Transient increase of interleukin-1β after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling

Feng, Bo; Tang, Yangshun; Chen, Bin; Xu, Cenglin; Wang, Yi; Dai, Yunjian; Wu, Dang; Zhu, Junmin; Wang, Shuang; Zhou, Yifeng; Shi, Liyun; Hu, Weiwei; Zhang, Xia; Chen, Zhong

doi:10.1038/srep21931

Cited by 58 publications

(57 citation statements)

References 55 publications

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“…anti-epileptogenic effects were lost when administration was delayed to 20 min after head trauma [109]. However, a single dose of SR141716A (1 and 10 mg/kg, i.p) administered 7 days after the induction of febrile seizures in immature (P8) rats attenuated the maximal electrical shock-induced seizures stage [111]. SR141716A appears to limit hyperexcitability and epileptogenesis by inhibiting the long-term postsynaptic mGluR5 receptor overexpression and activating the dynorphin-KOR system [110].…”

Section: Resultsmentioning

confidence: 99%

Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection

Rosenberg

Patra

Whalley

2017

Epilepsy & Behavior

162

139

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The isolation and identification of the discrete plant cannabinoids in marijuana revived interest in analyzing historical therapeutic claims made for cannabis in clinical case studies and anecdotes. In particular, sources as old as the 11th and 15th centuries claimed efficacy for crude marijuana extracts in the treatment of convulsive disorders, prompting a particularly active area of preclinical research into the therapeutic potential of plant cannabinoids in epilepsy. Since that time, a large body of literature has accumulated describing the effects of several of the >100 individual plant cannabinoids in preclinical models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. We surveyed the literature for relevant reports of such plant cannabinoid effects and critically reviewed their findings. We found that acute CB1R agonism in simple models of acute seizures in rodents typically produces anti-convulsant effects whereas CB1R antagonists exert converse effects in the same models. However, when the effects of such ligands are examined in more complex models of epilepsy, epileptogenesis and neuroprotection, a less simplistic narrative emerges. Here, the complex interactions between (i) brain regions involved in a given model, (ii) relative contributions of endocannabinoid signaling to modulation of synaptic transmission in such areas, (iii) multi-target effects, (iv) cannabinoid type 1 and type 2 receptor signaling interactions and, (v) timing, (vi) duration and (vii) localization of ligand administration suggest that there is both anti-epileptic therapeutic potential and a pro-epileptic risk in up- and down-regulation of endocannabinoid signaling in the central nervous system. Factors such receptor desensitization and specific pharmacology of ligands used (e.g. full vs partial agonists and neutral antagonists vs inverse agonists) also appear to play an important role in the effects reported. Furthermore, the effects of several plant cannabinoids, most notably cannabidiol (CBD) and cannabidavarin (CBDV), in models of seizures, epilepsy, epileptogenesis, and neuroprotection are less ambiguous, and consistent with reports of therapeutically beneficial effects of these compounds in clinical studies. However, continued paucity of firm information regarding the therapeutic molecular mechanism of CBD/CBDV highlights the continued need for research in this area in order to identify as yet under-exploited targets for drug development and raise our understanding of treatment-resistant epilepsies. The recent reporting of positive results for cannabidiol treatment in two Phase III clinical trials in treatment-resistant epilepsies provides pivotal evidence of clinical efficacy for one plant cannabinoid in epilepsy. Moreover, risks and/or benefits associated with the use of unlicensed Δ9-THC containing marijuana extracts in pediatric epilepsies remain poorly understood. Therefore, in light of these paradigm-changing clinical events, the present review's findings aim to drive future drug development ...

