Rosczyk HA, Sparkman NL, Johnson RW: Neuroinflammation and cognitive function in aged mice following minor surgery

Neuroscience Program, University of Illinois, Urbana, IL 61801, USA.
Experimental gerontology (Impact Factor: 3.49). 07/2008; 43(9):840-6. DOI: 10.1016/j.exger.2008.06.004
Source: PubMed


Following surgery, elderly patients often suffer from postoperative cognitive dysfunction (POCD) which can persist long after physical recovery. It is known that surgery-induced tissue damage activates the peripheral innate immune system resulting in the release of inflammatory mediators. Compared to adults, aged animals demonstrate increased neuroinflammation and microglial priming that leads to an exaggerated proinflammatory cytokine response following activation of the peripheral immune system. Therefore, we sought to determine if the immune response to surgical trauma results in increased neuroinflammation and cognitive impairment in aged mice. Adult and aged mice underwent minor abdominal surgery and 24h later hippocampal cytokines were measured and working memory was assessed in a reversal learning version of the Morris water maze. While adult mice showed no signs of neuroinflammation following surgery, aged mice had significantly increased levels of IL-1beta mRNA in the hippocampus. Minor surgery did not result in severe cognitive impairment although aged mice that underwent surgery did tend to perseverate in the old target during reversal testing suggesting reduced cognitive flexibility. Overall these results suggest that minor surgery leads to an exaggerated neuroinflammatory response in aged mice but does not result in significantly impaired performance in the Morris water maze.

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    • "This augmented response was not observed in the hypothalamus or in peripheral plasma samples, implicating a hippocampus-selective response. In addition, various surgical procedures have been reported to produce an IL-1b increase in the hippocampus of aged animals for up to several days compared to age-matched sham controls (Rosczyk et al., 2008; Cao et al., 2010; Barrientos et al., 2012). However, young adult animals that underwent the same surgical procedure showed no differences in IL-1b expression compared to their age-matched sham controls. "
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    ABSTRACT: A consequence of normal aging is a greater susceptibility to memory impairments following an immune challenge such as infection, surgery, or traumatic brain injury. The neuroinflammatory response, produced by these challenges results in increased and prolonged production of pro-inflammatory cytokines in the otherwise healthy aged brain. Here we discuss the mechanisms by which long lasting elevations in pro-inflammatory cytokines in the hippocampus produce memory impairments. Sensitized microglia are a primary source of this exaggerated neuroinflammatory response and appear to be a hallmark of the normal aging brain. We review the current understanding of the causes and effects of normal aging-induced microglial sensitization, including dysregulations of the neuroendocrine system, potentiation of neuroinflammatory responses following an immune challenge, and the impairment of memories. We end with a discussion of therapeutic approaches to prevent these deleterious effects. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Mar 2015 · Neuroscience
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    • "TNF-α has been found to be upregulated in SCD (Conran et al. 2009). Furthermore, populations with degraded vasculature, including older adults (Rosczyk et al. 2008) and children with SCD, may be especially vulnerable to neuroinflammation, as disruption in the blood brain barrier may expose the central nervous system to high levels of pro-inflammatory cytokines. "
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    ABSTRACT: Children with sickle cell disease (SCD) suffer from systemic processes (e.g., chronic anemia, recurrent hypoxic-ischemic events, chronic inflammation) that have been associated with neurocognitive impairment in a range of clinical populations, but which have been largely understudied in relation to specific domains of cognitive functioning in children with SCD. This review focuses on episodic memory, as the hippocampus may be especially vulnerable to the systemic processes associated with SCD. The first part of the paper outlines the pathophysiology of SCD and briefly reviews the extant literature on academic and cognitive functioning in children with SCD, emphasizing the dearth of research on episodic memory. Next, the complex systemic processes of hypoxia and inflammation associated with SCD are reviewed, along with research that has associated these processes with hippocampal damage and memory impairment. The paper concludes with suggestions for future research that are informed, in part, by the literature on developmental amnesia.
    Full-text · Article · Apr 2014 · Neuropsychology Review
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    • "Although the molecular mechanism of POCD has yet to be elucidated, surgical trauma has been suggested to be a prominent risk factor for the development of POCD, possibly through the activation of signaling pathways involved in inflammation, such as the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) and TLR4/TIR domain-containing adaptor inducing interferon-β (TRIF)/NF-κB pathways (3). It has been demonstrated that the release of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), increases following surgery (4,5). These pro-inflammatory cytokines may trigger broad neuroinflammation in the brain (6). "
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    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.
    Full-text · Article · Apr 2014 · Experimental and therapeutic medicine
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