Effects of hyperoxia on 18F-fluoro-misonidazole brain uptake and tissue oxygen tension following middle cerebral artery occlusion in rodents: Pilot studies

Abstract

PurposeMapping brain hypoxia is a major goal for stroke diagnosis, pathophysiology and treatment monitoring. 18F-fluoro-misonidazole (FMISO) positron emission tomography (PET) is the gold standard hypoxia imaging method. Normobaric hyperoxia (NBO) is a promising therapy in acute stroke. In this pilot study, we tested the straightforward hypothesis that NBO would markedly reduce FMISO uptake in ischemic brain in Wistar and spontaneously hypertensive rats (SHRs), two rat strains with distinct vulnerability to brain ischemia, mimicking clinical heterogeneity.MethodsThirteen adult male rats were randomized to distal middle cerebral artery occlusion under either 30% O2 or 100% O2. FMISO was administered intravenously and PET data acquired dynamically for 3hrs, after which magnetic resonance imaging (MRI) and tetrazolium chloride (TTC) staining were carried out to map the ischemic lesion. Both FMISO tissue uptake at 2-3hrs and FMISO kinetic rate constants, determined based on previously published kinetic modelling, were obtained for the hypoxic area. In a separate group (n = 9), tissue oxygen partial pressure (PtO2) was measured in the ischemic tissue during both control and NBO conditions.ResultsAs expected, the FMISO PET, MRI and TTC lesion volumes were much larger in SHRs than Wistar rats in both the control and NBO conditions. NBO did not appear to substantially reduce FMISO lesion size, nor affect the FMISO kinetic rate constants in either strain. Likewise, MRI and TTC lesion volumes were unaffected. The parallel study showed the expected increases in ischemic cortex PtO2 under NBO, although these were small in some SHRs with very low baseline PtO2.ConclusionsDespite small samples, the apparent lack of marked effects of NBO on FMISO uptake suggests that in permanent ischemia the cellular mechanisms underlying FMISO trapping in hypoxic cells may be disjointed from PtO2. Better understanding of FMISO trapping processes will be important for future applications of FMISO imaging.

The cellular basis of increased PET hypoxia tracer uptake in focal cerebral ischemia with comparison between [18F]FMISO and [64Cu]CuATSM

“…The difference between the [ 18 F]FMISO SUV% of the hypoxic region and the control region was approximately +25%. The difference is substantially lower than what has been observed in spontaneously hypertensive rats 34 , 35 but comparable to what has previously been recorded in healthy animals of the Wistar strain. 26 In animals examined with [ 64 Cu]CuATSM, as well as DWI MRI, we could not find any increase in tracer uptake, even though regions of restricted diffusion were found in DWI and IF analysis revealed areas of pimonidazole increase in the M2CAO cortex of these animals.…”

Assessing the Effects of Cytoprotectants on Selective Neuronal Loss, Sensorimotor Deficit and Microglial Activation after Temporary Middle Cerebral Occlusion

“…Microclip distal temporary MCAo (md-tMCAo) was performed using the method described by Buchan et al, [33] as implemented in our laboratory and detailed previously [9,19,20,21,23,34,35,36]. The MCA clip was applied onto the left MCA and removed after 15 min and the wound was closed.…”

The Roles of Hypoxia Imaging Using 18F-Fluoromisonidazole Positron Emission Tomography in Glioma Treatment

“…FMISO trapping was present mainly in the penumbra but also in the ischemic core, raising the possibility that there may be viable cells even in the ischemic core. In a pilot study by Fryer et al, normobaric hyperoxia (NBO) treatment was tested in a rodent ischemic stroke model to determine whether this treatment reduces FMISO uptake [32]. NBO did not appear to substantially reduce the size of FMISO uptake volume nor affect the FMISO kinetic rate constants.…”