Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 47, Pages 20518-20522Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1014557107
Keywords
innate immunity; surgical complications; delirium; dementia
Categories
Funding
- Westminster Medical School Research Trust, London, United Kingdom
- Mathilda and Terence Kennedy Institute of Rheumatology Trust
- Arthritis Research United Kingdom
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Cognitive decline following surgery in older individuals is a major clinical problem of uncertain mechanism; a similar cognitive decline also follows severe infection, chemotherapy, or trauma and is currently without effective therapy. A variety of mechanisms have been proposed, and exploring the role of inflammation, we recently reported the role of IL-1 beta in the hippocampus after surgery in mice with postoperative cognitive dysfunction. Here, we show that TNF-alpha is upstream of IL-1 and provokes its production in the brain. Peripheral blockade of TNF-alpha is able to limit the release of IL-1 and prevent neuroinflammation and cognitive decline in a mouse model of surgery-induced cognitive decline. TNF-alpha appears to synergize with MyD88, the IL-1/TLR superfamily common signaling pathway, to sustain postoperative cognitive decline. Taken together, our results suggest a unique therapeutic potential for preemptive treatment with anti-TNF antibody to prevent surgery-induced cognitive decline.
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