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Background and Purpose —The early ischemic lesions demonstrated by diffusion-weighted imaging (DWI) are potentially reversible. The purposes of this study were to determine whether resolution of initial DWI lesions is transient or permanent after different brief periods of focal brain ischemia and to evaluate histological outcomes. Methods —Sixteen rats were subjected to 10 minutes (n=7) or 30 minutes (n=7) of temporary middle cerebral artery occlusion or sham operation (n=2). DWI, perfusion-weighted imaging (PWI), and T 2 -weighted imaging (T 2 WI) were performed during occlusion; immediately after reperfusion; and at 0.5, 1.0, 1.5, 12, 24, 48, and 72 hours after reperfusion. After the last MRI study, the brains were fixed, sectioned, stained with hematoxylin and eosin, and evaluated for neuronal necrosis. Results —No MRI or histological abnormalities were observed in the sham-operated rats. In both the 10-minute and 30-minute groups, the perfusion deficits and DWI hyperintensities that occurred during occlusion disappeared shortly after reperfusion. The DWI, PWI, and T 2 WI results remained normal thereafter in the 10-minute group, whereas secondary DWI hyperintensity and T 2 WI abnormalities developed at the 12-hour observation point in the 30-minute group. Histological examinations demonstrated neuronal necrosis in both groups, but the number of necrotic neurons was significantly higher in the 30-minute group (95±4%) than in the 10-minute group (17±10%, P Conclusions —Transient or permanent resolution of initial DWI lesions depends on the duration of ischemia. Transient resolution of DWI lesions is associated with widespread neuronal necrosis; moreover, permanent resolution of DWI lesions does not necessarily indicate complete salvage of brain tissue from ischemic injury.

Not only blood pressure but also behavioral activity, brain morphology, and cerebral ventricular size differ between young spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. This suggests that cerebral blood flow and cerebral metabolism may vary between these two rat strains. To test this hypothesis, we measured local cerebral glucose utilization in 31 brain areas of 26-30-week-old rats. Local cerebral blood flow was also assessed in these same areas. Cerebral glucose utilization was measured by the 2-deoxyglucose method; cerebral blood flow was determined by the iodoantipyrene method. In virtually all gray matter structures, the apparent rate of glucose utilization was lower in SHR than in normotensive WKY rats; the interstrain differences varied significantly among structures and were statistically significant (uncorrected t tests) in 14 of 28 gray matter areas. Local cerebral blood flow was fairly similar in the two rat strains. The coupling of blood flow to glucose utilization varied significantly among brain areas in normotensive WKY rats as well as in SHR. In a number of gray matter structures, the coupling of flow to metabolism differed between hypertensive and normotensive animals. These data suggest that for many brain areas, either glucose utilization or glucose partitioning differs between WKY rats and SHR.

P85 Stroke is a vascular disease in which brain cell death is initiated by a great reduction in blood flow. Only a few minutes of markedly lowered local blood flow (focal ischemia) may injure neurons and non-neuronal cells (e.g., endothelial cells and astrocytes) and lead to their death. The size and type of lesion depend on the duration and extent of flow reduction plus other local, mainly intrinsic variables. To understand the interplay between flow reduction and intrinsic factors in short-term, focal ischemic damage, blood flow and cell injury were assessed in three strains of mice. Method: The middle cerebral artery (MCA) was unilaterally occluded for 15 min in SV129, C57Bl/6, and Balb/C mice. Local cerebral blood flow (LCBF) was measured at the end of MCA occlusion by quantitative autoradiography (N=6 per strain). In other mice, cell damage and infarct size were assayed after 1–7days of reperfusion. Results: LCBF in the ischemic core region during MCA occlusion was greatly and similarly reduced in all three strains (range=3–20 ml/100g/min); LCBF in the penumbra, however, differed among the strains (LCBF in descending order: SV129>C57Bl/6>Balb/c mice). In addition, the penumbral zone was strikingly narrow in Balb/C mice. After 24 hr of reperfusion, the frequency of TUNEL positive cells in the ischemic core was highest (and most widespread) in Balb/C mice, much less in C57B1/6 mice, and nil in SV129 mice. Consistently, infarcts were seen after 3-day reperfusion in Balb/C and C57B1/6 mice but not in SV129 mice; increasing MCA occlusion to 30 min, however, caused infarction in the cerebral cortex of SV129 mice. Conclusion: These results indicate considerable dependence of brain cell damage on LCBF reduction with transient focal ischemia and suggest that there are intrinsic differences in cerebrovascular structure and/or function among these three mouse strains. Other differences in genetic background may, however, contribute to this interstrain variation in vulnerability to transient focal ischemic. Supported by NIH grants NS37372 and NS25545.

