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Comparative Study
. 2011 Feb;116(4):499-507.
doi: 10.1111/j.1471-4159.2010.07127.x. Epub 2011 Jan 25.

Exacerbated brain damage, edema and inflammation in type-2 diabetic mice subjected to focal ischemia

Kudret Tureyen  1 , Kellie Bowen, Jin Liang, Robert J Dempsey, Raghu Vemuganti
Affiliations
Comparative Study

Exacerbated brain damage, edema and inflammation in type-2 diabetic mice subjected to focal ischemia

Kudret Tureyen et al. J Neurochem. 2011 Feb.

"VSports" Abstract

One of the limiting factors in stroke therapeutic development is the use of animal models that do not well represent the underlying medical conditions of patients. In humans, diabetes increases the risk of stroke incidence as well as post-stroke mortality VSports手机版. To understand the mechanisms that render diabetics to increased brain damage, we evaluated the effect of transient middle cerebral artery occlusion in adult db/db mice. The db/db mouse is a model of type-2 diabetes with four times higher blood sugar than its normoglycemic genetic control(db/+ mouse). Following transient middle cerebral artery occlusion, the db/db mice showed significantly higher mortality, bigger infarcts, increased cerebral edema, worsened neurological status compared to db/+ mice. The db/db mice also showed significantly higher post-ischemic inflammatory markers (ICAM1(+) capillaries, extravasated macrophages/neutrophils and exacerbated proinflammatory gene expression) compared to db/+ mice. In addition, the post-ischemic neuroprotective heat-shock chaperone gene expression was curtailed in the db/db compared to db/+ mice. .

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Figures

Fig. 1
Fig. 1
Body weights (A) and blood glucose levels (B) of db/db and db/+ mice at 5 weeks and 14 weeks of age. Values are mean ± SD (n = 35/group). Statistics: ap<0.05 compared with the respective 5 week old group, bp<0.05 compared with the 14 week old db/+ group.
Fig. 2
Fig. 2
Survival rates (A) in 14 week old db/db and db/+ mice within the first 24h of reperfusion following transient MCAO. In panel A, the solid line is 2h MCAO in db/db, dotted line is 2h MCAO in db/+, long dashed line is 45 min MCAO in db/db and short dashed line is 45 min MCAO in db/+ cohorts. The number in the parenthesis after each line is the number of mice used for that group (A). The rCBF was not significantly different between db/db and db/+ mice subjected to 45 min transient MCAO (B). Values are mean ± SD (n = 13/group).
Fig. 3
Fig. 3
The db/db mice showed significantly bigger infarcts (A) and worsened neurological function (B) compared to db/+ mice following 45 min transient MCAO (A). Mice were tested at 3 days of reperfusion for both measures. *p<0.05 compared to db/+ group (one-way ANOVA followed by Tukey-Kramer multiple comparisons post-test). Bars in A represents mean ± SD (n = 9 for the db/db and 12 for the db/+ groups). The number of mice used for infarct measurement in the 2 groups was not equal as 3 mice in the db/db and 1 mouse in the db/+ groups died before 3 days of reperfusion. Bars in B represent individual neuroscore of each animal (n = 14 for the db/db and 17 for the db/+ groups). The number of mice for the neuroscoring includes those used for infarct measurement and MPO activity. The mean ± SD neuroscore was 88% higher (p<0.05) in the db/db (3.33±0.46) compared to db/+ (1.76 ±0.47) cohort. The bottom images are Cresyl violet-stained serial section from representative mice from db/db and db/+ cohorts subjected to 45 min transient MCAO and 3 days of reperfusion.
Fig. 4
Fig. 4
The cerebral water content was observed to be significantly higher in the ipsilateral cortex in comparison with the respective contralateral cortex in both db/+ and db/db cohorts subjected to 45 min transient MCAO and 1 day of reperfusion (A). The ipsilateral cortex of db/db group also showed significantly increased water content compared to the ipsilateral cortex of the db/+ mice. The MPO activity which is an indicator of the presence neutrophils was observed to be significantly higher in the ipsilateral cortex compared to the respective contralateral cortex of both db/+ and db/db mice subjected to transient MCAO and 3 days of reperfusion (B). In addition, the ipsilateral cortex of db/db showed significantly higher MPO activity than the ipsilateral cortex of the db/+ mice (B). The values are mean ± SD (n = 5/group). Statistics: ap<0.05 compared with the respective contralateral cortex, bp<0.05 compared with the ipsilateral cortex of db/+ and cp<0.05 compared with the contralateral cortex of db/+ (one-way ANOVA followed by Tucky-Kramer multiple comparisons post-test).
Fig. 5
Fig. 5
ICAM-1 immunopositive capillaries (A and B) and the OX-42 immunopositive activated microglia/macrophages (C and D) were higher in the ipsilateral cortex of db/db (B and D) compared to the db/+ (A and C) mice subjected to 45 min transient MCAO and 3 days of reperfusion. Scale bar is 100 μm. The images were taken from the ipsilateral cortex from the coordinates +1.0 from Bregma. The OX42+ cells were observed to be significantly higher (by 67% ± 11%; p<0.05 by Student’s t test) in the ipsilateral cortex of db/db (85 ± 15 cells/high power field) compared to db/+ (44 ± 8 cells/high power field) mice (n = 3/genotype).
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