Methylene blue treatment delays progression of perfusion-diffusion mismatch to infarct in permanent ischemic stroke

Abstract

Stroke is a leading cause of morbidity and mortality in the world. Low-dose methylene blue (MB), which has been used safely to treat methemoglobinemia and cyanide poisoning in humans, has energy enhancing and antioxidant properties. We tested the hypothesis that methylene blue treatment delays progression of at-risk tissue (ca. perfusion-diffusion mismatch) to infarct in permanent middle cerebral artery occlusion in rats at two MB treatment doses. Serial MRI was used to evaluate MB treatment efficacy. The major findings were: (i) MB significantly prolonged the perfusion-diffusion mismatch, (ii) MB mildly increased the CBF in the hypoperfused tissue, (iii) MB did not change the final infarct volume in permanent ischemic stroke, and (iv) there were no dose-dependent effects on mismatch progression for the 1 and 3mg/kg doses studied. This neuroprotective effect is likely the result of sustained ATP production and increased CBF to tissue at risk. This work has the potential to readily lead to clinical stroke trials given MB's excellent safety profile.

Keywords: Infarct volume; Ischemic penumbra; MRI; Middle-cerebral artery occlusion; Neuroprotection; Oxidative stress.

Copyright © 2014 Elsevier B.V. All rights reserved.

Figures

Figure 1

Representative baseline cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) lesion volumes at 30min, ADC volumes at 180min and T2 volumes at 24hrs for the vehicle, 1m/kg and 3mg/kg methylene blue (MB) groups.

Figure 2

Temporal evolution of ADC and CBF lesion volumes for the 1mg/kg MB and vehicle rats (n=12 for each group). Closed circles (CBF) and squares (ADC) (*p

Figure 3

Temporal evolution of ADC and CBF lesion volumes for the 3mg/kg groups (n=12 for vehicle ADC and CBF, and n= 5 for 3mg/kg CBF, and n=7 for 3mg/kg ADC). Closed circles (CBF) and squares (ADC) (*p

Figure 4

(A) Depiction of central and peripheral ADC volumes (B) Temporal evolution of ADC and CBF lesion volumes in peripheral and (C) central slices (n=12 for each group) in the 1mg/kg MB and vehicle-groups. Open circles (CBF) and squares (ADC) (*p<0.05).