The IL-1β system in epilepsy-associated malformations of cortical development

Ravizza, Teresa; Boer, Karin; Redeker, Sandra; Spliet, Wim G.M.; Rijen, Peter C. van; Troost, Dirk; Vezzani, Annamaria; Aronica, Eleonora

doi:10.1016/j.nbd.2006.06.003

Cited by 248 publications

(199 citation statements)

References 96 publications

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“…The activation of the IL-1β system in neurons and glia during experimental seizures is corroborated by clinical observations showing overexpression of IL-1β and IL-1R1 and induction of ICE/caspase-1 in surgically resected epileptic tissue from individuals with drugresistant seizures [10,18,21,22]. Notably, the expression of IL-1β measured in human epileptogenic tissue positively correlates with the frequency of seizures in the same patients before surgery, highlighting a possible link between the brain level of this cytokine and seizure recurrence [21].…”

Section: Discussionmentioning

confidence: 75%

“…Notably, the expression of IL-1β measured in human epileptogenic tissue positively correlates with the frequency of seizures in the same patients before surgery, highlighting a possible link between the brain level of this cytokine and seizure recurrence [21].…”

Section: Discussionmentioning

confidence: 95%

“…There is evidence of increased levels of IL-1β and IL-1R1, and ICE/caspase-1 activation [18] in surgically resected epileptogenic tissue from pharmaco resistant patients with temporal lobe epilepsy (TLE) or malformations of cortical development [10,[19][20][21][22],suggesting that the IL-1β/IL-1R1 axis is activated in human epilepsy as in experimental models.…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

et al. 2011

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Summary: Experimental evidence and clinical observations indicate that brain inflammation is an important factor in epilepsy. In particular, induction of interleukin-converting enzyme (ICE)/caspase-1 and activation of interleukin (IL)-1β/ IL-1 receptor type 1 axis both occur in human epilepsy, and contribute to experimentally induced acute seizures. In this study, the anticonvulsant activity of VX-765 (a selective ICE/ caspase-1 inhibitor) was examined in a mouse model of chronic epilepsy with spontaneous recurrent epileptic activity refractory to some common anticonvulsant drugs. Moreover, the effects of this drug were studied in one acute model of seizures in mice, previously shown to involve activation of ICE/caspase-1. Quantitative analysis of electroencephalogram activity was done in mice exposed to acute seizures or those developing chronic epileptic activity after status epilepticus to assess the anticonvulsant effects of systemic administration of VX-765.Histological and immunohistochemical analysis of brain tissue was carried out at the end of pharmacological experiments in epileptic mice to evaluate neuropathology, glia activation and IL-1β expression, and the effect of treatment. Repeated systemic administration of VX-765 significantly reduced chronic epileptic activity in mice in a dose-dependent fashion (12.5-200 mg/kg). This effect was observed at doses ≥50 mg/ kg, and was reversible with discontinuation of the drug. Maximal drug effect was associated with inhibition of IL-1β synthesis in activated astrocytes. The same dose regimen of VX-765 also reduced acute seizures in mice and delayed their onset time. These results support a new target system for anticonvulsant pharmacological intervention to control epileptic activity that does not respond to some common anticonvulsant drugs.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

et al. 2011

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“…As discussed above, the activation of inflammatory pathways and the consequent release of inflammatory molecules alter neural network excitability, inducing various mechanisms, with either a direct or indirect impact on neuronal functions (for reviews see [71][72][73][74]). Activation of cells of the microglia/macrophage lineage and astrocytes and concomitant induction of various inflammatory pathways have also been observed in FCD with activation of both innate and the adaptive immune response [77,120,172,173]. In a cohort of FCD II patients, the density of activated microglial cells correlated significantly with the duration of epilepsy, as well as with the frequency of seizures prior to surgical resection [172].…”

Section: Epileptogenesismentioning

confidence: 97%

“…In particular, a prominent expression of components of the interleukin (IL)-1/Toll-like receptor (TLR) signaling and complement cascade has been observed in GNT [57,77]. Recent findings indicate a prominent upregulation of major histocompatibility complex class I (MHC-I) in neuronal cells as part of the immune response occurring in different epileptogenic glioneuronal lesions characterized by mTOR pathway activation (GG, FCD, and TSC; [76]).…”

Section: Epileptogenesismentioning

confidence: 99%

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

Aronica

Crino

2014

Neurotherapeutics

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Neuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator Protein

et al. 2015

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IMPORTANCE Neuroinflammation may play a role in epilepsy. Translocator protein 18 kDa (TSPO), a biomarker of neuroinflammation, is overexpressed on activated microglia and reactive astrocytes. A preliminary positron emission tomographic (PET) imaging study using carbon 11 ([ 11 C])-labeled PBR28 in patients with temporal lobe epilepsy (TLE) found increased TSPO ipsilateral to seizure foci. Full quantitation of TSPO in vivo is needed to detect widespread inflammation in the epileptic brain. OBJECTIVES To determine whether patients with TLE have widespread TSPO overexpression using [ 11 C]PBR28 PET imaging, and to replicate relative ipsilateral TSPO increases in patients with TLE using [ 11 C]PBR28 and another TSPO radioligand, [ 11 C]DPA-713. DESIGN, SETTING, AND PARTICIPANTS In a cohort study from March 2009 through September 2013 at the Clinical Epilepsy Section of the National Institute of Neurological Disorders and Stroke, participants underwent brain PET and a subset had concurrent arterial sampling. Twenty-three patients with TLE and 11 age-matched controls were scanned with [ 11 C]PBR28, and 8 patients and 7 controls were scanned with [ 11 C]DPA-713. Patients with TLE had unilateral temporal seizure foci based on ictal electroencephalography and structural magnetic resonance imaging. Participants with homozygous low-affinity TSPO binding were excluded. MAIN OUTCOMES AND MEASURESThe [ 11 C]PBR28 distribution volume (V T ) corrected for free fraction (f P ) was measured in patients with TLE and controls using FreeSurfer software and T1-weighted magnetic resonance imaging for anatomical localization of bilateral temporal and extratemporal regions. Side-to-side asymmetry in patients with TLE was calculated as the ratio of ipsilateral to contralateral [ 11 C]PBR28 and [ 11 C]DPA-713 standardized uptake values from temporal regions.RESULTS The [ 11 C]PBR28 V T to f p ratio was higher in patients with TLE than in controls for all ipsilateral temporal regions (27%-42%; P < .05) and in contralateral hippocampus, amygdala, and temporal pole (approximately 30%-32%; P < .05). Individually, 12 patients, 10 with mesial temporal sclerosis, had asymmetrically increased hippocampal [ 11 C]PBR28 uptake exceeding the 95% confidence interval of the controls. Binding of [ 11 C]PBR28 was increased significantly in thalamus. Relative [ 11 C]PBR28 and [ 11 C]DPA-713 uptakes were higher ipsilateral than contralateral to seizure foci in patients with TLE ([ 11 C]PBR28: 2%-6%; [ 11 C]DPA-713: 4%-9%). Asymmetry of [ 11 C]DPA-713 was greater than that of [ 11 C]PBR28 (F = 29.4; P = .001).CONCLUSIONS AND RELEVANCE Binding of TSPO is increased both ipsilateral and contralateral to seizure foci in patients with TLE, suggesting ongoing inflammation. Anti-inflammatory therapy may play a role in treating drug-resistant epilepsy.

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The IL-1β system in epilepsy-associated malformations of cortical development

Cited by 248 publications

References 96 publications

Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

Neuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator Protein

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