Innate and adaptive immunity during epileptogenesis and spontaneous seizures: Evidence from experimental models and human temporal lobe epilepsy

Ravizza, Teresa; Gagliardi, Barbara Sara Alessandra; Noè, Francesco M.; Boer, Karin; Aronica, Eleonora; Vezzani, Annamaria

doi:10.1016/j.nbd.2007.08.012

Cited by 634 publications

(629 citation statements)

References 69 publications

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“…For example, intrahippocampal administration of recombinant IL1-β in rats leads to the increased plasma CORT level [20]. This observation parallels events in epileptic rats, in which the increased expression of endogenous IL1-β and its receptor [15] results in the hyperactivity of the HPA axis [7].…”

Section: Il-1ra Monotherapymentioning

confidence: 72%

“…The effects if IL-1ra led us to propose that the increased IL-1β signaling, which has been a well-established hallmark of temporal lobe epilepsy [15,16], may also be the upstream-most factor that via the hyperactivity of the HPA axis [17][18][19][20] leads to the development of depressive impairments [1]. It has been long suggested that epilepsy and depression share certain pathophysiological mechanisms [21,22].…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression

et al. 2012

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Depression represents a common comorbidity of epilepsy and is frequently resistant to selective serotonin reuptake inhibitors (SSRI). We tested the hypothesis that the SSRI resistance in epilepsy associated depression may be a result of a pathologically enhanced interleukin-1β (IL1-β) signaling, and consequently that the blockade of IL1-β may restore the effectiveness of SSRI. Epilepsy and concurrent depression-like impairments were induced in Wistar rats by pilocarpine status epilepticus (SE). The effects of the 2-week long treatment with fluoxetine, interleukin-1 receptor antagonist (IL-1ra), and their combination were examined using behavioral, biochemical, neuroendocrine, and autoradiographic assays. In post-SE rats, depression-like impairments included behavioral deficits indicative of hopelessness and anhedonia; the hyperactivity of the hypothalamo-pituitaryadrenocortical axis; the diminished serotonin output from raphe nucleus; and the upregulation of presynaptic serotonin 1-A (5-HT1A) receptors. Fluoxetine monotherapy exerted no antidepressant effects, whereas the treatment with IL-1ra led to the complete reversal of anhedonia and to a partial improvement of all other depressive impairments. Combined administration of fluoxetine and IL-1ra completely abolished all hallmarks of epilepsy-associated depressive abnormalities, with the exception of the hyperactivity of the hypothalamopituitary-adrenocortical axis, the latter remaining only partially improved. We propose that in certain forms of depression, including but not limited to depression associated with epilepsy, the resistance to SSRI may be driven by the pathologically enhanced interleukin-1β signaling and by the subsequent upregulation of presynaptic 5-HT1A receptors. In such forms of depression, the use of interleukin-1β blockers in conjunction with SSRI may represent an effective therapeutic approach.

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Section: Il-1ra Monotherapymentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression

et al. 2012

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“…Experimental seizures in rodents induce inflammatory processes in brain regions in which epileptic activity originates and spreads [1,2]; in this respect, the activation of the interleukin (IL)-1β/IL-1 receptor type 1 (R1) signaling in glia and neurons is a key event contributing to intrinsic brain inflammation [3][4][5][6][7][8][9][10][11][12]. Paracrine and autocrine activation of this signaling by the brain application of IL-1β exacerbates kainic acid-or bicuculline-induced seizures in rats and mice [5,11,13], and lowers the seizure threshold in febrile seizure models [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…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%

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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“…Gliosis(glia extensive proliferation), and astrocytosis (astrocyte proliferationis) are very prominent in the sclerotic hippocampus of the epilepsy patients, particularly in the epileptogenic focus of mesial TLE [79, 80]. The phenomenon above is not only associated with inflammatory processes but also with alterations in astrocytic properties that impact on the DRE state [81].…”

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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Innate and adaptive immunity during epileptogenesis and spontaneous seizures: Evidence from experimental models and human temporal lobe epilepsy

Cited by 634 publications

References 69 publications

Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression

Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression

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

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