and treatment. In the present study, a lithium-pilocarpine-induced TLE model was employed to reveal the pathological changes of hippocampus in rats. Hippocampal samples were taken for proteomic analysis at 2 weeks after the onset of spontaneous seizure (a chronic stage of epileptogenesis). Isobaric tag for relative and absolute quantization (iTRAQ) coupled with liquid chromatography-tandem mass spectrometry (LC–MS/MS) technique was applied for proteomic analysis of hippocampus. A total of 4173 proteins were identified from the hippocampi of epileptic rats and its control, of which 27 differentially expressed proteins (DEPs) were obtained with a fold change > 1.5 and P < 0.05. Bioinformatics analysis indicated 27 DEPs were mainly enriched in “regulation of synaptic plasticity and structure” and “calmodulin-dependent protein kinase activity,” which implicate synaptic remodeling may play a vital role in the pathogenesis of TLE. Consequently, the synaptic plasticity-related proteins and synaptic structure were investigated to verify it. It has been demonstrated that CaMKII-α, CaMKII-β, and GFAP were significant upregulated coincidently with proteomic analysis in the hippocampus of TLE rats. Moreover, the increased dendritic spines and hippocampal sclerosis further proved that synaptic plasticity involves in the development of TLE. The present study may help to understand the molecular mechanisms underlying epileptogenesis and provide a basis for further studies on synaptic plasticity in TLE.

/pdf/proteomic-analysis-reveals-the-vital-role-of-synaptic-3v0qz6cy.pdf

Proteomic Analysis Reveals the Vital Role of Synaptic Plasticity in the Pathogenesis of Temporal Lobe Epilepsy

Targeting Endocannabinoid System in Epilepsy: For Good or for Bad

Epilepsy affects approximately 50 million people worldwide, with 60% of adult epilepsies presenting an onset of focal origin. The most common focal epilepsy is temporal lobe epilepsy (TLE). The role of astrocytes in the presentation and development of TLE has been increasingly studied and discussed within the literature. The most common histopathological diagnosis of TLE is hippocampal sclerosis. Hippocampal sclerosis is characterized by neuronal cell loss within the Cornu ammonis and reactive astrogliosis. In some cases, mossy fiber sprouting may be observed. Mossy fiber sprouting has been controversial in its contribution to epileptogenesis in TLE patients, and the mechanisms surrounding the phenomenon have yet to be elucidated. Several studies have reported that mossy fiber sprouting has an almost certain co-existence with reactive astrogliosis within the hippocampus under epileptic conditions. Astrocytes are known to play an important role in the survival and axonal outgrowth of central and peripheral nervous system neurons, pointing to a potential role of astrocytes in TLE and associated cellular alterations. Herein, we review the recent developments surrounding the role of astrocytes in the pathogenic process of TLE and mossy fiber sprouting, with a focus on proposed signaling pathways and cellular mechanisms, histological observations, and clinical correlations in human patients.

/pdf/astrocyte-role-in-temporal-lobe-epilepsy-and-development-of-3ide9btw6m.pdf

Astrocyte Role in Temporal Lobe Epilepsy and Development of Mossy Fiber Sprouting.

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Astrocyte Role in Temporal Lobe Epilepsy and Development of Mossy Fiber Sprouting.