Mismatches between tissue perfusion-weighted imaging (PWI; an index of blood flow deficit) and cellular diffusion-weighted imaging (DWI; an index of tissue injury) provide information on potentially salvageable penumbra tissue in focal stroke and can identify "treatable" stroke patients. The present pre-clinical studies were conducted to: a.) Determine PWI (using perfusion delay) and DWI measurements in two experimental stroke models, b.) Utilize these measurements to characterize selective ET(A) receptor antagonism (i.e., determine efficacy, time-to-treatment and susceptibility to treatment in the different stroke models), and c.) Determine if increasing the reduced blood flow following a stroke is a mechanism of protection. Permanent middle cerebral artery occlusion (MCAO) or sham surgeries were produced in Sprague Dawley rats (SD; proximal MCAO; hypothesized to be a model of slowly evolving brain injury with a significant penumbra) and in spontaneously hypertensive rats (SHR; distal MCAO; hypothesized to be a model of rapidly evolving brain injury with little penumbra). Infusions of vehicle or SB 234551 (3, 10, or 30 microg/kg/min) were initiated at 0, 75, and/or 180 min post-surgery and maintained for the remainder of 24 h post-surgery. Hyper-intense areas of perfusion delay (PWI) in the forebrain were measured using Gadolinium (Gd) bolus contrast. DWI hyper-intense areas were also measured, and the degree of forebrain DWI-PWI mismatch was determined. Region specific analyses (ROI) were also conducted in the core ischemic and low perfusion/penumbra areas to provide indices of perfusion and changes in the degree of tissue perfusion due to SB 234551 treatment. At 24 h post-surgery, final infarct volume was measured by DWI and by staining forebrain slices. Following SD proximal MCAO, there was a significant mismatch in the ischemic forebrain PWI compared to DWI (PWI>DWI) at 60 min which was maintained up to 150 min (all p<0.05). By 24 h post-stroke, infarct volume was identical to the area of early perfusion deficit/PWI, suggesting a slow progression of infarct development that expanded into the significant, earlier cortical penumbra (i.e., model with salvageable tissue with potential for intervention). When SB 234551 was administered within the period of peak mismatch (i.e., at 75 min post-stroke), SB 234551 provided significant dose-related reductions in cortical (penumbral) progression to infarction (p<0.05). Cortical protection was related to an increased/normalization of the stroke-induced decrease in tissue perfusion in cortical penumbra areas (p<0.05). No SB 234551-induced changes in reduced tissue perfusion were observed in the striatum core ischemic area. Also, when SB-234551 was administered beyond the time of mismatch, no effect on cortical penumbra progression to infarct was observed. In comparison and strikingly different, following SHR distal MCAO there was no mismatch between PWI and DWI (PWI=DWI) as early as 60 min post-stroke, with this early change in SHR DWI being identical to the final infarct volume at 24 h, suggesting a rapidly occurring brain injury with little cortical penumbra (i.e., model with little salvageable tissue or potential for intervention). In distal MCAO, SB 234551 administered immediately at the time of stroke did not have any effect on infarct volume in SHR. These data demonstrate that selective blockade of ET(A) receptors is protective following proximal MCAO in SD (i.e. a model similar to "treatable" clinical patients). The protective mechanism appears to be due to enhanced collateral blood flow and salvage of penumbra. Therefore, the use of PWI-DWI mismatch signatures can identify treatable stroke models characterized by a salvageable penumbra and can define appropriate time to treatment protocols. In addition, tissue perfusion information obtained under these conditions might clarify mechanism of protection in the evaluation of protective compounds for focal stroke.

Objective: To non-invasively characterize ectopic uterine tissue (EUT) development in a modified autologous rat surgical model of endometriosis using magnetic resonance imaging (MRI). Design: Investigational MRI study. Setting: A pharmaceutical company. Animal(S): Female Sprague Dawley rats. I ntervention(s): Uterine tissue was autotransplanted on the right peritoneal wall of rats. Rats were serially imaged after surgery and after endogenous hormone suppression, hormone supplementation, or ovariectomy. In addition, an MRI contrast agent was administered to examine EUT perfusion characteristics. Main Outcome Measure(s): Changes in transplanted EUT volume and perfusion were monitored using MRI. Result(s): The EUT growth could be readily monitored non-invasively by MRI. Although EUT growth was rapid during the initial 4 days after surgery, volume stabilized by the third week and maintained for at least 9 weeks after transplantation. The EUT volumes varied with the estrous cycle and were hormonally sensitive to ovariectomy, to Antide (GnRH antagonist), and to Antide followed by 17 beta-E-2 supplementation. The use of an MRI contrast agent facilitated visualization of EUT wall perfusion. Conclusion(s): MRI allows for noninvasive, dynamic evaluation of transplanted EUT growth in the rat. This reproducible model will allow for performing quantifiable pharmacologic studies in pre-clinical drug discovery for therapies targeting endometriosis. (Fertil Steril (R) 2007;88(Suppl 2):1058-64. (C)2007 by American Society for Reproductive Medicine.)

Image Analyses: The perfusion delay index (PDI) was calculated from the 4 ipsilateral areas and their corresponding contralateral counterparts using the DWI image as a reference. Of these four areas, three were chosen in the cortical region and one in the striatal region. The PDI index was defined as a ratio of the mean signal intensity in the ipsilateral area to that in the contralateral counterpart and expressed as a percentage. This calculation was done only at that instance of time when the contrast uptake was maximal in the contralateral hemisphere. Analysis of variance was used followed by appropriate post-hoc comparisons with p<0.05 considered significant. Results A representative graph showing the perfusion delay index (PDI) at one cortical region is shown in Fig 1. In all the three cortical regions evaluated, we found significant differences between vehicle and 10 ug/kg/min SB-234551 group in the perfusion delay index (PDI). The 3 ug/kg/min group did not show a significant effect at any site. Moreover, neither dose had any significant effects on the striatum. The histological data confirmed the protective effects of SB-234551 by demonstrating statistically significant reductions in lesion sizes in both treatment groups (Fig. 2). Fig. 1- Percent PDI values measured from a cortical region following treatment with 10 ug/kg/min (n=10), 3 ug/kg/min (n=10), and vehicles group (n=9). A significant difference between the 10 ug/kg/min and vehicle groups was found (*p<0.01).