Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression

Binder, Devin K.; Boison, Detlev; Eid, Tore; Frankel, Wayne N.; Mingorance, Ana; Smith, Bret N.; Dacks, Penny A.; Whittemore, Vicky; Poduri, Annapurna

doi:10.1177/1535759719895274

Cited by 11 publications

(8 citation statements)

References 99 publications

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“…However, the issue of developing an optimal method for stimulating neurotrophic factors and the safety of their use as therapeutic agents at the organismic level remains open. Thus, a number of studies have shown that an increase in the concentration of neurotrophic factors can provoke the development of seizure activity and disrupt the development of the vertebrate nervous system [ 22 ]. It was found that the neurotrophic factor BDNF has an excitatory effect on neuron cultures and brain slices of animals.…”

Section: Discussionmentioning

confidence: 99%

“…Gene therapy based on the use of viral vectors is considered the most promising option for the clinical application of neurotrophic factors BDNF and GDNF [ 20 ]. In particular, viral vectors are actively used in the therapy of various neuronal disorders and can be directly transduced into cells secreting neurotrophic factors [ 21 , 22 ]. Modern vectors provide stable, long-term gene expression, have an extensive spectrum of tropism for various organs and tissues, and also exhibit relatively low pathogenicity [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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The Influence of Neurotrophic Factors BDNF and GDNF Overexpression on the Functional State of Mice and Their Adaptation to Audiogenic Seizures

et al. 2022

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The high prevalence of diagnosed cases of severe neurological disorders, a significant proportion of which are epilepsy, contributes to a high level of mortality and disability in the population. Neurotrophic factors BDNF and GNDF are considered promising agents aimed at increasing the central nervous system’s adaptive potential for the development of the epileptiform activity. Despite the pronounced neuroprotective and anticonvulsant potential, an appropriate way to stimulate these endogenous signaling molecules with minimal risk of side effects remains an open question. Herein, we assessed the safety of gene therapy using original adeno-associated viral constructs carrying the genes of neurotrophic factors BDNF and GDNF in the early postnatal period of development of experimental animals. The intraventricular injection of AAV-Syn-BDNF-eGFP and AAV-Syn-GDNF-eGFP viral constructs into newborn mice was found to provide persistent overexpression of target genes in the hippocampus and cerebral cortex in vivo for four weeks after injection. The application of viral constructs has a multidirectional effect on the weight and body length characteristics of mice in the early postnatal period; however, it ensures the animals’ resistance to the development of seizure activity under audiogenic stimulation in the late postnatal period and preserves basic behavioral reactions, emotional status, as well as the mnestic and cognitive abilities of mice after simulated stress. Our results demonstrated the safety of using the AAV-Syn-BDNF-eGFP and AAV-Syn-GDNF-eGFP viral constructs in vivo, which indicates the expediency of further testing the constructs as therapeutic anticonvulsants.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Influence of Neurotrophic Factors BDNF and GDNF Overexpression on the Functional State of Mice and Their Adaptation to Audiogenic Seizures

et al. 2022

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“…5 In general, ASM discovery and development are encouraged for orphan diseases (ie affecting <5/10 000 people in the general population), such as Dravet syndrome (DS). 6,7 This strategy has led to the discovery of fenfluramine (FA), a serotonergic drug, that successfully reduces seizures in DS patients. 8 This serotonergic drug is also under evaluation for other severe epilepsy syndromes, such as Lennox-Gastaut and Sunflower syndrome.…”

Section: Introductionmentioning

confidence: 99%

Serotonin receptors in epilepsy: Novel treatment targets?

