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.
Highlights
Temporal lobe epilepsy (TLE) is often characterized pathologically by severe neuronal loss in the hippocampus
NLRP1 inflammasome components were upregulated in human mesial temporal lobe epilepsy We first investigated whether the expression of NLRP1 was altered in the brains of individuals with pharmacoresistant mTLE
We found that the NLRP1 levels of TLE patients were significantly elevated, while the levels of NeuN were slightly reduced compared to control samples (Figure 1a, b)
Summary
Temporal lobe epilepsy (TLE) is often characterized pathologically by severe neuronal loss in the hippocampus. 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. We hypothesized that the activation of NLRP1-inflammasome may have key roles in the pathogenesis of TLE, in which inflammatory events and neuronal death contribute powerful pathogenetic forces [10,11]. To test this hypothesis, we first investigated whether the expression profiles of the NLRP1 inflammasome components, including NLRP1 and caspase-1, are altered in resected hippocampus from patients with intractable mTLE when compared to matched control samples. We applied small interfering RNAs (siRNAs) to knock down NLRP1 and caspase-1 in the brain of amygdala kindling-induced TLE rat model and measured the NLRP1 component alterations as well as the functional outcomes
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