title: NLRP1 inflammasome is activated in patients with medial temporal lobe epilepsy and contributes to neuronal pyroptosis in amygdala kindling-induced rat model.
abstract: BACKGROUND
  Temporal 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Western 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China. 573528475@qq.com.
authors.forename: Chen-Chen
authors.initials: CC
authors.lastname: Tan
authors.affiliation: Department of Functional Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, No.6, Tiantan Xili, Beijing, 100050, China. zjguo73@126.com.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No.6, Tiantan Xili, Beijing, 100050, China. zjguo73@126.com.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.affiliation: College of Medicine and Pharmaceutics, Ocean University of China, No.5 Yushan Road, Qingdao, 266003, China. tanmengshan@163.com.
authors.forename: Meng-Shan
authors.initials: MS
authors.lastname: Tan
authors.affiliation: Department of Pathology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China. chenhua62@163.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Functional Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, No.6, Tiantan Xili, Beijing, 100050, China. 446899488@qq.com.|Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No.6, Tiantan Xili, Beijing, 100050, China. 446899488@qq.com.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Meng
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, No.5 Donghai Middle Road, Qingdao, 266071, China. jt870918@163.com.
authors.forename: Teng
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China. 2634833762@qq.com.
authors.forename: Xiang-Fei
authors.initials: XF
authors.lastname: Meng
authors.affiliation: Department of Pathology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China. liying91588@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China. leleya0602@163.com.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China. limengmeng0602@126.com.
authors.forename: Meng-Meng
authors.initials: MM
authors.lastname: Li
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China. yu-jintai@163.com.|College of Medicine and Pharmaceutics, Ocean University of China, No.5 Yushan Road, Qingdao, 266003, China. yu-jintai@163.com.|Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, No.5 Donghai Middle Road, Qingdao, 266071, China. yu-jintai@163.com.|Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, 94158, USA. yu-jintai@163.com.
authors.forename: Jin-Tai
authors.initials: JT
authors.lastname: Yu
authors.affiliation: Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao, 266071, China. dr.tanlan@163.com.|College of Medicine and Pharmaceutics, Ocean University of China, No.5 Yushan Road, Qingdao, 266003, China. dr.tanlan@163.com.|Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, No.5 Donghai Middle Road, Qingdao, 266071, China. dr.tanlan@163.com.
authors.forename: Lan
authors.initials: L
authors.lastname: Tan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D000679:Amygdala / Q000502:physiology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000009:adverse effects; D004833:Epilepsy, Temporal Lobe / Q000150:complications* / Q000209:etiology / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070576:NLR Proteins; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D000069292:Pyroptosis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000070576:NLR Proteins; C427903:NLRP1 protein, human; D020170:Caspase 1; D010751:Phosphopyruvate Hydratase