Inhibiting tumor necrosis factor-α signaling attenuates postoperative cognitive dysfunction in aged rats

Abstract

Postoperative cognitive dysfunction (POCD), commonly observed in elderly patients, is characterized by impaired concentration, memory and learning following surgery, and may persist for a long duration or progress into serious central nervous system diseases. It has been demonstrated neuroinflammation caused by surgery is involved in the development of POCD. However, the detailed molecular mechanism remains to be fully elucidated. The present study aimed to reveal the role of tumor necrosis factor (TNF)-α in the development of POCD in aged rats. Laparotomy was performed to mimic human abdominal surgery in the aged rats. Following surgery, the memory and learning functions were impaired, with significant upregulation of pro-inflammatory cytokines, including TNF-α, interleukin (IL)-1β, IL-4 and IL-6 in the hippocampal tissues. However, intracisternal administration of the TNF-α receptor antagonist, R-7050, during surgery attenuated these defects in cognitive function and inhibited the production of the pro-inflammatory cytokines in the hippocampal tissues. Furthermore, intracisternal administration of R-7050 inhibited the activation of the downstream nuclear factor-κB and mitogen-activated protein kinase signaling pathway in the hippocampal tissues. Therefore, the results of the present study suggested a key role of the TNF-α-mediated signaling pathway in the development of POCD.

Electroacupuncture Alleviates Postoperative Cognitive Dysfunction in Aged Rats by Inhibiting Hippocampal Neuroinflammation Activated via Microglia/TLRs Pathway

“…TNF- α is a multifunctional proinflammatory cytokine that is predominantly secreted by macrophages and microglia [45]. Inhibition of TNF- α led to inhibition of the activation of NF- κ B signaling, which in turn inhibited the production of key proinflammatory cytokines, including TNF- α , IL-1 β , and IL-6, in the hippocampal tissues of the aged rats [46]. HMGB1 is an abundant, evolutionarily conserved nonhistone protein and has a surprising additional function as a secreted protein with a central role in inflammation caused by tissue damage [47].…”

“…Thus, a vicious circle may be created that may exacerbate the impairment of cognitive function. Recent studies have shown that IL-1 β , IL-6, TNF- α , and HMGB1 played an important role in POCD pathogenesis [17, 46, 49]. Hence, we chose to explore all of their effects and involvement in EA treatment for cognitive decline postoperatively.…”

Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease

“…R-7050 is a small molecule that inhibits the internalization-dependent signaling of TNFR1 and TNFR2. [27][28][29] Preemptive R-7050 therapy partially protected wild-type mice from hyperoxaluria-induced nephrocalcinosis and CKD. The incomplete protection may be related either to other crystal adhesion molecules that are not under the control of TNFRs or to dosing and pharmacodynamics of R-7050, but the effects noted were consistent across all end points studied.…”

Upregulation of TREM2 Ameliorates Neuroinflammatory Responses and Improves Cognitive Deficits Triggered by Surgical Trauma in Appswe/PS1dE9 Mice

“…Mounting evidence indicates that POCD is associated with surgery-induced neuroinflammatory processes, which may influence neuronal function either directly or through modulation of intraneuronal pathways [5-7]. High levels of neuroinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α play a pivotal role in surgery-induced cognitive deficits [2, 8]. Inhibition of central proinflammatory cytokine signaling restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation [9].…”