Protective effect of senegenin on splenectomy-induced postoperative cognitive dysfunction in elderly rats

Abstract

Postoperative cognitive dysfunction (POCD) is common in elderly patients. Senegenin, an active component of extracts from Polygala tenuifolia root, a traditional Chinese medicine, has neuroprotective and neuroregenerative effects. However, the mechanism underlying the effects of senegenin against postoperative cognitive impairment in elderly individuals has yet to be elucidated. The aim of this study was to investigate the protective effects of senegenin on the cognitive functions of elderly rats with splenectomy-induced POCD. Results from a Morris water maze test suggested that splenectomy induced a transient cognitive deficiency in the elderly rats; however, when the rats were treated with senegenin, the cognitive impairment was notably attenuated. Further experiments showed that senegenin significantly inhibited the mRNA and protein expression of several key pro-inflammatory cytokines, specifically, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6 and IL-8, in the hippocampal tissues of elderly rats following splenectomy. In order to investigate the molecular mechanism involved, the expression and activity of the Toll-like receptor 4 (TLR4) signaling pathway was assessed. On day 1 postoperatively, it was observed that senegenin markedly suppressed the mRNA and protein expression of TLR4, myeloid differentiation factor 88 (MyD88) and TIR domain-containing adaptor-inducing interferon-β (TRIF). Furthermore, the phosphorylation levels of nuclear factor-κB (NF-κB) p65 and inhibitor of NF-κB (IκBα) were also decreased following senegenin treatment on the first day subsequent to surgery. These results suggest that senegenin suppressed splenectomy-induced transient cognitive impairment in elderly rats, possibly by downregulating two signaling pathways involved in inflammation, TLR4/MyD88/NF-κB and TLR4/TRIF/NF-κB, to further inhibit the expression of key pro-inflammatory cytokines, specifically, TNF-α, IL-1β, IL-6 and IL-8, and ultimately the neuroinflammation in the hippocampal tissues. In conclusion, the present study revealed that senegenin exhibited neuroprotective effects against splenectomy-induced transient cognitive impairment in elderly rats, which indicated that senegenin may be a promising agent for the treatment of POCD.

Neuroinflammation in the normal aging hippocampus

“…Various animal models of POCD have demonstrated elevations in pro-inflammatory cytokines and other proinflammatory mediators in the hippocampus (Cibelli et al, 2010; Barrientos et al, 2012; Terrando et al, 2013; Hovens et al, 2014a,b; Zhang et al, 2014). We, and others, have shown that hippocampal memory function was significantly more impaired by surgery in aged animals compared to younger control animals (Barrientos et al, 2012; Hovens et al, 2013, 2014b; Li et al, 2014; Sun et al, 2014; Yu et al, 2014). This pattern has been found following a variety of surgical procedures including exploratory abdominal surgery (Barrientos et al, 2012; Hovens et al, 2014b; Li et al, 2014), stabilized tibial fracture surgery (Sun et al, 2014), and partial hepatectomy (Li et al, 2013).…”

TNF-α receptor antagonist attenuates isoflurane-induced cognitive impairment in aged rats

“…Yang et al compared the roles of propofol and isoflurane in the neurodegeneration and cognitive impairment in neonatal mice, and found that both caused significant apoptosis in the developing brain, with isoflurane being more potent (17). In addition, isoflurane significantly increased the levels of the plasma neurodegenerative biomarker, S100β (18). Neuroinflammation has been demonstrated to be a key factor for the progression of cognitive dysfunction after surgery and/or anesthesia (19).…”

“…Neuroinflammation has been demonstrated to be a key factor for the progression of cognitive dysfunction after surgery and/or anesthesia (19). During the development of POCD, the expression levels of various proinflammatory cytokines has been reported to be significantly increased, including TNF-α, IL-1β, IL-6 and IL-8 (18). For example, Yu et al (18) showed that splenectomy induced a transient cognitive deficiency in elderly rats, accompanied by notable upregulation of TNF-α, IL-1β, IL-6 and IL-8 expression in the in the hippocampal tissues.…”

“…During the development of POCD, the expression levels of various proinflammatory cytokines has been reported to be significantly increased, including TNF-α, IL-1β, IL-6 and IL-8 (18). For example, Yu et al (18) showed that splenectomy induced a transient cognitive deficiency in elderly rats, accompanied by notable upregulation of TNF-α, IL-1β, IL-6 and IL-8 expression in the in the hippocampal tissues. Moreover, it has been reported that these proinflammatory cytokines further led to the activation of microglial cells and caused neuroinflammation responses and brain injury (20,21).…”

Neuroinflammatory challenges compromise neuronal function in the aging brain: Postoperative cognitive delirium and Alzheimer’s disease

“…In cases of POD, levels of pro-inflammatory cytokines are also significantly increased in hippocampus following peripheral surgical procedures [30,138,141,142–145]. Animal studies identifying the effects of surgical procedures have confirmed that deficits in learning and memory are associated with elevated levels of pro-inflammatory cytokines in hippocampus compared to young animals [138,144,146–149]. Biological and physiological mechanisms of the neuroinflammatory components underlying cognitive decline associated with POD and AD are unknown, however the role of pro-inflammatory cytokines in hippocampal function may provide an overlapping mechanism by which cognitive decline occurs in cases of POD that may manifest into AD.…”