Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures

Maroso, Mattia; Balosso, Silvia; Ravizza, Teresa; Liu, Jaron; Aronica, Eleonora; Iyer, Anand M.; Rossetti, Carlo; Molteni, Monica; Casalgrandi, Maura; Manfredi, Angelo A.; Bianchi, Marco E.; Vezzani, Annamaria

doi:10.1038/nm.2127

Cited by 816 publications

(962 citation statements)

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“…Mice were surgically implanted with an injection guide cannula and recording electrodes under deep Equithesin anesthesia and stereotaxic guidance [11,25]. Two Nichrome-insulated bipolar depth electrodes (60 μm OD; MOR Electric Heating Assoc.…”

Section: Mouse Model Of Acute Seizuresmentioning

confidence: 99%

“…Intrahippocampal injection of kainic acid in freely moving mice was done 7 days after surgery as previously described [11,25]. Kainic acid (7 ng in 0.5 μl; Sigma, Saint Louis, MO) was dissolved in 0.1 M phosphate-buffered solution (PBS, pH 7.4) and injected unilaterally in the dorsal hippocampus by using a needle protruding 2.0 mm from the bottom of the guide cannula.…”

Section: Mouse Model Of Acute Seizuresmentioning

confidence: 99%

“…Kainic acid (7 ng in 0.5 μl; Sigma, Saint Louis, MO) was dissolved in 0.1 M phosphate-buffered solution (PBS, pH 7.4) and injected unilaterally in the dorsal hippocampus by using a needle protruding 2.0 mm from the bottom of the guide cannula. This dose of kainic acid was proven to induce electroencephalographic (EEG) ictal episodes in the hippocampus in 100% of mice without mortality [11,25]. Selective cell loss in CA3 region of the injected hippocampus is observed 3 to 7 days after kainate injection [9,11,26].…”

Section: Mouse Model Of Acute Seizuresmentioning

confidence: 99%

“…EEG seizures induced by intrahippocampal injection of kainic acid in mice have been extensively described before [11,25,26]. Briefly, a 30-minute recording was done before kainic acid injection to assess the basal EEG pattern (FIG.…”

Section: Acute Seizures Assessment and Quantificationmentioning

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: Mouse Model Of Acute Seizuresmentioning

confidence: 99%

Section: Mouse Model Of Acute Seizuresmentioning

confidence: 99%

Section: Mouse Model Of Acute Seizuresmentioning

confidence: 99%

Section: Acute Seizures Assessment and Quantificationmentioning

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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“…It was reported that IL-1β and high-mobility group box 1 (HMGB1) were simultaneously synthesized and released by astrocytes and microglia in the brain of the mice seizure models. Notably, a rapid release of HMGB1 from neurons appears to be triggered by proconvulsant drugs even before seizure occurrence and is involved in their precipitation of seizures [39]. IL-1 is also involved in the synthesis of IL-6 and TNF-α [40].…”

Section: Roles Of Immune and Inflammation In Drementioning

confidence: 99%

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

Líu²,

Qin³

2013

Current Neuropharmacology

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Until recently, epilepsy medical therapy is usually limited to anti-epileptic drugs (AEDs). However, approximately 1/3 of epilepsy patients, described as drug-resistant epilepsy (DRE) patients, still suffer from continuous frequent seizures despite receiving adequate AEDs treatment of sufficient duration. More recently, with the remarkable progress of immunology, immunity and inflammation are considered to be key elements of the pathobiology of epilepsy. Activation of inflammatory processes in brain tissue has been observed in both experimental seizure animal models and epilepsy patients. Anti-inflammatory and immunotherapies also showed significant anticonvulsant properties both in clinical and in experimental settings. The above emerging evidence indicates that modulation of immunity and inflammatory processes could serve as novel specific targets to achieve potential anticonvulsant effects for the patients with epilepsy, especially DRE. Herein we review the recent evidence supporting the role of inflammation in the development and perpetuation of seizures, and also discuss the recent achievements in modulation of inflammation and immunotherapy applied to the treatment of epilepsy. Apart from medical therapy, we also discuss the influences of surgery, ketogenic diet, and electroconvulsive therapy on immunity and inflammation in DRE patients. Taken together, a promising perspective is suggested for future immunomodulatory therapies in the treatment of patients with DRE.

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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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Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures

Cited by 816 publications

References 55 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

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

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

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