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Monday, April 25, 2011
It’s All in the Genes: Another Example
J. Lance Lichtor
Note:  The article that is discussed appears in this month’s issue of Anesthesiology and was also selected as an editors’ choice in the journal Science Translational Medicine

Postoperative cognitive dysfunction (POCD) may be an issue for both the very young and the very old.  The evidence to show that this might occur largely comes from work with animals.  Given this initial work, the next step is to understand the mechanism for these findings.  Humans generally receive anesthesia when they are undergoing a surgical procedure.  The relevance of most animal studies of POCD to humans is unclear since the animals do not also undergo a surgical procedure.

In this month’s issue of Anesthesiology, an article was published where an animal model that involved both anesthesia and arthroplasty surgery was used to test the hypothesis that overexpression of a specific protein, heat shock protein 72 (Hsp72), could prevent or reduce POCD.  For some background, in a recent review in Anesthesiology, evidence was provided to show how Hsp72 might be involved in the development of cerebral ischemia.(1)  Hsp72 proteins are also thought to be involved in the proliferation of certain cancer cells.(2)

In the current study, wild-type mice and Hsp72 overexpressing transgenic mice (Hsp72-Tg) were randomly allocated to one of three groups:  control, isoflurane anesthesia alone (A), or anesthesia with tibial fracture and pinning (S).  The Hsp72-Tg mice had Hsp72 brain levels that were ten times that of wild-type mice.  The mice in groups A and S received buprenorphine intraperitoneally and the mice in group S also received an application of local anesthesia until day 3 postoperatively.  Before surgery, the mice learned the association between a tone and a mild shock.  Memory was assessed 1, 3 and 7 days after anesthesia; aspects of learning were either non-hippocampal- or hippocampal-dependant.  After 1 or 7 days, mice were sacrificed and immunoreactivity in the hippocampus was measured.

On day 1, hippocampal-dependent and –independent memory for wild-type group S mice was less compared to the Hsp72-Tg mice.   On day 3 when the effect was more notable, in both groups S and A, hippocamapal-dependent and –independent memory was less for wild-type mice compared to the Hsp72-Tg mice.  No differences were seen on day 7.  Activated microglia were more prominent in the animals that underwent surgery, though no genotype effect was seen.

The fact that Hsp72 over-expression results in full maintenance of memory after surgery and anesthesia is fascinating.  The mechanistic basis for these findings is unclear.


References
1.  Giffard RG, Han RQ, Emery JF, Duan M, Pittet JF: Regulation of apoptotic and inflammatory cell signaling in cerebral ischemia: The complex roles of heat shock protein 70. Anesthesiology 2008; 109:339–48

2.  Sherman M: Major heat shock protein Hsp72 controls oncogene-induced senescence. Ann N Y Acad Sci 2010; 1197: 152-7

3. Vizcaychipi MP, Xu L, Barreto GE, Ma D, Maze M, Giffard RG: Heat Shock Protein 72 Overexpression Prevents Early Postoperative Memory Decline after Orthopedic Surgery under General Anesthesia in Mice. Anesthesiology 2011; 114: 891-900

About the Author

J. Lance Lichtor, M.D
J. Lance Lichtor, M.D. is a professor of anesthesiology and pediatrics at The University of Massachusetts Medical School. He is the web editor and an associate editor for Anesthesiology.

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