Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

Ravizza, Teresa; Vezzani, Annamaria

doi:10.1002/epi4.12242

Cited by 71 publications

(49 citation statements)

References 167 publications

(316 reference statements)

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“…Clinical and experimental evidence indicates that inflammatory processes contribute to the pathophysiology of several types of epilepsy [79]. However, the respective contribution of brain resident vs. brain invading (bloodborne) immune cells to epileptogenesis is not completely understood.…”

Section: Impairment Of Barrier Functions and The Invasion Of Inflammamentioning

confidence: 99%

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

Löscher¹,

Friedman

2020

IJMS

144

117

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The blood-brain barrier (BBB) is a dynamic, highly selective barrier primarily formed by endothelial cells connected by tight junctions that separate the circulating blood from the brain extracellular fluid. The endothelial cells lining the brain microvessels are under the inductive influence of neighboring cell types, including astrocytes and pericytes. In addition to the anatomical characteristics of the BBB, various specific transport systems, enzymes and receptors regulate molecular and cellular traffic across the BBB. While the intact BBB prevents many macromolecules and immune cells from entering the brain, following epileptogenic brain insults the BBB changes its properties. Among BBB alterations, albumin extravasation and diapedesis of leucocytes from blood into brain parenchyma occur, inducing or contributing to epileptogenesis. Furthermore, seizures themselves may modulate BBB functions, permitting albumin extravasation, leading to activation of astrocytes and the innate immune system, and eventually modifications of neuronal networks. BBB alterations following seizures are not necessarily associated with enhanced drug penetration into the brain. Increased expression of multidrug efflux transporters such as P-glycoprotein likely act as a ‘second line defense’ mechanism to protect the brain from toxins. A better understanding of the complex alterations in BBB structure and function following seizures and in epilepsy may lead to novel therapeutic interventions allowing the prevention and treatment of epilepsy as well as other detrimental neuro-psychiatric sequelae of brain injury.

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Section: Impairment Of Barrier Functions and The Invasion Of Inflammamentioning

confidence: 99%

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

Löscher¹,

Friedman

2020

IJMS

144

117

View full text Add to dashboard Cite

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“…Clinical observations and data from animal studies have proposed that neuroinflammation is a common factor contributing to, or predisposing one to, the occurrence of seizures in various kinds of epilepsy, especially TLE [34,35]. For instance, some inflammatory cytokines (IL-1β, IL-6, TNF-α, etc.)…”

Section: Rev-erbα and Neuroinflammationmentioning

confidence: 99%

Decreased expression of Rev-Erbα in the epileptic foci of temporal lobe epilepsy and activation of Rev-Erbα have anti-inflammatory and neuroprotective effects in the pilocarpine model

Yue

Wei

et al. 2020

J Neuroinflammation

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Background: A hallmark of temporal lobe epilepsy (TLE) is brain inflammation accompanied by neuronal demise. Accumulating evidence demonstrates that Rev-Erbα is involved in regulating neuroinflammation and determining the fate of neurons. Therefore, we studied the expression and cellular distribution of Rev-Erbα in the epileptogenic zone of TLE and the effect of treatment with the Rev-Erbα specific agonist SR9009 in the pilocarpine model. Methods:The expression pattern of Rev-Erbα was investigated by western blotting, immunohistochemistry, and immunofluorescence labeling in patients with TLE. Next, the effects of SR9009 on neuroinflammation, neuronal apoptosis, and neuronal loss in the mouse hippocampus 7 days after status epilepticus (SE) were assessed by western blotting, immunofluorescence labeling staining, and TUNEL staining.Results: The western blotting, immunohistochemistry, and immunofluorescence labeling results revealed that Rev-Erbα was downregulated in the epileptogenic zone of TLE patients and mainly localized in neurons, astrocytes, and presumably microglia. Meanwhile, the expression of Rev-Erbα was decreased in the hippocampus and temporal neocortex of mice treated with pilocarpine in the early post-SE and chronic phases. Interestingly, the expression of Rev-Erbα in the normal hippocampus showed a 24-h rhythm; however, the rhythmicity was disturbed in the early phase after SE, and this disturbance was still present in epileptic animals. Our further findings revealed that treatment with SR9009 inhibited NLRP3 inflammasome activation, inflammatory cytokine (IL-1β, IL-18, IL-6, and TNFα) production, astrocytosis, microgliosis, and neuronal damage in the hippocampus after SE.Conclusions: Taken together, these results suggested that a decrease in Rev-Erbα in the epileptogenic zone may contribute to the process of TLE and that the activation of Rev-Erbα may have anti-inflammatory and neuroprotective effects.

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“…As neuroinflammation and oxidative stress are intimately related hallmarks of many epileptic syndromes, this offers a window of opportunity for the use of anti-inflammatory and antioxidant drugs in these conditions. This possibility is supported by recent reports that clearly state that neuroinflammatory pathways may serve as treatment targets and biomarkers in different forms of epilepsy [153,155].…”

Section: Rare Epilepsiesmentioning

confidence: 52%

“…This is an important issue since it enhances the importance of astrocytes and microglia in this pathology and identifies these cells as the primary cause of the disease instead of the neurocentric idea that they are produced by initial neuronal problems. In addition, it has been demonstrated that anti-inflammatory interventions in animal models of epilepsy have both anti-epileptogenic and disease-modifying therapeutic effects [153,155]. However, it has also been stated that general anti-inflammatory drugs should not be used due to their wide central and peripheral effects [199] and that the anti-inflammatory strategy should be based on the signaling pathways that are altered in each epileptic condition.…”

Section: Oxidative Stress and Neuroinflammation As Therapeutic Targetmentioning

confidence: 99%

Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration

et al. 2020

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Oxidative stress is an imbalance between production and accumulation of oxygen reactive species and/or reactive nitrogen species in cells and tissues, and the capacity of detoxifying these products, using enzymatic and non-enzymatic components, such as glutathione. Oxidative stress plays roles in several pathological processes in the nervous system, such as neurotoxicity, neuroinflammation, ischemic stroke, and neurodegeneration. The concepts of oxidative stress and rare diseases were formulated in the eighties, and since then, the link between them has not stopped growing. The present review aims to expand knowledge in the pathological processes associated with oxidative stress underlying some groups of rare diseases: Friedreich's ataxia, diseases with neurodegeneration with brain iron accumulation, Charcot-Marie-Tooth as an example of rare neuromuscular disorders, inherited retinal dystrophies, progressive myoclonus epilepsies, and pediatric drug-resistant epilepsies. Despite the discrimination between cause and effect may not be easy on many occasions, all these conditions are Mendelian rare diseases that share oxidative stress as a common factor, and this may represent a potential target for therapies.

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Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

Cited by 71 publications

References 167 publications

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

Decreased expression of Rev-Erbα in the epileptic foci of temporal lobe epilepsy and activation of Rev-Erbα have anti-inflammatory and neuroprotective effects in the pilocarpine model

Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration

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