An examination of the temporal and spatial evolution of a small permanent focal ischemic lesion
Date
2003
Authors
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Publisher
ORCID
Type
Degree Level
Doctoral
Abstract
The research reported here was designed to validate our hypothesis that noninvasive
imaging could delineate the evolution of a small ischemic infarct.
Furthermore, the alterations observed by MR were correlated to histological and
inflammatory markers. Finally, intervention with a calcium buffering agent was
hypothesized to prevent many of these changes.
The first part of this study investigated the development of a small focal
cortical lesion produced as a result of a cortical devascularization injury. Diffusion-weighted
images (DWI) were collected before injury and at 12, 24, 48 hours and 3, 5,
7 and 14 days after injury and apparent diffusion coefficient (ADC) maps were
calculated from the DW images to quantify lesion development. As a second
measure of injury, tissue morphology was analyzed using cresyl violet
histochemistry. Results indicated a significant reduction in ADC values within the
lesion cortex that first appeared at 12 hours after injury and then recovered to control
levels by 14 days. ADC changes were also observed in the contralateral cortex. This
type of injury also resulted in the progressive but relatively slow formation of a pannecrotic
infarct. Both astrocyte and microglia activation occurred early and were
present in both hemispheres, however inflammatory cell infiltration was delayed
until 48 hours after the injury. Many of these inflammatory cells were tumor
necrosis factor a (TNF-a) and interferon y (IFN-y) immunoreactive. Overall, the
quantitative and histological measures of this lesion were consistent with those
observed in ischemic injury. Moreover, we found DWI to be a sensitive measure of
damage associated with a cortical devascularization injury.
The second part of this study used 2-aminophenol-N, N, O-triacetic acid
acetoxymethyl ester (APTRA-AM) to determine the effectiveness of a calcium buffer
in providing neuroprotection after a cortical devascularization injury. Animals were
given two intravenous injections of either saline, DMSO, or APTRA-AM at 1 and 12
hours after injury. Animals were then imaged using a multiple b-value DWI
sequence prior to injury and then at 12, 24,48 hours, 3 and 7 days after injury. After
7 days the animals were sacrificed and correlative histological and
immunocytochemical studies were done. Our results indicate that saline injection
after injury resulted in a decrease in the ADC of the lesion cortex within the first 12
hours of injury, which then slowly returned to prescan levels. In contrast, the
injection of either DMSO or APTRA-AM after injury resulted in no significant
changes in the ADC within the lesion area. Histologically, both saline and DMSO
injected animals had pan-necrotic infarcts with concomitant glial activation and
inflammatory cell infiltration. APTRA-AM treated animals showed an 86%
reduction in lesion area and no evidence of inflammatory cell infiltration. The results
presented here clearly demonstrate the effectiveness of APTRA-AM in preventing
neuronal cell death and the accompanying inflammatory response when administered
post-injury, suggesting that this molecule may be an excellent candidate for future
clinical neuroprotection studies.
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Degree
Doctor of Philosophy (Ph.D.)
Department
Anatomy and Cell Biology
Program
Anatomy and Cell Biology