Neurokinin-1 receptor antagonism improves postoperative neurocognitive disorder in mice.

Abstract

Postoperative neurocognitive disorder (PND) is a major complication in surgical patients, especially the elderly, leading to mild memory impairment after surgery. The underlying pathophysiology remains unknown, although neuroinflammation and blood-brain barrier (BBB) disruption have been increasingly implicated in PND. Emerging evidence suggests that neurokinin-1 receptor (NK-1R), the principal target of proinflammatory neuropeptide substance P (SP), plays a pivotal role in modulating neuroinflammation and BBB integrity. In this study, we used an established mouse model for PND to investigate the effects of a selective NK-1R antagonist L-733,060 on PND-like features after peripheral surgery. Hippocampal SP started to increase at 6 h, peaked at 1 day, and returned to baseline at 3 days after surgery. At 1 day after surgery, NK-1R expression was increased in the hippocampus. At this time point, NK-1R antagonist pretreatment attenuated microgliosis and prevented neutrophil infiltration after surgery. Similarly, proinflammatory cytokines interleukin-1 beta and interleukin-6 were reduced in the hippocampus in NK-1R antagonist-treated mice at 6 h after surgery. Furthermore, surgery-induced BBB disruption, assessed by albumin deposition and expression of tight junction protein claudin-5, was attenuated by NK-1R antagonism at postoperative day 1. Finally, trace fear conditioning test revealed NK-1R antagonism reversed surgery-induced cognitive impairment at 3 days after surgery. Our findings suggest that inhibition of NK-1R signaling protects hippocampus-dependent memory from surgical insult, probably through modulations of neuroinflammation and BBB integrity.

• Authors: Zhanjun Li, Ting Luo, Xinyu Ning, Chao Xiong, Anshi Wu
• Journal: Neuroscience letters (Neurosci Lett) Vol. 687 Pg. 189-195 (11 20 2018) ISSN: 1872-7972 [Electronic] Ireland
• PMID: 30273701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Neurokinin-1 Receptor Antagonists
• Receptors, Neurokinin-1

Topics

• Animals
• Blood-Brain Barrier (drug effects, metabolism)
• Disease Models, Animal
• Hippocampus (drug effects, metabolism)
• Male
• Memory (drug effects)
• Mice, Inbred C57BL
• Neurocognitive Disorders (drug therapy, surgery)
• Neurokinin-1 Receptor Antagonists (pharmacology)
• Receptors, Neurokinin-1 (drug effects, metabolism)