The Hsp90 Inhibitor 17-DMAG Attenuates Hyperglycemia-Enhanced Hemorrhagic Transformation in Experimental Stroke

Abstract

Introduction: Hemorrhagic transformation (HT) is one of the most common complications of ischemic stroke which is exacerbated by hyperglycemia. Oxidative stress, inflammatory response, and matrix metalloproteinases (MMPs) have been evidenced to play a vital role in the pathophysiology of HT. Our previous study has reported that 17-DMAG, an Hsp90 inhibitor, protects the brain against ischemic injury via inhibiting inflammation and reducing MMP-9 after ischemia. However, whether 17-DMAG would attenuate HT in hyperglycemic middle cerebral artery occlusion (MCAO) rats is still unknown.

Methods: Acute hyperglycemia was induced by an injection of 50% dextrose. Rats were pretreated with 17-DMAG before MCAO. Infarction volume, hemorrhagic volume neurological scores, expressions of inflammatory molecules and tight junction proteins, and activity of MMP-2 and MMP-9 were assessed 24 h after MCAO.

Results: 17-DMAG was found to reduce HT, improve neurological function, and inhibit expressions of inflammatory molecules and the activation of MMPs at 24 h after MCAO.

Conclusion: These results implicated that Hsp90 could be a novel therapeutic target in HT following ischemic stroke.

Figure 1

The effects of 17-DMAG on HT and neurological function in hyperglycemic MCAO rats. (a) 17-DMAG had no effects on blood glucose at the 4 time points. (b) Representative pictures of whole brain and TTC stained slices. 17-DMAG reduced hemorrhagic transformation following MCAO and decreased infarction volume. (c) Statistical analysis of blood volume in each group. 17-DMAG significantly reduced hyperglycemia-enhanced hemorrhagic volume at 24 h after MCAO. (d) Neurological function scoring at 24 h after MCAO. 17-DMAG significantly improved the neurological deficit at 24 h. ^∗p < 0.05 compared with sham group; ^#p < 0.05 compared with MCAO group. n = 5‐8 for each group.

Figure 2

Effects of 17-DMAG on tight junction proteins in hyperglycemic MCAO rats. (a) Representative Western blots of ZO-1 and occludin. (b) 17-DMAG significantly restored occludin and ZO-1 downregulation. ^∗p < 0.05, compared with the sham group; ^#p < 0.05, compared with the MCAO group; n = 3 for each group.

Figure 3

Effects of 17-DMAG on MMP activation in hyperglycemic rats after MCAO. (a) Representative bans for MMP-9 and MMP-2. (b) Statistical analysis for MMP-9 and MMP-2 activation. 17-DMAG remarkably decreased the activity of MMP-9 and MMP-2. ^∗p < 0.05, compared with the sham group; ^#p < 0.05, compared with the MCAO group; n = 3 for each group.

Figure 4

Effects of 17-DMAG on oxidative stress in hyperglycemic rats after MCAO. (a) Representative immunoblots of histidine adduct and nitrotyrosine at 24 h in the ischemic hemisphere. (b) Statistical analysis for the Western blot showed increased histidine adduct and nitrotyrosine levels in the MCAO group which were restored by 17-DMAG. ^∗p < 0.05, compared with the sham group; ^#p < 0.05, compared with the MCAO group; n = 3‐4 for each group.

Figure 5

Effects of 17-DMAG on inflammation in hyperglycemic rats after MCAO. (a) Representative Western blots of TNF-α and IL-1β. (b) 17-DMAG effectively inhibited the increase of TNF-α and IL-1β in hyperglycemic rats after MCAO. ^∗p < 0.05, compared with the sham group; ^#p < 0.05, compared with the MCAO group; n = 3 for each group.