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.
Highlights
Hemorrhagic transformation (HT) is one of the most common complications of ischemic stroke which is exacerbated by hyperglycemia
This blood-brain barrier (BBB) disruption is thought to be primarily mediated by matrix metalloproteinases (MMP-2 and MMP-9) that are produced in response to inflammation and oxidative stress, thereby leading to the development of HT in ischemic stroke patients [5]
We have previously found that serum Hsp90 levels are significantly in patients following ischemic stroke and that these levels correlate with MMP-9 expression, raising the possibility that Hsp90 may play a key role in regulating MMP-9 expression and consequent disruption of the BBB after cerebral ischemia [8]
Summary
Hemorrhagic transformation (HT) occurs in 10–4% of patients suffering from ischemic stroke, leading to significant morbidity and mortality in affected individuals [1, 2]. Previous studies have clearly demonstrated that hyperglycemia can increase HT incidence following ischemic stroke, potentially leading to more serious brain infarction in these patients [3] This hyperglycemia-mediated enhancement of HT is known to be associated with increased oxidative stress and inflammatory activity, potentially leading to blood-brain barrier (BBB) disruption and the death of neurons [4]. In the context of inflammation and oxidative stress as occurs during ischemic stroke, Hsp has further been shown to play an essential role in regulating the expression and activity of MMP proteins [7]. As MMPs are known to be key mediators of hyperglycemiaenhanced HT development after ischemic stroke, we hypothesized that inhibiting Hsp may represent an effective means of treating HT in this context. We tested the ability of 17-DMAG to suppress the development or severity of acute hyperglycemiaenhanced HT in an experimental stroke model and to explore the molecular mechanisms underlying such suppression
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