Abstract
BackgroundLimiting expansion of the ischemic core lesion by reinstating blood flow and protecting the penumbral cells is a priority in acute stroke treatment. However, at present, methods are not available for effective drug delivery to the ischemic penumbra. To address these issues this study compared the extravasation and subsequent interstitial spread of a magnetic resonance contrast agent (MRCA) beyond the ischemic core into the surrounding brain in a rat model of ischemia-reperfusion for bolus injection and step-down infusion (SDI) protocols.MethodsMale Wistar rats underwent middle cerebral artery (MCA) occlusion for 3 h followed by reperfusion. Perfusion-diffusion mismatched regions indicating the extent of spread were identified by measuring cerebral blood flow (CBF) deficits by arterial spin-labeled magnetic resonance imaging and the extent of the ischemic core by mapping the apparent diffusion coefficient (ADC) of water with diffusion-weighted imaging. Vascular injury was assessed via MRCA, gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) penetration, by Look-Locker T1-weighted MR imaging after either a bolus injection (n = 8) or SDI (n = 6). Spatial and temporal expansion of the MRCA front during a 25 min imaging period was measured from images obtained at 2.5 min intervals.ResultsThe mean ADC lesion was 20 ± 7% of the hemispheric area whereas the CBF deficit area was 60 ± 16%, with the difference between the areas suggesting the possible presence of a penumbra. The bolus injection led to MRCA enhancement with an area that initially spread into the ischemic core and then diminished over time. The SDI produced a gradual increase in the area of MRCA enhancement that slowly enlarged to occupy the core, eventually expanded beyond it into the surrounding tissue and then plateaued. The integrated area from SDI extravasation was significantly larger than that for the bolus (p = 0.03). The total number of pixels covered by the SDI at its maximum was significantly larger than the pixels covered by bolus maximum (p = 0.05).ConclusionsThese results demonstrate that the SDI protocol resulted in a spread of the MRCA beyond the ischemic core. Whether plasma-borne acute stroke therapeutics can be delivered to the ischemic penumbra in a similar way needs to be investigated.
Highlights
Limiting expansion of the ischemic core lesion by reinstating blood flow and protecting the penumbral cells is a priority in acute stroke treatment
Occlusion of the middle cerebral artery (MCA) reduced cerebral blood flow (CBF) to ~30% compared to the corresponding contralateral values in the region affected by occlusion
In the superior sagittal sinus, used to measure blood magnetic resonance contrast agent (MRCA) levels, the bolus injection resulted in a maximum ΔR1 (R1 = 1/T1, longitudinal relaxation rate and a measure of contrast agent concentration [24]) of 0.02 ms−1 in the first acquired image at 2.5 min corresponding to the peak blood level during that period and decreased sharply over the 2.5 min
Summary
Limiting expansion of the ischemic core lesion by reinstating blood flow and protecting the penumbral cells is a priority in acute stroke treatment. At present, methods are not available for effective drug delivery to the ischemic penumbra To address these issues this study compared the extravasation and subsequent interstitial spread of a magnetic resonance contrast agent (MRCA) beyond the ischemic core into the surrounding brain in a rat model of ischemia-reperfusion for bolus injection and step-down infusion (SDI) protocols. Preserving the penumbra, the potentially salvageable area of brain tissue adjacent to an infarct core, is a primary objective following cerebral ischemia [1,2,3]. If successful, it can counter the expansion of the irreversibly damaged core and conserve penumbral cells for subsequent restorative and rehabilitative therapeutic interventions. How to best use this route to preserve the penumbra has received relatively little attention
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