Inhibition of the NLRP3 inflammasome by OLT1177 induces functional protection and myelin preservation after spinal cord injury

Exp Neurol. 2022 Jan;347:113889. doi: 10.1016/j.expneurol.2021.113889. Epub 2021 Oct 12.

Abstract

Spinal cord injury (SCI) leads to irreversible functional deficits due to the disruption of axons and the death of neurons and glial cells. The inflammatory response that occurs in the injured spinal cord results in tissue degeneration; thus, targeting inflammation after acute SCI is expected to ameliorate histopathological evidence indicative of damage and, consequently, reduce functional disabilities. Interleukin 1 beta (IL-1β) and interleukin 18 (IL-18) are pro-inflammatory cytokines members of the IL-1 family that initiate and propagate inflammation. Here, we report that protein levels of IL-1β and IL-18 were increased in spinal cord parenchyma after SCI, but with different expression profiles. Whereas levels of IL-1β were rapidly increased reaching peak levels at 12 h after the injury, levels of IL-18 did not increase until 7 days after the injury. Since activation of the NLRP3 inflammasome is required for the processing and release of IL-1β and IL-18, we intraperitoneally administered OLT1177, a selective inhibitor of the NLRP3 inflammasome, to reduce the contribution of these cytokines to SCI. At a dose of 200 mg/kg, OLT1177 protected against neurological deficits and histological evidence of damage. OLT1177 also reduced the levels of IL-1β in the spinal cord after contusion injury and diminished the accumulation of neutrophils and macrophages at later time points. These data suggest that targeting the NLRP3 inflammasome with OLT1177 could be a novel therapeutic strategy to arrest neuroinflammation and reduce functional impairments after acute SCI in humans.

Keywords: Inflammasome; Interleukin 1; Interleukin 18; NLRP3; OLT1177; Spinal cord injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Female
  • Inflammasomes / drug effects*
  • Mice
  • Myelin Sheath / pathology*
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology
  • Neuroinflammatory Diseases / immunology
  • Neuroinflammatory Diseases / pathology
  • Nitriles / pharmacology*
  • Spinal Cord Injuries / immunology*
  • Spinal Cord Injuries / pathology
  • Sulfones / pharmacology*

Substances

  • Anti-Inflammatory Agents
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nitriles
  • Sulfones
  • dapansutrile