Editors' ChoiceNeuroscience

Inflammatory Decline

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Science Signaling  07 Dec 2010:
Vol. 3, Issue 151, pp. ec368
DOI: 10.1126/scisignal.3151ec368

Postoperative cognitive decline (POCD) is a long-lasting defect in cognitive function that occurs in 7 to 26% of patients (particularly the elderly) after surgery, which leads to increased dementia and mortality. The mechanisms involved are unclear, although a role for inflammation has been implicated (see commentary by Steinman). Terrando et al. investigated POCD in a mouse model of orthopedic surgery under general anesthesia. Tumor necrosis factor (TNF) was the cytokine detected earliest in the blood of animals after surgery, with other pro-inflammatory cytokines, including interleukin 6 (IL-6) and IL-1β, which was previously implicated in POCD in mice, appearing some hours later. This inflammatory response was preceded by the release of HMGB-1, a damage-associated molecular pattern (DAMP) molecule, from necrotic cells. Administration of a TNF-blocking antibody to mice before surgery inhibited the systemic production of IL-1β, whereas adding the antibody after surgery had no effect. The antibody to TNF also reduced the amount of IL-1β that accumulated in the hippocampi of mice after surgery and reduced the activation of microglia, which can release compounds that disrupt neuronal function. Mice after surgery exhibited a defect in a contextual fear response, which indicated that they had impaired hippocampal-dependent memory compared to that of mice that had not undergone surgery. Administration of antibody to TNF before surgery prevented this hippocampal dysfunction. Together, these data suggest that preoperative treatment with a blocking antibody against TNF, which is already used in patients with inflammatory conditions such as rheumatoid arthritis, may be an effective therapy against POCD.

N. Terrando, C. Monaco, D. Ma, B. M. J. Foxwell, M. Feldmann, M. Maze, Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline. Proc. Natl. Acad. Sci. U.S.A. 107, 20518–20522 (2010). [Abtstract] [Full Text]

L. Steinman, Modulation of postoperative cognitive decline via blockade of inflammatory cytokines outside the brain. Proc. Natl. Acad. Sci. U.S.A. 107, 20595–20596 (2010). [Full Text]

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