Overexpression of human S100B exacerbates brain damage and periinfarct gliosis after permanent focal ischemia - PubMed (original) (raw)

Overexpression of human S100B exacerbates brain damage and periinfarct gliosis after permanent focal ischemia

Takashi Mori et al. Stroke. 2008 Jul.

Abstract

Background and purpose: We have previously demonstrated that augmented and prolonged activation of astrocytes detrimentally influences both the subacute and chronic phases of cerebral ischemia. Furthermore, we have suggested that the astrocyte-derived protein S100B may be important in these pathogenic events. However, the causal relationship between S100B and exacerbation of brain damage in vivo remains to be elucidated.

Methods: Using transgenic mice overexpressing human S100B (Tg huS100B mice), we examined whether S100B plays a cardinal role in aggravation of brain damage after permanent middle cerebral artery occlusion (pMCAO).

Results: Tg huS100B mice had significantly larger infarct volumes and worse neurological deficits at any time point examined after pMCAO as compared with CD-1 background strain-matched control mice. Infarct volumes in Tg huS100B mice were significantly increased from 1 to 3 and 5 days after pMCAO (delayed infarct expansion), whereas those in control mice were not significantly altered. S100, glial fibrillary acidic protein, and Iba1 burdens in the periinfarct area were significantly increased through to 7 days after pMCAO in Tg huS100B mice, whereas those in control mice reached a plateau at 3 days after pMCAO.

Conclusions: These results provide genetic evidence that overexpression of human S100B acts to exacerbate brain damage and periinfarct reactive gliosis (astrocytosis and microgliosis) during the subacute phase of pMCAO.

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Figures

Figure 1

Figure 1

Infarct expansion after pMCAO is S100B transgene-dependent. Infarct volumes are shown at 1, 3, 5, and 7 days after pMCAO in Tg huS100B and CD-1 mice. **P<0.01, ***P<0.001 (versus CD-1 mice); ##P<0.01 (versus 1 day).

Figure 2

Figure 2

A, There are no remarkable differences between 2 lines of mice in terms of the circle of Willis, anterior cerebral artery, middle cerebral artery, posterior cerebral artery, or microvessels, except for a minor variation of the branching angle. Both of the posterior communicating arteries are detected in 2 lines of mice (inset). Arrowhead, posterior communicating artery; PCA, posterior cerebral artery; BA, basilar artery. Scale bar=50 µm. B, Regional cerebral blood flow after pMCAO in Tg huS100B and CD-1 mice. Statistical analysis revealed a within-each line of mice main effect of time after pMCAO (***P<0.001 for the core, **P<0.01 for the periphery). CCAO indicates common carotid artery occlusion; CBF, cerebral blood flow.

Figure 3

Figure 3

A, Expression of S100 in the periinfarct areas. In both lines of mice, S100 immunoreactivity appears to be enhanced at 3, 5, and 7 days versus 1 day after pMCAO. Most importantly, S100 immunoreactivity appears to be more pronounced in Tg huS100B mice versus CD-1 mice at all time points after pMCAO. Scale bar=50 µm. B, Five open rectangles in the inset of the coronal brain section diagram designate the regions of interest. ***P<0.001 (versus CD-1 mice); †††_P_≤0.001 (versus 1 day); ###P<0.001 (versus 3 days).

Figure 4

Figure 4

A, Expression of GFAP in the periinfarct areas. GFAP immunoreactivity appears to be enhanced at 3, 5, and 7 days versus 1 day after pMCAO in both lines of mice. Most importantly, GFAP immunoreactivity appears to be more prominent in Tg huS100B mice versus CD-1 mice at 3, 5, and 7 days after pMCAO. Scale bar=50 µm. B, Five open rectangles in the inset of the coronal brain section diagram designate the regions of interest. ***P_≤0.001 (versus CD-1 mice); †††_P<0.001 (versus 1 day); ###P<0.001 (versus 3 days).

Figure 5

Figure 5

A, Expression of Iba1 in the periinfarct areas. Iba1 immunoreactivity appears to be enhanced at 3, 5, and 7 days versus 1 day after pMCAO in both lines of mice. Most importantly, Iba1 immunoreactivity appears to be more prominent in Tg huS100B mice versus CD-1 mice at 3, 5, and 7 days after pMCAO. Scale bar=50 µm. B, Five open rectangles in the inset of the coronal brain section diagram designate the regions of interest. ***P_≤0.001 (versus CD-1 mice); †††_P<0.001 (versus 1 day); ###P<0.001 (versus 3 days).

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