Seizures and memory impairment induced by patient-derived anti-N-methyl-D-aspartate receptor antibodies in mice are attenuated by anakinra, an interleukin-1 receptor antagonist

Olga Taraschenko, Howard S. Fox, Anastasia Zekeridou, Sean J. Pittock, Ember Eldridge, Fnu Farukhuddin, Fetweh Al-Saleem, Chandana Devi Kattala, Scott K. Dessain, George Casale, Gregory Willcockson, Raymond Dingledine

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Objective: Neuroinflammation associated with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may facilitate seizures. We previously showed that intraventricular administration of cerebrospinal fluid from patients with anti-NMDAR encephalitis to mice precipitates seizures, thereby confirming that antibodies are directly pathogenic. To determine whether interleukin (IL)-1-mediated inflammation exacerbates autoimmune seizures, we asked whether blocking the effects of IL-1 by anakinra, a selective IL-1 receptor antagonist, blunts antibody-induced seizures. Methods: We infused C57BL/6 mice intraventricularly with purified serum IgG from patients with anti-NMDAR encephalitis or monoclonal anti-NMDAR IgG; subdural electroencephalogram was continuously recorded. After a 6-day interval, mice received anakinra (25 mg/kg sc, twice daily) or vehicle for 5 days. Following a 4-day washout period, we performed behavioral tests to assess motor function, anxiety, and memory, followed by hippocampus tissue analysis to assess astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adapter molecule [Iba]-1) activation. Results: Of 31 mice infused with purified patient NMDAR-IgG (n = 17) or monoclonal NMDAR-IgG (n = 14), 81% developed seizures. Median baseline daily seizure count during exposure to antibodies was 3.9; most seizures were electrographic. Median duration of seizures during the baseline was 82.5 s. Anakinra administration attenuated daily seizure frequency by 60% (p =.02). Anakinra reduced seizure duration; however, the effect was delayed and became apparent only after the cessation of treatment (p =.04). Anakinra improved novel object recognition in mice with antibody-induced seizures (p =.03) but did not alter other behaviors. Anakinra reduced the expression of GFAP and Iba-1 in the hippocampus of mice with seizures, indicating decreased astrocytic and microglial activation. Significance: Our evidence supports a role for IL-1 in the pathogenesis of seizures in anti-NMDAR encephalitis. These data are consistent with therapeutic effects of anakinra in other severe autoimmune and inflammatory seizure syndromes. Targeting inflammation via blocking IL-1 receptor-mediated signaling may be promising for developing novel treatments for refractory autoimmune seizures.

Original languageEnglish (US)
Pages (from-to)671-682
Number of pages12
JournalEpilepsia
Volume62
Issue number3
DOIs
StatePublished - Mar 2021

Keywords

  • IL-1
  • anti-NMDA receptor encephalitis
  • autoantibodies
  • autoimmune seizures
  • cytokines
  • neuroinflammation

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Fingerprint Dive into the research topics of 'Seizures and memory impairment induced by patient-derived anti-N-methyl-D-aspartate receptor antibodies in mice are attenuated by anakinra, an interleukin-1 receptor antagonist'. Together they form a unique fingerprint.

Cite this