The role of astrocytes in seizure generation: insights from a novel in vitro seizure model based on mitochondrial dysfunction

Chan, Felix; Lax, Nichola Z.; Voss, Caroline M.; Aldana, Blanca I.; Whyte, Shuna; Jenkins, Alistair; Nicholson, Claire; Nichols, Sophie; Tilley, Elizabeth; Powell, Zoe; Davies, Ceri H.; Turnbull, D.M.; Cunningham, Mark O.

doi:10.1093/brain/awy320

Cited by 53 publications

(48 citation statements)

References 50 publications

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“…They also decrease the activity of the glutamine synthase, preventing the production of glutamine from glutamate and reducing in this way the rate of the glutamate-glutamine cycle. This eventually leads to lower production of GABA neurotransmitter in the GABAergic neurons, diminishing its firing [70,109]. Finally, the pro-inflammatory mediators severely affect the permeability of the BBB; this allows the entry of albumin, and peripheral inflammatory leukocytes which will aggravate inflammation.…”

Section: Neuroinflammation and Seizuresmentioning

confidence: 99%

Reactive Glia Inflammatory Signaling Pathways and Epilepsy

Sanz

García-Gimeno

2020

IJMS

116

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Neuroinflammation and epilepsy are interconnected. Brain inflammation promotes neuronal hyper-excitability and seizures, and dysregulation in the glia immune-inflammatory function is a common factor that predisposes or contributes to the generation of seizures. At the same time, acute seizures upregulate the production of pro-inflammatory cytokines in microglia and astrocytes, triggering a downstream cascade of inflammatory mediators. Therefore, epileptic seizures and inflammatory mediators form a vicious positive feedback loop, reinforcing each other. In this work, we have reviewed the main glial signaling pathways involved in neuroinflammation, how they are affected in epileptic conditions, and the therapeutic opportunities they offer to prevent these disorders.

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Section: Neuroinflammation and Seizuresmentioning

confidence: 99%

Reactive Glia Inflammatory Signaling Pathways and Epilepsy

Sanz

García-Gimeno

2020

IJMS

116

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“…Moreover, drug-resistant MTLE patients were found to have inhibited neurogenesis, reactive astrocyte proliferation, and HS (Muro-García et al, 2019 ). Interestingly, in both mitochondrial epilepsy (a type of epilepsy that is extremely difficult to treat and has a poor prognosis due to mutations in mitochondrial DNA) and Rasmussen’s encephalitis (RE; a type of epilepsy with chronic brain inflammation), patients experienced astrocyte apoptosis and loss (Bauer et al, 2007 ; Chan et al, 2019 ). Above all, reactive astrocytes play an important role in epileptogenesis and epileptic development.…”

Section: Il-4 Glial Cells and Epilepsymentioning

confidence: 99%

Interleukin 4 Affects Epilepsy by Regulating Glial Cells: Potential and Possible Mechanism

Chen

Zhu

Lü

et al. 2020

Front. Mol. Neurosci.

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Epilepsy is a chronic brain dysfunction induced by an abnormal neuronal discharge that is caused by complicated psychopathologies. Recently, accumulating studies have revealed a close relationship between inflammation and epilepsy. Specifically, microglia and astrocytes are important inflammatory cells in the central nervous system (CNS) that have been proven to be related to the pathogenesis and development of epilepsy. Additionally, interleukin 4 (IL-4) is an anti-inflammatory factor that can regulate microglia and astrocytes in many aspects. This review article focuses on the regulatory role of IL-4 in the pathological changes of glial cells related to epilepsy. We additionally propose that IL-4 may play a protective role in epileptogenesis and suggest that IL-4 may be a novel therapeutic target for the treatment of epilepsy.

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“…Astrocytes are intimately involved in diverse neuronal functions, such as modulating synaptic activity and plasticity; regulating the extracellular microenvironment by buffering neurotransmitter, ion, and water content, and regulating local blood flow and the delivery of energy substrates (Devinsky et al, 2012). Dysregulation of astrocyte function may cause seizures or promote epileptogenesis (Wetherington et al, 2008;Chan et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Valeriana officinalis Counteracts Rotenone Effects on Spreading Depression in the Rat Brain in vivo and Protects Against Rotenone Cytotoxicity Toward Rat Glioma C6 Cells in vitro

et al. 2020

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Astrocytes can protect neurons against oxidative stress and excitability-dependent disorders, such as epilepsy. Valeriana officinalis has been used as anticonvulsant and can exert an antioxidant effect, which may underlie its opposing action against the toxic effects of the pesticide rotenone. We investigated the V. officinalis/rotenone interaction in the cortical spreading depression (CSD), a phenomenon that depends upon brain excitability (in vivo model). In addition, we analyzed the protective action of V. officinalis against the cytotoxic effects of rotenone in cultures of rat C6 glioma cells (in vitro model). For the CSD study, Wistar rats received either V. officinalis (250 mg/kg/day via gavage for 15 days; n = 8) or 10 mg/kg/day rotenone via subcutaneous injections for 7 days (n = 7), or they received both substances (n = 5). Two control groups received either saline (vehicle for V. officinalis; n = 8) or 1% Tween-80 aqueous solution (vehicle for rotenone; n = 9). After treatment, CSD was recorded for 4 h. The rotenone-and V. officinalistreated groups presented, respectively, with lower (2.96 ± 0.14 mm/min), and higher CSD propagation velocity (3.81 ± 0.10 mm/min) when compared with the controls (Tween-80, 3.37 ± 0.06 mm/min and saline, 3.35 ± 0.08 mm/min; p < 0.05). The rotenone plus V. officinalis-treated group displayed a CSD velocity (3.38 ± 0.07 mm/min) that was similar to controls. In line with these results, in vitro experiments on rat glioma C6 cells revealed a protective effect (MTT assay) of V. officinalis against rotenoneinduced cytotoxicity. These results suggest the therapeutic potential of V. officinalis for treating neurological diseases involving redox imbalance and astrocyte dysfunction.

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The role of astrocytes in seizure generation: insights from a novel in vitro seizure model based on mitochondrial dysfunction

Cited by 53 publications

References 50 publications

Reactive Glia Inflammatory Signaling Pathways and Epilepsy

Reactive Glia Inflammatory Signaling Pathways and Epilepsy

Interleukin 4 Affects Epilepsy by Regulating Glial Cells: Potential and Possible Mechanism

Valeriana officinalis Counteracts Rotenone Effects on Spreading Depression in the Rat Brain in vivo and Protects Against Rotenone Cytotoxicity Toward Rat Glioma C6 Cells in vitro

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