Seizure activity triggers tau hyperphosphorylation and amyloidogenic pathways

Epilepsia, Journal Year: 2022, Volume and Issue: 63(4), P. 919 - 935

Published: Feb. 28, 2022

Abstract Objective Although epilepsies and neurodegenerative disorders show pathophysiological similarities, their direct functional associations are unclear. Here, we tested the hypothesis that experimental seizures can induce tau hyperphosphorylation amyloidogenic modifications over time, with intersections neuroinflammation. Methods We used a model of mesial temporal lobe epilepsy (MTLE) where unilateral intrahippocampal injection kainic acid (KA) in C57BL/6 mice elicits epileptogenesis spontaneous focal seizures. generalized status epilepticus (SE) obtained by intraperitoneal KA mice. performed analyses cross‐comparisons according to schedule 72 h, 1 week, 8 weeks after injection. Results In MTLE, AT100, PHF1, CP13 during (72 h–1 week) long‐term (8 weeks) ipsilateral hippocampi, epileptogenic zone. These pathological extended contralateral hippocampus, seizure propagating zone no histological lesion or sclerosis. Two kinases, Cdk5 GSK3β, implicated phosphorylation tau, were activated. this MTLE model, induction pathway (APP, C99, BACE1) was prominent long‐lasting Alzheimer's disease (AD)‐relevant markers, established progression recurrence, reciprocated an enduring glial (GFAP, Iba1) inflammation inadequate activation endogenous, anti‐inflammatory, glucocorticoid receptor system. By contrast, SE episode provoked predominantly transient markers along resolving inflammation. Finally, identified overlapping profiles hippocampal comparing J20 mice, latter relevant AD. Significance prompt persistent varying hippocampus. AD‐relevant molecular trajectory intertwines neuroinflammation, spatiotemporally involving nonlesional zones.

Language: Английский

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Role of Impaired Astrocyte Gap Junction Coupling in Epileptogenesis

Cells, Journal Year: 2023, Volume and Issue: 12(12), P. 1669 - 1669

Published: June 20, 2023

The gap-junction-coupled astroglial network plays a central role in the regulation of neuronal activity and synchronisation, but its involvement pathogenesis diseases is not yet understood. Here, we present current state knowledge about impact impaired glial coupling development progression epilepsy discuss whether astrocytes represent alternative therapeutic targets. We focus mainly on temporal lobe (TLE), which most common form adults characterised by high therapy resistance. Functional data from TLE patients corresponding experimental models point to complete loss astrocytic coupling, preservation gap junction forming proteins connexin43 connexin30 hippocampal sclerosis. Several studies further indicate that astrocyte uncoupling causal event initiation TLE, as it occurs very early epileptogenesis, clearly preceding dysfunctional changes neurons. However, more research needed fully understand channels develop safe effective strategies targeting astrocytes.

Language: Английский

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PM2.5 exposure exacerbates seizure symptoms and cognitive dysfunction by disrupting iron metabolism and the Nrf2-mediated ferroptosis pathway

The Science of The Total Environment, Journal Year: 2023, Volume and Issue: 910, P. 168578 - 168578

Published: Nov. 18, 2023

Language: Английский

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Seizure progression is slowed by enhancing neurosteroid availability in the brain of epileptic rats

Epilepsia, Journal Year: 2024, Volume and Issue: 65(3)

Published: Jan. 20, 2024

Abstract Trilostane is a 3β‐hydroxysteroid dehydrogenase/Δ 5‐4 isomerase inhibitor able to produce manyfold increase in brain levels of various neurosteroids, including allopregnanolone. We previously found that treatment with trilostane can slow down epileptogenesis the kainic acid (KA) model temporal lobe epilepsy. It unknown whether may have similar effect on progression epilepsy severity, as observed KA‐treated rats. Consequently, we investigated effects (50 mg/kg/day, 1 week) epileptic rats, given 64 days after KA administration. Seizures were monitored by video‐electrocorticographic recordings before and during or vehicle (sesame oil), neurosteroid measured serum cerebral tissue using liquid chromatography–electrospray tandem mass spectrometry treatment. Pregnenolone sulfate, pregnenolone, progesterone, 5α‐dihydroprogesterone, allopregnanolone peripheral massively increased trilostane. With only exception hippocampal pregnenolone other neurosteroids augmented both neocortex hippocampus. Only pregnanolone not upregulated As expected, significant seizure occurrence was rats receiving vehicle, but group. This suggests availability produced disease‐modifying

Language: Английский

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Epilepsy and its neurobehavioral comorbidities: Insights gained from animal models

Epilepsia, Journal Year: 2022, Volume and Issue: 64(1), P. 54 - 91

Published: Oct. 5, 2022

It is well established that epilepsy associated with numerous neurobehavioral comorbidities, a bidirectional relationship; people have an increased incidence of depression, anxiety, learning and memory difficulties, other psychosocial challenges, the occurrence higher in individuals those comorbidities. Although cause-and-effect relationship uncertain, fuller understanding mechanisms comorbidities within epilepsies could lead to improved therapeutics. Here, we review recent data on its discussing mainly rodent models, which been studied most extensively, emphasize clinically relevant information can be gained from preclinical models. Furthermore, explore potential factors may confound interpretation emerging animal such as specific seizure induction method (e.g., chemical, electrical, traumatic, genetic), role species strain, environmental laboratory environment, handling, epigenetics), behavioral assays are chosen evaluate various aspects neural behavior cognition. Overall, interplay between undoubtedly multifactorial, involving brain structural changes, network-level differences, molecular signaling abnormalities, factors. Animal models poised help dissect shared pathophysiological mechanisms, neurological sequelae, biomarkers

Language: Английский

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Seizure-induced strengthening of a recurrent excitatory circuit in the dentate gyrus is proconvulsant

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(32)

Published: Aug. 5, 2022

Epilepsy is a devastating brain disorder for which effective treatments are very limited. There growing interest in early intervention, requires better mechanistic understanding of the stages this disorder. While diverse insults can lead to epileptic activity, common cellular mechanism relies on uncontrolled recurrent excitatory activity. In dentate gyrus, mossy cells (MCs) project extensively onto granule (GCs) throughout hippocampus, thus establishing MC-GC-MC loop. MCs implicated temporal lobe epilepsy, form but their role during initial seizures (i.e., before characteristic MC loss that occurs late stages) unclear. Here, we show acutely induced with an intraperitoneal kainic acid (KA) injection adult mice, well-established model leads experimental not only increased and GC activity vivo also triggered brain-derived neurotrophic factor (BDNF)-dependent long-term potentiation (LTP) at MC-GC synapses. Moreover, induction LTP using MC-selective optogenetic stimulation worsened KA-induced seizures. Conversely,

Language: Английский

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Sleep, oscillations, and epilepsy

Epilepsia, Journal Year: 2023, Volume and Issue: 64(S3)

Published: May 25, 2023

Abstract Sleep and wake are defined through physiological behavioral criteria can be typically separated into non‐rapid eye movement (NREM) sleep stages N1, N2, N3, rapid (REM) sleep, wake. states not homogenous in time. Their properties vary during the night day cycle. Given that brain activity changes as a function of NREM, REM, cycle, seizures more likely to occur or at specific time? More generally, what is relationship between sleep–wake cycles epilepsy? We will review examples from clinical data results experimental models, focusing on diversity heterogeneity these relationships. use top‐down approach, starting with general architecture followed by oscillatory activities, ending ionic correlates selected for illustrative purposes, respect interictal spikes. The picture emerges complexity; disruption pathological epileptic activities emerge reorganized circuits. That different circuit alterations across patients models may explain why timing cycle patient‐specific.

Language: Английский

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Anti-seizure effects of JNJ-54175446 in the intra-amygdala kainic acid model of drug-resistant temporal lobe epilepsy in mice

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 8, 2024

There remains a need for new drug targets treatment-resistant temporal lobe epilepsy. The ATP-gated P2X7 receptor coordinates neuroinflammatory responses to tissue injury. Previous studies in mice reported that the antagonist JNJ-47965567 suppressed spontaneous seizures intraamygdala kainic acid model of epilepsy and reduced attendant gliosis hippocampus. drug-resistance profile this is not fully characterised, however, newer antagonists with superior pharmacokinetic profiles have recently entered clinical trials. Using telemetry-based continuous EEG recordings mice, we demonstrate recurrent are refractory common anti-seizure medicine levetiracetam. In contrast, once-daily dosing JNJ-54175446 (30 mg/kg, intraperitoneal) resulted significant reduction which lasted several days after end administration. combination immunohistochemistry ex vivo radiotracer assay, find JNJ-54175446-treated at display astrogliosis altered microglia process morphology within ipsilateral CA3 subfield hippocampus, but no difference surface expression. present study extends characterisation provides further evidence targeting may therapeutic applications treatment

Language: Английский

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Machine learning-based high-frequency neuronal spike reconstruction from low-frequency and low-sampling-rate recordings

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 20, 2024

Language: Английский

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Neferine, an Alkaloid from Lotus Seed Embryos, Exerts Antiseizure and Neuroprotective Effects in a Kainic Acid-Induced Seizure Model in Rats

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(8), P. 4130 - 4130

Published: April 8, 2022

Current anti-seizure drugs fail to control approximately 30% of epilepsies. Therefore, there is a need develop more effective drugs, and medicinal plants provide an attractive source for new compounds. This study aimed evaluate the possible neuroprotective effects neferine, alkaloid from lotus seed embryos Nelumbo nucifera, in kainic acid (KA)-induced seizure rat model its underlying mechanisms. Rats were intraperitoneally (i.p.) administrated neferine (10 50 mg/kg) 30 min before KA injection (15 mg/kg, i.p.). Neferine pretreatment increased latency reduced scores, prevented glutamate elevation neuronal loss, presynaptic protein synaptophysin postsynaptic density 95 expression hippocampi rats with KA. also decreased glial cell activation proinflammatory cytokine (interleukin-1β, interleukin-6, tumor necrosis factor-α) In addition, NOD-like receptor 3 (NLRP3) inflammasome, caspase-1, interleukin-18 levels pretreated neferine. These results indicated that severity, exerted effects, ameliorated neuroinflammation KA-treated rats, possibly by inhibiting NLRP3 inflammasome decreasing inflammatory secretion. Our findings highlight potential as therapeutic option treatment epilepsy.

Language: Английский

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