P92 Background and Purpose: Inhibiting interleukin-1 action with its receptor antagonist (IL-1ra) following permanent middle cerebral artery occlusion (MCA-O) reduces the volume of brain infarction and improves neurological function in Wistar rats. We varied the times of IL-1ra administration and tested if IL-1ra treatment reduces the lesion produced by transient MCA-O (tMCA-O). Methods: One MCA was transiently occluded for 1hr in 49 adult male Wistar rats. These animals were grouped according to time of starting IL-1ra treatment (100 mg/Kg, 3 times/day): A) before MCA occlusion; B) at time of reperfusion); C) after 1hr of reperfusion; and D) controls, i.e., placebo given at time of reperfusion. Neurological function and body weight were measured on the day of tMCA-O and daily thereafter. After 7 days of reperfusion, fixed brain sections were obtained and either stained with H&E or immunostained for NeuN, GFAP, and ED-I (neuronal, astroglial, and microglial proteins, respectively). Cellular damage was assessed using quantitative image analysis. Results: Body weight and neurological function were not significantly different among groups A-D. Most rats of groups A-D had small, focal areas of pannecrosis in the striatum at 7 days, but selective neuronal necrosis was the predominant change in the cortex. In the striatum, the area of focal infarction was less in IL-1ra treated groups than in placebo group, but the difference was not statistically significant because of the variability (i.e., large SD). The frequency (mean number/mm 2 ) of surviving neurons in the cortex (showing strong positive nuclear staining with NeuN) was significantly greater (p < 0.001) in the treated groups (A = 532 ± 32; B = 556 ± 33; and C = 588 ± 31) than the untreated group (D = 276 ± 14). Conclusion: The neuroprotective effects derived from reopening the artery after 1 hr of MCA-O were enhanced by administering IL-1ra even when treatment was started 1hr after beginning reperfusion. The protection induced by treatment with IL-1ra seems to be more effective in cortex than striatum.

The morbidity and mortality of subarachnoid hemorrhage (SAH) is directly related to blood in the subarachnoid space. Blood was injected intracisternally in 10 monkeys, and the absorption resistance of cerebrospinal fluid (CSF) was studied. The monkeys given injections of nonheparinized blood maintained high absorptive resistances, whereas the resistances of the group that received heparinized blood returned to the original levels. If heparinization of the CSF can be achieved rapidly after SAH and the deposition of fibrin clots along the pathways of CSF drainage can be prevented, the resorption of blood through the arachnoid granulations might be facilitated.

Spinal subarachnoid perfusions of rhesus monkeys were performed to study spinal transport of homovanillic acid in control and probenecid-treated animals. Homovanillic acid enters capillaries within spinal tissue throughout the spinal cord. The mean capillary exchange half-time for homovanillic acid was 19.2 ± 2.8 minutes; probenecid did not affect this value significantly. Despite its polar nature, homovanillic acid crosses cell boundaries easily and equilibrates in a distribution volume (55 percent) approaching the total water space. The spinal cord clears homovanillic acid from 21 ± 4 μl per minute of cerebrospinal fluid. The rate of clearance after probenecid administration was not significantly different. The apparent diffusion coefficient in tissue of homovanillic acid approximated the diffusion coefficient in water (8.0 ± 10- −6 cm 2 per second). The data show that homovanillic acid is transported by capillaries throughout spinal tissue by a mechanism largely insensitive to inhibition by probenecid. Lumbar cerebrospinal fluid concentrations of homovanillic acid even after probenecid administration therefore reflect only part of the total dopamine metabolism.