NLRP1 inflammasome is activated in patients with medial temporal lobe epilepsy and contributes to neuronal pyroptosis in amygdala kindling-induced rat model

Abstract

BackgroundTemporal lobe epilepsy (TLE) is often characterized pathologically by severe neuronal loss in the hippocampus. Understanding the mechanisms of neuron death is key to preventing the neurodegeneration associated with TLE. However, the involvement of neuronal loss to the epileptogenic process has yet to be fully determined. Recent studies have shown that the activation of NLRP1 can generate a functional caspase-1-containing inflammasome in vivo to drive the proinflammatory programmed cell death termed ‘pyroptosis’, which has a key role in the pathogenesis of neurological disorders. To the best of our knowledge, there are no reported studies that performed detailed identification and validation of NLRP1 inflammasome during the epileptogenic process.MethodsWe first compared expression of NLRP1 and caspase-1 in resected hippocampus from patients with intractable mesial temporal lobe epilepsy (mTLE) with that of matched control samples. To further examine whether the activation of NLRP1 inflammasome contributes to neuronal pyroptosis, we employed a nonviral strategy to knock down the expression of NLRP1 and caspase-1 in the amygdala kindling-induced rat model. Proinflammatory cytokines levels and hippocampal neuronal loss were evaluated after 6 weeks of treatment in these NLRP1 or caspase-1 deficiency TLE rats.ResultsWestern blotting detected upregulated NLRP1 levels and active caspase-1 in mTLE patients in comparison to those levels seen in the controls, suggesting a role for this inflammasome in mTLE. Moreover, we employed direct in vivo infusion of nonviral small interfering RNA to knockdown NLRP1 or caspase-1 in the amygdala kindling-induced rat model, and discovered that these NLRP1 or caspase-1 silencing rats resulted in significantly reduced neuronal pyroptosis.ConclusionsOur data suggest that NLRP1/caspase-1 signaling participates in the seizure-induced degenerative process in humans and in the animal model of TLE and points to the silencing of NLRP1 inflammasome as a promising strategy for TLE therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0233-0) contains supplementary material, which is available to authorized users.

Heme Oxygenase-1 Promotes Neuron Survival through Down-Regulation of Neuronal NLRP1 Expression after Spinal Cord Injury

“…High extracellular potassium opens pannexin channels leading to inflammasome activation in primary neurons and astrocytes [44]. Importantly, recent studies have showed inflammasome formation in different neuronal disorders including SCI [12,21,38,45].…”

“…Several molecular biological processes, including changes of cell cycle-related gene expression, endoplasmic reticulum (ER) stress, glutamate excitotoxicity, free radical production, and inflammatory cytokine release contribute to neuronal death [1,[5][6][7][8]. Recently, inflammasome-associated neuronal programmed cell death, termed pyroptosis, has been shown to contribute to neuronal death in distinct neurological diseases [9][10][11][12]. Pyroptosis is induced by inflammasomes which consist of an apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adaptor protein, and caspase-1, an inflammatory cysteine-aspartic protease [13,14].…”

Complement system biomarkers in epilepsy

“…This lack of consensus and growing evidence of an immune/inflammatory component in epilepsy development makes it necessary to enlarge diagnostic and prognostic assessment to include other immunological biomarkers [16]. In response to this need, the involvement of different immune pathways in epilepsy pathogenesis is increasingly investigated in animal models and in humans [17][18][19].…”

Prevention of Epilepsy by Low-Dose Artesunate + Esomeprazole-Furosemide Sequential Therapy.

“…[37] [38] In the same vein, artemisinins, a pannexin-I blocker, inhibit the NLRP-3 inflammasome activation to decrease glutamate and cytokine release. [ Oriaifo et al…”