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Section: Resultsmentioning

confidence: 99%

Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection

Rosenberg

Patra

Whalley

2017

Epilepsy & Behavior

162

139

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“…Expression of IL‐1R1 was increased in peripheral blood mononuclear cells of patients with schizophrenia compared to healthy controls . The IL‐1β‐induced activation of IL‐1R1 was found at the basis of pathological epileptic seizure susceptibility . The aspirin‐exacerbated respiratory disease is based on the decreased expression of IL‐1R1 and consequent decrease of the IL‐1β effects of PGE 2 induction .…”

Section: Focus On the Il‐1r Familymentioning

confidence: 99%

“…144 The IL-1β-induced activation of IL-1R1 was found at the basis of pathological epileptic seizure susceptibility. 145 The aspirin-exacerbated respiratory disease is based on the decreased expression of IL-1R1 and consequent decrease of the IL-1β effects of PGE 2 induction. 146 Increased levels of circulating sIL-1R1…”

Section: Mutations Known In Diseasesmentioning

confidence: 99%

The family of the interleukin‐1 receptors

Boraschi

Italiani

Weil

et al. 2017

Immunological Reviews

264

225

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The extracellular forms of the IL-1 cytokines are active through binding to specific receptors on the surface of target cells. IL-1 ligands bind to the extracellular portion of their ligand-binding receptor chain. For signaling to take place, a non-binding accessory chain is recruited into a heterotrimeric complex. The intracellular approximation of the Toll-IL-1-receptor (TIR) domains of the 2 receptor chains is the event that initiates signaling. The family of IL-1 receptors (IL-1R) includes 10 structurally related members, and the distantly related soluble protein IL-18BP that acts as inhibitor of the cytokine IL-18. Over the years the receptors of the IL-1 family have been known with many different names, with significant confusion. Thus, we will use here a recently proposed unifying nomenclature. The family includes several ligand-binding chains (IL-1R1, IL-1R2, IL-1R4, IL-1R5, and IL-1R6), 2 types of accessory chains (IL-1R3, IL-1R7), molecules that act as inhibitors of signaling (IL-1R2, IL-1R8, IL-18BP), and 2 orphan receptors (IL-1R9, IL-1R10). In this review, we will examine how the receptors of the IL-1 family regulate the inflammatory and anti-inflammatory functions of the IL-1 cytokines and are, more at large, involved in modulating defensive and pathological innate immunity and inflammation. Regulation of the IL-1/IL-1R system in the brain will be also described, as an example of the peculiarities of organ-specific modulation of inflammation.

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“…Day of birth was considered as postnatal day 0 (P0). Experimental FSs were induced as we previously described in rat pups on P10 . Briefly, the body temperature of the pups was raised in a chamber with an ambient temperature of 42‐44°C.…”

Section: Methodsmentioning

confidence: 99%

“…Experimental FSs were induced as we previously described in rat pups on P10. 9,13,14 Briefly, the body temperature of the pups was raised in a chamber with an ambient temperature of 42-44°C. Core temperature was measured at baseline (34.1 ± 0.7°C) and seizure onset (40.3 ± 0.7°C).…”

Section: Generation Of Experimental Complex Fssmentioning

confidence: 99%

Prolonged febrile seizures induce inheritable memory deficits in rats through DNA methylation

Dai

Feng

et al. 2019

CNS Neurosci Ther

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Summary Aims Febrile seizures (FSs) are the most common types of seizures in young children. However, little is known whether the memory deficits induced by early‐life FSs could transmit across generations or not. Methods The memory functions of different generations of FS rats were behaviorally evaluated by morris water maze, inhibitory avoidance task, and contextual fear conditioning task. Meanwhile, molecular biology and pharmacological methods were used to investigate the role of DNA methylation in transgenerational transmission of memory defects. Results Prolonged FSs in infant rats resulted in memory deficits in adult and transgenerationally transmitted to next generation, which was mainly through mothers. For these two generations, DNA methyltransferase (DNMT) 1 was upregulated, leading to transcriptional inhibition of the synaptic plasticity protein reelin but not the memory suppressor protein phosphatase 1. DNMT inhibitors prevented the high expression of DNMT1 and hypermethylation of reelin gene and reversed the transgenerationally memory deficits. In addition, enriched environment in juvenile rats rescued memory deficits induced by prolonged FSs. Conclusions Our study demonstrated early experience of prolonged FSs led to memory deficits in adult rats and their unaffected offspring, which involved epigenetic mechanisms, suggesting early environmental experiences had a significant impact on the transgenerational transmission of neurological diseases.

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Transient increase of interleukin-1β after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling

Cited by 58 publications

References 55 publications

Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection

Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection

The family of the interleukin‐1 receptors

Prolonged febrile seizures induce inheritable memory deficits in rats through DNA methylation

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