Alterations in the α<sub>2</sub>δ ligand, thrombospondin‐1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies

Santolini, Ines; Celli, Roberta; Cannella, Milena; Imbriglio, Tiziana; Guiducci, Michela; Parisi, Pasquale; Schubert, Julian; Iacomino, Michele; Zara, Federico; Lerche, Holger; Moyanova, S; Ngomba, Richard Teke; Luijtelaar, Gilles van; Battaglia, Giuseppe; Bruno, Valeria; Striano, Pasquale; Nicoletti, Ferdinando

doi:10.1111/epi.13898

Cited by 9 publications

(7 citation statements)

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“…CACNA2D2 is an important epilepsy-related calcium channel protein involved in small molecule ligand interactions as well as neuronal cell death pathways [ 30 ] VWF is involved in inflammation, seizures, neurodegeneration, and blood brain barrier permeability [ 34 , 35 ]. Thrombospondin-1 (THBS1) and DNA topoisomerase 3-beta-1 (TOP3B), proteins reported to be associated with various forms of epilepsy [ 31 , 33 , 55 ], were also over-represented in SCG patients compared with IE [ 31 , 33 , 55 ]. Other notable findings included higher observation in the IE group compard to the SCG group of SLIT2 (Slit Guidance Ligand 2 protein), an extracellular matrix protein and member of the SLIT family of proteins which has a role(s) in the blood brain barrier (BBB) integrity [ 37 , 56 ] The mitochondrial protein MT-ND1 with epilepsy background was also found to be observed more in the IE group compared to the SCG group (40).…”

Section: Discussionmentioning

confidence: 99%

“…A PubMed/Medline literature search showed 53% of these differentially expressed proteins were related to neurological function, 36% to immune/inflammation, and 19% to seizures. Notable epilepsy/seizure related proteins (shaded cells in Table 3) include CACNA2D2 [30], THBS1 [31], VLDLR [30,32], THBS1 [31], VLDLR [32], TOP3B [33], VWF [34,35], KIF1A [36], SLIT2 [37], MT-ND1 [38], EPHB2 [39], OCA2 [40], AKAP11 [41], ADAM11 [42], MAOB [43], and VPS13D [44].…”

Section: Plos Onementioning

confidence: 99%

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Distinguishing patients with idiopathic epilepsy from solitary cysticercus granuloma epilepsy and biochemical phenotype assessment using a serum biomolecule profiling platform

et al. 2020

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A major source of epilepsy is Neurocysticercosis (NCC), caused by Taenia solium infection. Solitary cysticercus granuloma (SCG), a subgroup of NCC induced epilepsy, is the most common form of NCC in India. Current diagnostic criteria for SCG epilepsy require brain imaging which may not be available in communities where the disease is endemic. Identification of serum changes and potential biomolecules that could distinguish SCG epilepsy from idiopathic generalized epilepsy (IE), without the initial need for imaging, could assist in disease identification, understanding, and treatment. The objective here was to investigate, using mass spectrometry (MS), sera biomolecule differences between patients with SCG epilepsy or IE to help distinguish these disorders based on physiological differences, to understand underlying phenotypes and mechanisms, and to lay ground work for future therapeutic and biomarker analyses. Sera were obtained from patients with SCG or IE (N = 29 each group). Serum mass peak profiling was performed with electrospray ionization (ESI) MS, and mass peak area means in the two groups were compared using leave one [serum sample] out cross validation (LOOCV). Serum LOOCV analysis identified significant differences between SCG and IE patient groups (p = 10 −20), which became non-significant (p = 0.074) when the samples were randomly allocated to the groups and reanalyzed. Tandem MS/MS peptide analysis of serum mass peaks from SCG or IE patients was performed to help identify potential peptide/protein biochemical and phenotypic changes involving these two forms of epilepsy. Bioinformatic analysis of these peptide/protein changes suggested neurological, inflammatory, seizure, blood brain barrier, cognition, ion channel, cell death, and behavior related biochemical systems were being altered in these disease states. This

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Section: Discussionmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Distinguishing patients with idiopathic epilepsy from solitary cysticercus granuloma epilepsy and biochemical phenotype assessment using a serum biomolecule profiling platform

et al. 2020

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“…The dentate gyrus of rats showed impaired paired pulse suppression and excitation ratio, and increased VGLUT-1 (Vesicular Glutamate Transporter 1) immunoreactivity 10–12 weeks after FSs ( Kwak et al, 2008 )). Due to the importance of VGLUTs in maintaining low extracellular glutamate concentrations and their association with epilepsy syndromes ( van der Hel et al, 2009 ; Santolini et al, 2017 ), it is highly recommended to conduct more research to discover more drug targets.…”

Section: Possible Mechanisms For Long-term Neurodevelopmental Outcome...mentioning

confidence: 99%

The long-term neurodevelopmental outcomes of febrile seizures and underlying mechanisms

You

Chen

2023

Front. Cell Dev. Biol.

