Abstract
Acute ischemic stroke causes significant chronic disability worldwide. We designed this study to clarify the mechanism by which hypothermia helps alleviate acute ischemic stroke. In a middle cerebral artery occlusion model (4 h ischemia without reperfusion), hypothermia effectively reduces mean infarct volume. Hypothermia also prevents neurons in the infarct area from releasing high mobility group box 1 (HMGB1), the most well-studied damage-associated molecular pattern protein. By preventing its release, hypothermia also prevents the typical middle cerebral artery occlusion-induced increase in serum HMGB1. We also found that both glycyrrhizin-mediated inhibition of HMGB1 and intracerebroventricular neutralizing antibody treatments before middle cerebral artery occlusion onset diminish infarct volume. This suggests a clear neuroprotective effect of HMGB1 inhibition by hypothermia in the brain. We next used real-time polymerase chain reaction to measure the levels of pro-inflammatory cytokines in peri-infarct regions. Although middle cerebral artery occlusion increases the expression of interleukin-1β and tissue necrosis factor-α, this elevation is suppressed by both hypothermia and glycyrrhizin treatment. We show that hypothermia reduces the production of inflammatory cytokines and helps salvage peri-infarct regions from the propagation of ischemic injury via HMGB1 blockade. In addition to suggesting a potential mechanism for hypothermia’s therapeutic effects, our results suggest HMGB1 modulation may lengthen the therapeutic window for stroke treatments.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0260-0) contains supplementary material, which is available to authorized users.
Highlights
Traditional stroke treatments comprise aspirin, surgery, and thrombolysis [1,2,3]
Infarcts induced by 4 h middle cerebral artery occlusion (MCAO) are significantly diminished by hypothermia at 33 °C compared with normothermia (Fig. 1c, see in Additional file 1: Figure S1)
By measuring triphenyltetrazolium chloride (TTC) staining-negative tissue volumes, we found that mild hypothermia at 33 °C attenuates mean infarct volume from 256.40 ± 29.01 mm3 to 73.60 ± 37.67 mm3 (Fig. 1d)
Summary
Traditional stroke treatments comprise aspirin, surgery, and thrombolysis [1,2,3]. If they can be rapidly applied, intravenous tissue plasminogen activator (IV-tPA) and intra-arterial thrombolysis are the most effective treatmentsThe ischemic penumbra is an important target for stroke therapeutics. Traditional stroke treatments comprise aspirin, surgery, and thrombolysis [1,2,3]. If they can be rapidly applied, intravenous tissue plasminogen activator (IV-tPA) and intra-arterial thrombolysis are the most effective treatments. The ischemic penumbra is an important target for stroke therapeutics. According to its original delineation, the ischemic penumbra is the region of brain tissue receiving reduced cerebral blood flow that surrounds the. Lee et al Molecular Brain (2016) 9:81 infarct core [8]. If a therapeutic intervention fails, the ischemic penumbra can be encompassed into the developing infarct core [9, 10]. The principal molecular mediator of these neuroprotective effects of hypothermia is unknown
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