Excitotoxicity, neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration: The role of vitamin E

Ambrogini, Patrizia; Torquato, Pierangelo; Bartolini, Desirée; Albertini, Maria Cristina; Lattanzi, Davide; Palma, Michael Di; Marinelli, Rita; Betti, Michele; Minelli, Andrea; Cuppini, Riccardo; Galli, Francesco

doi:10.1016/j.bbadis.2019.01.026

Cited by 121 publications

(82 citation statements)

References 206 publications

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“…Intrinsic neuronal hyperexcitability and glutamate-mediated excitotoxicity can cause imbalance in excitatory/inhibitory inputs in the epileptic brain. When these mechanisms are overwhelming, they induce neuronal death (necrosis, apoptosis, or autophagy) and further accentuate seizure activity ( Barker-Haliski and White 2015 ; Ambrogini et al. 2019 ; Mao et al.…”

Section: Emerging Role Of the Cytoskeleton In Seizure Activity In Thementioning

confidence: 99%

Postnatal Role of the Cytoskeleton in Adult Epileptogenesis

Gavrilovici

Jiang

Kiroski

et al. 2020

Cerebral Cortex Communications

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Mutations in cytoskeletal proteins can cause early infantile and childhood epilepsies by misplacing newly born neurons and altering neuronal connectivity. In the adult epileptic brain, cytoskeletal disruption is often viewed as being secondary to aberrant neuronal activity and/or death, and hence simply representing an epiphenomenon. Here, we review the emerging evidence collected in animal models and human studies implicating the cytoskeleton as a potential causative factor in adult epileptogenesis. Based on the emerging evidence, we propose that cytoskeletal disruption may be an important pathogenic mechanism in the mature epileptic brain.

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Section: Emerging Role Of the Cytoskeleton In Seizure Activity In Thementioning

confidence: 99%

Postnatal Role of the Cytoskeleton in Adult Epileptogenesis

Gavrilovici

Jiang

Kiroski

et al. 2020

Cerebral Cortex Communications

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“…3B), so retina and vitreous samples were collected from these mice at disease onset (P15), mid-stage (P30) and late-stage disease (P90 ; Table S4). Retina and vitreous samples for wild-type and Pde6ɑ D670G mice were trypsinized and underwent LC-MS/MS analysis (Table S5- 6). Notably there were fewer unique proteins in the Pde6ɑ D670G mouse retina at 90 days (484 ± 63 individual proteins) than 15 days (1,135 ± 55 individual proteins), suggesting a decrease in protein expression as neurodegeneration progresses (Table S7).…”

Section: Proteomic Analysis Of Pde6ɑ D670g Retina and Vitreous Identimentioning

confidence: 99%

“…They are typically characterized by abnormal proteostasis, where the cell is unable to maintain regulation of protein folding, translation, and degradation pathways. These defects in proteostasis lead to processes of cell death such as apoptosis and disrupted signaling mechanisms within the cell from oxidative stress, glutamate-mediated cytotoxicity, neuroinflammation, mitochondrial dysfunction, and increased endoplasmic reticulum (ER) stress [2][3][4][5][6][7]. However, the early factors involved in neuronal cell death are still not understood.…”

Section: Introductionmentioning

confidence: 99%

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Wert

Vélez

Vijayalakshmi

et al. 2019

Preprint

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One Sentence Summary: The study shows protein and metabolite pathways affected during neurodegeneration and that replenishing metabolites provides a neuroprotective effect on the retina. Abstract: 244Main Text: 9,039References: 83 AbstractNeurodegenerative diseases are debilitating, incurable disorders caused by progressive neuronal cell death.Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in retinal photoreceptor cell death and progresses to the loss of the entire neural retinal network. We previously found that proteomic analysis of the adjacent vitreous serves as way to indirectly biopsy the neural retina and identify changes in the retinal proteome. We therefore analyzed protein expression in liquid vitreous biopsies from autosomal recessive retinitis pigmentosa (arRP) patients with PDE6A mutations and arRP mice with Pde6ɑ mutations. Proteomic analysis of retina and vitreous samples identified molecular pathways affected at the onset of photoreceptor cell death. Based on affected molecular pathways, arRP mice were treated with a ketogenic diet or metabolites involved in fatty-acid synthesis, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle. Dietary supplementation of a single metabolite, ɑ-ketoglutarate, increased docosahexaeonic acid (DHA) levels, provided neuroprotection, and enhanced visual function in arRP mice. A ketogenic diet delayed photoreceptor cell loss, while vitamin B supplementation had a limited effect. Finally, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) revealed restoration of key metabolites that correlated with our proteomic findings: pyrimidine and purine metabolism (uridine, dihydrouridine, and thymidine), glutamine and glutamate (glutamine/glutamate conversion), and succinic and aconitic acid (TCA cycle). This study demonstrates that replenishing TCA cycle metabolites via oral supplementation prolongs vision and provides a neuroprotective effect on the photoreceptor cells and inner retinal network.

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“…Studies have also explored the mechanisms underlying neuronal injury, which could be a cause of epilepsy; rst, hypoxic-ischemic encephalopathy (HIE) initially affects various processes that potentially contribute to energy failure and loss of mitochondrial function, including brain edema, membrane depolarization, increased levels of neurotransmitter release and uptake inhibition, and increased levels of intracellular calcium (which can cause the initiation of further pathological cascades) [31]. Second, excitotoxic cellular injury occurring through excess activation of the four glutamate receptors (N-methyl-d-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid, kainate, and metabotropic glutamate receptors), which leads to several forms of cell death, is another possible seizure mechanism associated with HIE [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

Lin

Chou

Hong

2020

Preprint

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Background Drug-resistant epilepsy (DRE) affects 7–20% of children with epilepsy. Although some risk factors for DRE have been identified, the results have not been consistent. Moreover, data regarding the risk factors for epilepsy and its seizure outcome in the first 2 years of life are limited. Methods We analyzed data for children aged 0–2 years with epilepsy and neurodevelopmental disability (NDD) from January, 2013, through December, 2017. These patients were followed up to compared the risk of DRE in patients with genetic defect (genetic group) with that without genetic defect (nongenetic group). Additionally, we conducted a meta-analysis to identify the pooled prevalence of genetic factors in children with DRE Results A total of 96 patients were enrolled. A total of 68 patients were enrolled in the nongenetic group, whereas 28 patients were enrolled in the genetic group. The overall DRE risk in the genetic group was 6.5 times (95% confidence interval [CI], 2.15–19.6; p = 0.03) higher than that in the nongenetic group. Separately, a total of 1308 DRE patients were participated in the meta-analysis. The pooled prevalence of these patients with genetic factors was 22.8% (95% CI 17.4–29.3) Conclusions The genetic defect plays a crucial role in the development of DRE in younger children with epilepsy and NDD. The results can serve as a reference for further studies of epilepsy panel design and may also assist in the development of improved treatments and prevention strategies for DRE.

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Excitotoxicity, neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration: The role of vitamin E

Cited by 121 publications

References 206 publications

Postnatal Role of the Cytoskeleton in Adult Epileptogenesis

Postnatal Role of the Cytoskeleton in Adult Epileptogenesis

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

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