roderic g. eckenhoff, md dept. anesthesiology & critical care, university of pennsylvania...
Post on 12-Jan-2016
233 Views
Preview:
TRANSCRIPT
Roderic G. Eckenhoff, MDDept. Anesthesiology & Critical Care, University of Pennsylvaniaroderic.eckenhoff@uphs.upenn.edu
Hypothesis: Inhaled anesthetics promote aggregation and toxicity of disease-associated peptides, and thereby accelerate the onset of neurodegenerative disorders, like Alzheimers.
Methods:1. In vitro protein studies – Aβ.1-40 and Aβ1-42 .2. Cell culture models – exogenous and endogenous.3. Transgenic animal models of enhanced Aβ expression.
Background: 1. Durable post-operative cognitive decline in older people. 2. Positive odds ratio for Alzheimer disease and prior surgery.3. Biophysical basis for enhanced protein oligomerization.
Disclosure: No conflicts
Anesthesiology 2004;101:703Anesthesiology 2004;101:703Current Alzheimer Research 2007 (in press)Current Alzheimer Research 2007 (in press)
0 10 20 30 40 50 60 700
250
500
750
0
1
2
3
4
5
6
time, hrs
Flu
ore
sc
en
ce
@ 4
80
nm
[Ha
loth
an
e], m
M
0 5 10 150
25
50
75
100
125HalothaneIsofluraneEthanol (X100)
Propofol (100)
concentration, mM
"So
lub
le"
A 1-
42,
% r
emai
nin
g
0 10 20 300
5.0×10 3
1.0×10 4
1.5×10 4
2.0×10 4
2.5×10 4
Time (minutes)
Abs
orba
nce
Isolated proteinsIsolated proteins
LD
H r
ele
ase,
%
ch
an
ge
from
con
trol
Halothane
-25
0
25
50
Isoflurane
-25
0
25
50
1 M
AC
2 M
AC A
A
+ 1M
AC
A
+ 2
MA
C
* #
†
*#†
Propofol, ethanol
-25
0
25
50
prop
ofol
etha
nol A
A
+ pr
opof
ol
A
+ et
hano
l
* * *
Cell CultureCell Culture
Anesthesiology 2004;101:703Anesthesiology 2004;101:703
WT Vector L286V0
50
100
150
- Isoflurane + Isoflurane
***
*+
LD
H (
% C
ont
rol)
WT Vector L286V0
25
50
75
100
125
- Isoflurane + Isoflurane
*+
**
MT
T (%
Co
ntro
l)
WT Vector L286V0
50
100
150
-Halothane +Halothane
***
*+
LD
H (
% C
ont
rol)
WT Vector L286V0
25
50
75
100
125
- Halothane + Halothane
***
MT
T (%
Co
ntro
l)
Animals: Tg2576Animals: Tg2576
Tg-Con Tg-Iso Tg-Hal0.0
2.5
5.0
7.5
10.0
To
tal
# P
laq
ues
WT Tg
C H I C H I
Impact of Prior Anesthesia History on ADImpact of Prior Anesthesia History on ADSilber & Rosenbaum analysis of Bohnen papersSilber & Rosenbaum analysis of Bohnen papers
0
0.5
1
1.5
2
Odds Ratio
None 1-5 >6
Number of Anesthetics
Number of Prior Anesthetics
0
0.5
1
1.5
2
Odds Ratio
None <10 hr >10 hr
Hours of Anesthesia
Hours of Prior Anesthesia
P=0.08 one sided P=0.11 one sided
Conclusions:
1. Inhaled anesthetics accelerate aggregation of Aβ. Halo>Iso2. Inhaled anesthetics stabilize the toxic Aβ oligomer.3. Aβ plus anesthetic is more cytotoxic than either alone.4. Inhaled anesthetics enhance plaque in transgenic mouse brain.5. Isoflurane causes learning/memory impairment in old WT mice.
Future directions:
1. Rank-order effects for all these actions.2. Effects at pre-symptomatic stage.3. Large epidemiologic studies. 4. Biomarker studies.
top related