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

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.

Surgery, neuroinflammation and cognitive impairment

“…Inhibition of NF-κB p65 activation using the cell-penetrating fusion protein, nt-p65-TMD, regulates and attenuates post-surgical systemic inflammation [ 114 ]. These preliminary results indicate that NF-κB p65 inhibition may be a potential future therapeutic option in the prevention of POCD.…”

Inflammasome and Cognitive Symptoms in Human Diseases: Biological Evidence from Experimental Research

“…The pathophysiology of PNDs has not been fully clarified; however, inflammatory response, age, and anesthesia duration may be associated with PNDs [68][69][70][71]. Pain, disruption of circadian rhythms, and systemic inflammation in response to surgery, infection, or injury are regarded as causative factors of delirium, a specific form of PND [72][73][74][75].…”

“…Aged mice subjected to abdominal surgery displayed increased hippocampal β-amyloid (Aβ) and beta-site APP cleaving enzyme (BACE1) levels in the hippocampus and cognitive impairment, while general anesthesia did not cause such cognitive deficits [76]. Abdominal surgery is involved in peripheral inflammation and infiltration of immune cells via the disruption of the BBB, leading to neuroinflammation and cognitive impairment [69]. Moreover, orthopedic surgery results in systemic inflammation, followed by IL-1β-mediated inflammation in the plasma and hippocampus, and deficits in contextual fear memory.…”

“…The inflammasome has been reported to be related to the pathogenesis of PND in various murine models [16,69,77,78]. In a mouse model subjected to anesthesia (isoflurane), aged mice, but not young ones, showed activation of the NLRP3-caspase-1 pathway, poor performance in the Morris water maze, and increased levels of IL-1β and IL-18 [16].…”

“…Also, the inhibition of NF-κB p65, which is a transcriptional regulator for inflammatory mediators, results in the reduction of NLRP1 inflammasome constituents and IL-18 and IL-1β production in the spleen and reduction of cell death in the spleen. It also reduces long-term potentiation (LTP) deficits and memory impairment [69,77]. Honokiol, a poly phenolic compound, has anti-inflammatory, anti-oxidant, and anti-tumor properties and has shown inhibitory effects on NLRP3 inflammasome and restorative effects on cognitive impairment [78].…”