Cell-penetrating interactomic inhibition of nuclear factor-kappa B in a mouse model of postoperative cognitive dysfunction

Sci Rep. 2017 Oct 18;7(1):13482. doi: 10.1038/s41598-017-14027-2.

Abstract

Some patients experience impaired cognitive functioning after surgery, a phenomenon referred to as postoperative cognitive dysfunction (POCD). Signs of POCD are closely associated with the development of systemic or hippocampal inflammation. However, the precise pathophysiological mechanisms of prevention/treatment options for POCD still remain unclear. After injury, the transcriptional factor nuclear factor-kappa B (NF-κB) is thought to regulate or stimulate inflammation amplification. Therefore, we designed a cell-penetrating fusion protein called nt-p65-TMD, which inhibits NF-κB p65 activation by translocating into the nucleus. In the present study, we discovered that nt-p65-TMD exerted effects on surgery-induced cognitive impairment in mice. Specifically, nt-p65-TMD exhibited strong immunoregulatory properties that were able to reduce surgery-induced elevations in cerebrovascular integrity impairment, subsequent peripheral immune-cell recruitment, and inflammation amplification, which ultimately lead to cognitive decline. The nt-p65-TMD has the unique ability to regulate and reduce systemic inflammation and inflammation amplification, suggesting a new strategy for preventing development of cognitive decline that occurs in POCD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / etiology
  • Cognitive Dysfunction / metabolism
  • Male
  • Mice
  • Mice, Inbred ICR
  • Postoperative Complications / drug therapy*
  • Postoperative Complications / metabolism
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Transcription Factor RelA / antagonists & inhibitors*
  • Transcription Factor RelA / metabolism

Substances

  • Anti-Inflammatory Agents
  • Recombinant Proteins
  • Transcription Factor RelA