Sourbron

Lagae

2022

Epilepsia Open

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Despite the availability of over 30 antiseizure medications (ASMs), there is no “one size fits it all,” so there is a continuing search for novel ASMs. There are divergent data demonstrating that modulation of distinct serotonin (5‐hydroxytryptamine, 5‐HT) receptors subtypes could be beneficial in the treatment of epilepsy and its comorbidities, whereas only a few ASM, such as fenfluramine (FA), act via 5‐HT. There are 14 different 5‐HT receptor subtypes, and most epilepsy studies focus on one or a few of these subtypes, using different animal models and different ligands. We reviewed the available evidence of each 5‐HT receptor subtype using MEDLINE up to July 2021. Our search included medical subject heading (MeSH) and free terms of each “5‐HT subtype” separately and its relation to “epilepsy or seizures.” Most research underlines the antiseizure activity of 5‐HT1A,1D,2A,2C,3 agonism and 5‐HT6 antagonism. Consistently, FA, which has recently been approved for the treatment of seizures in Dravet syndrome, is an agonist of 5‐HT1D,2A,2C receptors. Even though each study focused on a distinct seizure/epilepsy type and generalization of different findings could lead to false interpretations, we believe that the available preclinical and clinical studies emphasize the role of serotonergic modulation, especially stimulation, as a promising avenue in epilepsy treatment.

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“…It is now well-established that glial functions are commonly altered or disrupted in the process of epileptogenesis. Therefore, glial cells have come under recent focus as potential targets to promote homeostasis and functional recovery after a seizure or initiating epileptogenic event [14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Reactivity and increased proliferation of NG2 cells following central nervous system infection with Theiler’s murine encephalomyelitis virus

Bell

Wallis

Wilcox

2020

J Neuroinflammation

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Background Neuron-glial antigen 2 (NG2) cells are a glial cell type tiled throughout the gray and white matter of the central nervous system (CNS). NG2 cells are known for their ability to differentiate into oligodendrocytes and are commonly referred to as oligodendrocyte precursor cells. However, recent investigations have begun to identify additional functions of NG2 cells in CNS health and pathology. NG2 cells form physical and functional connections with neurons and other glial cell types throughout the CNS, allowing them to monitor and respond to the neural environment. Growing evidence indicates that NG2 cells become reactive under pathological conditions, though their specific roles are only beginning to be elucidated. While reactive microglia and astrocytes are well-established contributors to neuroinflammation and the development of epilepsy following CNS infection, the dynamics of NG2 cells remain unclear. Therefore, we investigated NG2 cell reactivity in a viral-induced mouse model of temporal lobe epilepsy. Methods C57BL6/J mice were injected intracortically with Theiler’s murine encephalomyelitis virus (TMEV) or PBS. Mice were graded twice daily for seizures between 3 and 7 days post-injection (dpi). At 4 and 14 dpi, brains were fixed and stained for NG2, the microglia/macrophage marker IBA1, and the proliferation marker Ki-67. Confocal z stacks were acquired in both the hippocampus and the overlying cortex. Total field areas stained by each cell marker and total field area of colocalized pixels between NG2 and Ki67 were compared between groups. Results Both NG2 cells and microglia/macrophages displayed increased immunoreactivity and reactive morphologies in the hippocampus of TMEV-injected mice. While increased immunoreactivity for IBA1 was also present in the cortex, there was no significant change in NG2 immunoreactivity in the cortex following TMEV infection. Colocalization analysis for NG2 and Ki-67 revealed a significant increase in overlap between NG2 and Ki-67 in the hippocampus of TMEV-injected mice at both time points, but no significant differences in cortex. Conclusions NG2 cells acquire a reactive phenotype and proliferate in response to TMEV infection. These results suggest that NG2 cells alter their function in response to viral encephalopathy, making them potential targets to prevent the development of epilepsy following viral infection.

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Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression

Cited by 11 publications

References 99 publications

The Influence of Neurotrophic Factors BDNF and GDNF Overexpression on the Functional State of Mice and Their Adaptation to Audiogenic Seizures

The Influence of Neurotrophic Factors BDNF and GDNF Overexpression on the Functional State of Mice and Their Adaptation to Audiogenic Seizures

Serotonin receptors in epilepsy: Novel treatment targets?

Reactivity and increased proliferation of NG2 cells following central nervous system infection with Theiler’s murine encephalomyelitis virus

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