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Febrile seizures (FSs) are convulsions caused by a sudden increase in body temperature during a fever. FSs are one of the commonest presentations in young children, occurring in up to 4% of children between the ages of about 6 months and 5 years old. FSs not only endanger children’s health, cause panic and anxiety to families, but also have many adverse consequences. Both clinical and animal studies show that FSs have detrimental effects on neurodevelopment, that cause attention deficit hyperactivity disorder (ADHD), increased susceptibility to epilepsy, hippocampal sclerosis and cognitive decline during adulthood. However, the mechanisms of FSs in developmental abnormalities and disease occurrence during adulthood have not been determined. This article provides an overview of the association of FSs with neurodevelopmental outcomes, outlining both the underlying mechanisms and the possible appropriate clinical biomarkers, from histological changes to cellular molecular mechanisms. The hippocampus is the brain region most significantly altered after FSs, but the motor cortex and subcortical white matter may also be involved in the development disorders induced by FSs. The occurrence of multiple diseases after FSs may share common mechanisms, and the long-term role of inflammation and γ-aminobutyric acid (GABA) system are currently well studied.

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“…In addition, double mutant zi/zi, tm/tm rats, which spontaneously develop absence seizures after 6 weeks of age, show a low expression of the synaptic vesicle proteins, SV2A and synaptotagmin-1 [ 96 ]. We have found a selective reduction of the transcript encoding for TSP-1 in the ventrobasal thalamus of presymptomatic and symptomatic WAG/Rij rats [ 97 ], which model human absence epilepsy [ 98 , 99 ].…”

Section: Potential Explanations For the Ambiguous Role Of The α2δ Submentioning

confidence: 99%

The α2δ Subunit and Absence Epilepsy: Beyond Calcium Channels?

Celli

Santolini

Guiducci

et al. 2017

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Background: Spike-wave discharges, underlying absence seizures, are generated within a cortico-thalamo-cortical network that involves the somatosensory cortex, the reticular thalamic nucleus, and the ventrobasal thalamic nuclei. Activation of T-type voltage-sensitive calcium channels (VSCCs) contributes to the pathological oscillatory activity of this network, and some of the first-line drugs used in the treatment of absence epilepsy inhibit T-type calcium channels. The α2δ subunit is a component of high voltage-activated VSCCs (i.e., L-, N-, P/Q-, and R channels) and studies carried out in heterologous expression systems suggest that it may also associate with T channels. The α2δ subunit is also targeted by thrombospondins, which regulate synaptogenesis in the central nervous system.Objective:To discuss the potential role for the thrombospondin/α2δ axis in the pathophysiology of absence epilepsy.Methods:We searched PubMed articles for the terms “absence epilepsy”, “T-type voltage-sensitive calcium channels”, “α2δ subunit”, “ducky mice”, “pregabalin”, “gabapentin”, “thrombospondins”, and included papers focusing this Review's scope.Results:We moved from the evidence that mice lacking the α2δ-2 subunit show absence seizures and α2δ ligands (gabapentin and pregabalin) are detrimental in the treatment of absence epilepsy. This suggests that α2δ may be protective against absence epilepsy via a mechanism that does not involve T channels. We discuss the interaction between thrombospondins and α2δ and its potential relevance in the regulation of excitatory synaptic formation in the cortico-thalamo-cortical network.Conclusion:We speculate on the possibility that the thrombospondin/α2δ axis is critical for the correct functioning of the cortico-thalamo-cortical network, and that abnormalities in this axis may play a role in the pathophysiology of absence epilepsy.

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Alterations in the α₂δ ligand, thrombospondin‐1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies

Abstract: These findings suggest that thrombospondin-1 may have a role in the pathogenesis of IGE/GGEs.

Cited by 9 publications

References 43 publications

Distinguishing patients with idiopathic epilepsy from solitary cysticercus granuloma epilepsy and biochemical phenotype assessment using a serum biomolecule profiling platform

Distinguishing patients with idiopathic epilepsy from solitary cysticercus granuloma epilepsy and biochemical phenotype assessment using a serum biomolecule profiling platform

The long-term neurodevelopmental outcomes of febrile seizures and underlying mechanisms

The α2δ Subunit and Absence Epilepsy: Beyond Calcium Channels?

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Alterations in the α2δ ligand, thrombospondin‐1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies

Abstract: These findings suggest that thrombospondin-1 may have a role in the pathogenesis of IGE/GGEs.

Cited by 9 publications

References 43 publications

Distinguishing patients with idiopathic epilepsy from solitary cysticercus granuloma epilepsy and biochemical phenotype assessment using a serum biomolecule profiling platform

Distinguishing patients with idiopathic epilepsy from solitary cysticercus granuloma epilepsy and biochemical phenotype assessment using a serum biomolecule profiling platform

The long-term neurodevelopmental outcomes of febrile seizures and underlying mechanisms

The α2δ Subunit and Absence Epilepsy: Beyond Calcium Channels?

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Product

Resources

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Alterations in the α₂δ ligand, thrombospondin‐1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies