Role of Pyroptosis, a Pro-inflammatory Programmed Cell Death, in Epilepsy

Atabaki, Rabi; Khaleghzadeh‐Ahangar, Hossein; Esmaeili, Nardana; Mohseni‐Moghaddam, Parvaneh

doi:10.1007/s10571-022-01250-3

Cited by 23 publications

(6 citation statements)

References 92 publications

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“…The effect on the release of LDH was similar to that on the level of mRNA of apoptosis-related genes for caspase 3, BAX, and Bcl-xL [36]. Proinflammatory factors can induce apoptosis to protect cells [37], and the changes in the expression of IL-6 and TNF-α mRNA showed that DON may be involved in the induction of several inflammatory markers. DON has dual effects of immunosuppression and immune stimulation.…”

Section: Discussionmentioning

confidence: 56%

Deoxynivalenol Mycotoxin Inhibits Rabies Virus Replication In Vitro

Liu

Zhu

2023

IJMS

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Rabies is a highly fatal disease, and it is vital to find effective ways to manage and control infection. There is a need for new effective antiviral drugs that are particularly effective treatments for rabies. Deoxynivalenol (DON) is known mainly for its toxicity, but at the molecular level, it can inhibit RNA and DNA replication, and there is increasing evidence that different doses of DON have a positive effect on inhibiting virus replication. Based on this, we evaluated the effect of DON on inhibiting the rabies virus in vitro. The inhibitory effect of DON on rabies virus activity was dose- and time-dependent, and 0.25 μg/mL of DON could inhibit 99% of rabies virus activity within 24 h. Furthermore, DON could inhibit the adsorption, entry, replication, and release of rabies virus but could not inactivate the virus. The inhibitory effect of DON on rabies virus may be achieved by promoting apoptosis. Our study provides a new perspective for the study of anti-rabies virus and expands the direction of action of mycotoxins.

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Section: Discussionmentioning

confidence: 56%

Deoxynivalenol Mycotoxin Inhibits Rabies Virus Replication In Vitro

Liu

Zhu

2023

IJMS

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“… 26 The activation of inflammatory response might destroy the balance between glutamate and GABA, leading to the increase of excitability in the nervous system and seizure activity. 27 Here, we detected that the increase of pro‐inflammatory factors was related to the epilepsy severity, more pro‐inflammatory factors were found in the transgenic zebrafish showing more severe phenotype. The results suggested a positive correlation between inflammatory response and epileptic phenotype.…”

Section: Discussionmentioning

confidence: 78%

“…Proinflammatory factors, such as IL‐1β, IL‐6, TNF‐α, and TGF‐β, were reported to play important roles in epileptogenesis, 23–25 indicating that inflammatory response in the brain is a crucial mechanism in the pathophysiology of epilepsy 26 . The activation of inflammatory response might destroy the balance between glutamate and GABA, leading to the increase of excitability in the nervous system and seizure activity 27 . Here, we detected that the increase of pro‐inflammatory factors was related to the epilepsy severity, more pro‐inflammatory factors were found in the transgenic zebrafish showing more severe phenotype.…”

Section: Discussionmentioning

confidence: 99%

Differential inflammation responses determine the variable phenotypes of epilepsy induced by GABRG2 mutations

Sui,

Zhan,

et al. 2024

CNS Neurosci Ther

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ObjectiveTo explore the mechanism involved in variable phenotypes of epilepsy models induced by γ‐aminobutyric acid type A γ2 subunit (GABRG2) mutations.MethodsThe zebrafish carrying wild‐type (WT) GABRG2, mutant GABRG2(P282S), GABRG2(F343L) and GABRG2(I107T) were established by Tol2kit transgenesis system and Gateway method. Behavioral analysis of different transgenic zebrafish was performed with the DanioVision Video‐Track framework and the brain activity was analyzed by field potential recording with MD3000 Bio‐signal Acquisition and Processing System. The transcriptome analysis was applied to detect the underlying mechanisms of variable phenotypes caused by different GABRG2 mutations.ResultsThe established Tg(hGABRG2P282S) zebrafish showed hyperactivity and spontaneous seizures, which were more sensitive to chemical and physical epileptic stimulations. Traditional antiepileptic drugs, such as Clonazepam (CBZ) and valproic acid (VPA), could ameliorate the hyperactivity in Tg(hGABRG2P282S) zebrafish. The metabolic pathway was significantly changed in the brain transcriptome of Tg(hGABRG2P282S) zebrafish. In addition, the behavioral activity, production of pro‐inflammatory factors, and activation of the IL‐2 receptor signal pathway varied among the three mutant zebrafish lines.ConclusionWe successfully established transgenic zebrafish epileptic models expressing human mutant GABRG2(P282S), in which CBZ and VPA showed antiepileptic effects. Differential inflammatory responses, especially the SOCS/JAK/STAT signaling pathway, might be related to the phenotypes of genetic epilepsy induced by GABRG2 mutations. Further study will expand the pathological mechanisms of genetic epilepsies and provide a theoretical basis for searching for effective drug treatment.

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“…Studies have shown a link between epilepsy and pyroptosis. Classical pyroptosis mediated by NLRP3 inflammasome activation has been found to contribute to seizure development, and inhibiting the NLRP3 inflammasome can alleviate seizures [8], suggesting the involvement of pyroptosis in the pathophysiological mechanisms of epilepsy. Our previous transcriptome sequencing results showed that differentially expressed molecules in patients with epilepsy were mainly enriched in the pyroptosis pathway.…”

Section: Introductionmentioning

confidence: 99%

IRAK4 in the hippocampus increases susceptibility to seizures through NF-κB/NLRP3-mediated neuronal pyroptosis

Zhao,

张,

Cui

et al. 2024

Preprint

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Background Interleukin-1 receptor-associated kinase 4 (IRAK4) plays an important role in immune modulation in various central nervous system disorders. Previous studies have found that the IRAK4 pathway is involved in lead-induced cell pyroptosis. However, there is no report on the role of IRAK4 in epilepsy models and its involvement in regulating cell pyroptosis in epilepsy, both in animal and clinical studies. Method Firstly, we performed transcriptome sequencing, qPCR, and Western blot analysis on hippocampal tissues of refractory epilepsy patients to detect the mRNA and protein levels of IRAK4 and pyroptosis-related proteins. Secondly, we successfully established a Pentylenetetrazol (PTZ)-induced seizure mouse model. We conducted behavioral tests, electroencephalography (EEG), virus injection, and molecular biology experiments to investigate the role of IRAK4 in seizure activity regulation. Results IRAK4 is upregulated in the hippocampal lesions of epilepsy patients and in the hippocampus of PTZ-induced seizure mice. In PTZ mice, IRAK4 expression is observed in neurons. Knocking out IRAK4 in PTZ mice downregulates pyroptosis-related proteins and alleviates seizure activity. Conversely, overexpressing IRAK4 in naïve mice upregulates pyroptosis-related proteins and increases PTZ-induced neuronal abnormal discharges. PDTC can reverse the increased expression of pyroptosis-related proteins caused by PTZ. PF-06650833 can alleviate seizure activity and inhibit pyroptosis in PTZ-induced seizure mice. Conclusion In summary, we hypothesize that IRAK4 promotes the expression of pyroptosis-related proteins through the NF-κB/NLRP3 pathway, suggesting that IRAK4 may promote seizure activity by mediating pyroptosis. IRAK4 plays a crucial role in epilepsy and may serve as a potential therapeutic target for this neurological disorder.

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Role of Pyroptosis, a Pro-inflammatory Programmed Cell Death, in Epilepsy

Cited by 23 publications

References 92 publications

Deoxynivalenol Mycotoxin Inhibits Rabies Virus Replication In Vitro

Deoxynivalenol Mycotoxin Inhibits Rabies Virus Replication In Vitro

Differential inflammation responses determine the variable phenotypes of epilepsy induced by GABRG2 mutations

IRAK4 in the hippocampus increases susceptibility to seizures through NF-κB/NLRP3-mediated neuronal pyroptosis

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