Wan Y, Xu J, Ma D, et al. Postoperative impairment of cognitive function in rats: a possible role for cytokine-mediated inflammation in the hippocampus
ABSTRACT Postoperative cognitive dysfunction is being increasingly reported as a complication. The authors investigated the role of cytokine-mediated inflammation within the central nervous system in the development of cognitive dysfunction in a rat model.
Adult rats were subjected to neuroleptic anesthesia (20 microg/kg fentanyl plus 500 microg/kg droperidol, intraperitoneal) for splenectomy or no surgery. On postanesthetic days 1, 3, and 7, cognitive function was assessed in a Y maze. To evaluate the immune response in the hippocampus, the authors measured glial activation, as well as transcription and expression of key proinflammatory cytokines interleukin 1beta and tumor necrosis factor alpha. To determine propensity for apoptosis, they measured expression of Bax and Bcl-2.
Cognitive function in splenectomized animals was impaired at days 1 and 3 after surgery compared with cognitive function in nonanesthetized rats. At all times, anesthetized rats that were not subjected to surgery were no different from control rats. Glial activation was observed in the hippocampus only in splenectomized rats at postsurgery days 1 and 3. Interleukin-1beta messenger RNA (mRNA) was significantly increased at postsurgery days 1 and 3, with an increase in protein expression detected on day 1. There was a significant increase in tumor necrosis factor-alpha mRNA on day 1 after surgery, although this was not associated with an increase in protein expression. The ratio of Bcl-2:Bax was significantly decreased in the splenectomized animals.
These results suggest that splenectomy performed during neuroleptic anesthesia triggers a cognitive decline that is associated with a hippocampal inflammatory response that seems to be due to proinflammatory cytokine-dependent activation of glial cells.
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- "In cognitive disorders, neurodegeneration and neuroinflammation have been implicated   . Neuroinflammation has been associated with altered neural circuitry after trauma and in neurodegenerative diseases, which suggests that the central nervous system (CNS) is involved in changing cognitive function by directly and indirectly affecting neurons  . "
ABSTRACT: Excessive production of cytokines by microglia may cause cognitive dysfunction and long-lasting behavioral changes. Activating the peripheral innate immune system stimulates cytokine secretion in the central nervous system, which modulates cognitive function. Histone deacetylases (HDACs) modulate cytokine synthesis and release. Trichostatin A (TSA), an HDAC inhibitor, is documented to be anti-inflammatory and neuroprotective. We investigated whether TSA reduces lipopolysaccharide- (LPS-) induced neuroinflammation and cognitive dysfunction. ICR mice were first intraperitoneally (i.p.) injected with vehicle or TSA (0.3 mg/kg). One hour later, they were injected (i.p.) with saline or Escherichia coli LPS (1 mg/kg). We analyzed the food and water intake, body weight loss, and sucrose preference of the injected mice and then determined the microglia activation and inflammatory cytokine expression in the brains of LPS-treated mice and LPS-treated BV-2 microglial cells. In the TSA-pretreated mice, microglial activation was lower, anhedonia did not occur, and LPS-induced cognitive dysfunction (anorexia, weight loss, and social withdrawal) was attenuated. Moreover, mRNA expression of HDAC2, HDAC5, indoleamine 2,3-dioxygenase (IDO), TNF-α, MCP-1, and IL-1β in the brain of LPS-challenged mice and in the LPS-treated BV-2 microglial cells was lower. TSA diminished LPS-induced inflammatory responses in the mouse brain and modulated the cytokine-associated changes in cognitive function, which might be specifically related to reducing HDAC2 and HDAC5 expression.Mediators of Inflammation 01/2015; 2015:163140. DOI:10.1155/2015/163140 · 3.24 Impact Factor
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- "Various surgical procedures have been used in the literature for studying POCD. They include tibial fracture and fixation, hepatic resection and spleen resection [5,36,37]. These procedures are invasive and provide strong surgical stimulation. "
ABSTRACT: Background Patients with postoperative cognitive dysfunction have poor outcomes. Neuroinflammation may be the underlying pathophysiology for this dysfunction. We determined whether proinflammatory cytokines affect the trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors to the plasma membrane, a fundamental biochemical process for learning and memory. Methods Four-month-old male Fischer 344 rats were subjected to right carotid exposure under isoflurane anesthesia. Some rats received intravenous lidocaine infusion during anesthesia. Rats were tested two weeks later by Barnes maze. The hippocampus was harvested six hours after the surgery for western blotting of interleukin (IL)-1β or IL-6. Hippocampal slices were prepared from control rats or rats subjected to surgery two weeks previously. They were incubated with tetraethylammonium, an agent that can induce long term potentiation, for determining the trafficking of GluR1, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit. Results Surgery or anesthesia increased the time to identify the target box during the Barnes maze test training sessions and one day after the training sessions. Surgery also prolonged the time to identify the target box eight days after the training sessions. Surgery increased IL-1β and IL-6 in the hippocampus. The tetraethylammonium–induced GluR1 phosphorylation and trafficking were abolished in the hippocampal slices of rats after surgery. These surgical effects were partly inhibited by lidocaine. The incubation of control hippocampal slices with IL-1β and IL-6 abolished tetraethylammonium–induced GluR1 trafficking and phosphorylation. Lidocaine minimally affected the effects of IL-1β on GluR1 trafficking. Conclusions Our results suggest that surgery increases proinflammatory cytokines that then inhibit GluR1 trafficking, leading to learning and memory impairment.Journal of Neuroinflammation 05/2014; 11(1):93. DOI:10.1186/1742-2094-11-93 · 4.90 Impact Factor
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- "The neuropathogenesis of POCD remains largely to be determined. Neuroinflammation has been reported to be associated with POCD in humans and cognitive impairment in animals (, , , , reviewed in ). Our recent studies have shown that peripheral surgical wounding without the influence of general anesthesia can induce an age-dependent Aβ accumulation and cognitive impairment in mice . "
ABSTRACT: Post-operative cognitive dysfunction is associated with morbidity and mortality. However, its neuropathogenesis remains largely to be determined. Neuroinflammation and accumulation of β-amyloid (Aβ) have been reported to contribute to cognitive dysfunction in humans and cognitive impairment in animals. Our recent studies have established a pre-clinical model in mice, and have found that the peripheral surgical wounding without the influence of general anesthesia induces an age-dependent Aβ accumulation and cognitive impairment in mice. We therefore set out to assess the effects of peripheral surgical wounding, in the absence of general anesthesia, on neuroinflammation in mice with different ages. Abdominal surgery under local anesthesia was established in 9 and 18 month-old mice. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), Iba1 positive cells (the marker of microglia activation), CD33, and cognitive function in mice were determined. The peripheral surgical wounding increased the levels of TNF-α, IL-6, and Iba1 positive cells in the hippocampus of both 9 and 18 month-old mice, and age potentiated these effects. The peripheral surgical wounding increased the levels of CD33 in the hippocampus of 18, but not 9, month-old mice. Finally, anti-inflammatory drug ibuprofen ameliorated the peripheral surgical wounding-induced cognitive impairment in 18 month-old mice. These data suggested that the peripheral surgical wounding could induce an age-dependent neuroinflammation and elevation of CD33 levels in the hippocampus of mice, which could lead to cognitive impairment in aged mice. Pending further studies, anti-inflammatory therapies may reduce the risk of postoperative cognitive dysfunction in elderly patients.PLoS ONE 05/2014; 9(5):e96752. DOI:10.1371/journal.pone.0096752 · 3.23 Impact Factor