Abstract
Loss of integrity of the blood-brain barrier (BBB) in ischemic stroke victims initiates a devastating cascade of events causing brain damage. Maintaining the BBB is important to preserve brain function in ischemic stroke. Unfortunately, recombinant tissue plasminogen activator (tPA), the only effective fibrinolytic treatment at the acute stage of ischemic stroke, also injures the BBB and increases the risk of brain edema and secondary hemorrhagic transformation. Thus, it is important to identify compounds that maintain BBB integrity in the face of ischemic injury in patients with stroke. We previously demonstrated that intravenously injected phosphorylated recombinant heat shock protein 27 (prHSP27) protects the brains of mice with transient middle cerebral artery occlusion (tMCAO), an animal stroke-model. Here, we determined whether prHSP27, in addition to attenuating brain injury, also decreases BBB damage in hyperglycemic tMCAO mice that had received tPA. After induction of hyperglycemia and tMCAO, we examined 4 treatment groups: 1) bovine serum albumin (BSA), 2) prHSP27, 3) tPA, 4) tPA plus prHSP27. We examined the effects of prHSP27 by comparing the BSA and prHSP27 groups and the tPA and tPA plus prHSP27 groups. Twenty-four hours after injection, prHSP27 reduced infarct volume, brain swelling, neurological deficits, the loss of microvessel proteins and endothelial cell walls, and mortality. It also reduced the rates of hemorrhagic transformation, extravasation of endogenous IgG, and MMP-9 activity, signs of BBB damage. Therefore, prHSP27 injection attenuated brain damage and preserved the BBB in tPA-injected, hyperglycemic tMCAO experimental stroke-model mice, in which the BBB is even more severely damaged than in simple tMCAO mice. The attenuation of brain damage and BBB disruption in the presence of tPA suggests the effectiveness of prHSP27 and tPA as a combination therapy. prHSP27 may be a novel therapeutic agent for ischemic stroke patients whose BBBs are injured following tPA injections.
Highlights
Heat shock protein 27 (HSP27) is a small, highly conserved protein with various functions, including as a molecular chaperone, free radical scavenger, and anti-apoptotic factor, that interacts with cytochrome c and interferes with caspase activation complexes [1]
Ischemic mice were intravenously injected with bovine serum albumin (BSA) (n = 9), prHSP27 (n = 6), tissue plasminogen activator (tPA) (n = 7), and tPA plus prHSP27 (n = 7) 2 h after the start of reperfusion (Fig 1A)
Brain swelling was decreased by 63% (p = 0.016) in the prHSP27 group compared to the BSA group and by 46% (p = 0.023) in the prHSP27 plus tPA group compared to the tPA group. tPA did not significantly increase brain swelling compared to BSA (p = 0.385) (Fig 1C)
Summary
Heat shock protein 27 (HSP27) is a small, highly conserved protein with various functions, including as a molecular chaperone, free radical scavenger, and anti-apoptotic factor, that interacts with cytochrome c and interferes with caspase activation complexes [1]. HSP27-transgenic models exhibit numerous cytoprotective effects in in vivo models of various diseases, including cardiac ischemia [4,5], kainate-induced hippocampal cell death [6], nerve injury [7], the tau model of Alzheimer’s disease [8], [9], and the SOD1G93A model of amyotrophic lateral sclerosis [10]. HSP27-transgenic mice exhibit reduced infarcts after transient cerebral ischemia [14]. We previously demonstrated that intravenously injected phosphorylated HSP27 protected the brains of mice with transient middle cerebral artery occlusion (tMCAO) [18,19], whereby it suppressed apoptotic cell death, oxidative DNA damage, and inflammatory responses, and preserved the BBB
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