[Show abstract][Hide abstract] ABSTRACT: Peri-infarct depolarizations (PIDs) contribute to the evolution of focal ischemic lesions. Proposed mechanisms include both increased metabolic demand under conditions of attenuated perfusion and overt vasoconstrictive responses to depolarization. The present studies investigated the relative contributions of metabolic and perfusion effects to PID-associated infarct expansion during middle cerebral artery (MCA) occlusion in the Spontaneously Hypertensive Rat. The initial distribution of ischemic depolarization (ID) was established within minutes after MCA occlusion at a cerebral blood flow threshold of ∼40 mL/100 g per minute, with expansion of the depolarized territory during 3 hours detected in half of the animals. Peri-infarct depolarizations were associated with transient metabolic responses, comparable to those observed after spreading depression, with no evidence of cumulative energy failure after multiple transient depolarizations during 1 hour. Speckle contrast imaging of PID-associated flow transients documented prominent distal hyperemic flow responses that became progressively attenuated in regions of already impaired perfusion, with modest propagated flow decreases more proximal to the ischemic core. However, sporadic PIDs were associated with persistent decrements in perfusion, increasing tissue volume below the threshold for energy failure, ID and infarction. These latter, comparatively rare, events can account for the pattern of stepwise infarct expansion in this model.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 04/2011; 31(9):1863-73. · 5.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Some previous studies in Long-Evans rats noted larger infarcts after transient middle cerebral artery (MCA) occlusions than after permanent occlusions, interpreted to demonstrate "reperfusion injury." Recent experiments failed to reproduce this phenomenon, prompting an investigation of the sources of variability in this animal model.
Male Long-Evans rats were subjected to surgical occlusion of the right MCA and ipsilateral common carotid artery. Variables tested included duration of occlusion and halothane anesthesia exposure and targeting of proximal or distal MCA occlusion sites. The temporal window for hypothermic protection was also investigated.
MCA occlusions at the level of the rhinal fissure produced graded increases in infarct volume with ischemia duration, and lesion size did not differ between 3-hour and permanent occlusions independent of anesthesia duration. Occlusions at a more distal site produced infarcts of comparable size after transient 3-hour occlusions and after permanent occlusions accompanied by prolonged anesthesia, but significantly smaller infarcts were seen when permanent occlusions were followed by rapid anesthesia termination. Hypothermia conferred protection only when initiated before reperfusion after transient proximal occlusions.
These results indicate that previously described "reperfusion injury" after transient MCA occlusions conversely reflects unexpected injury reduction when rats with permanent occlusions experience early anesthesia termination. More rapid blood pressure recovery under such conditions permits improved collateral perfusion. The absence of a detectable postischemic window for hypothermic protection further argues against a significant component of delayed postreperfusion injury in this model.
[Show abstract][Hide abstract] ABSTRACT: The temperature threshold for protection by brief postischemic cooling was evaluated in a model of transient focal ischemia in the Spontaneously Hypertensive Rat, using an array of epidural probes to monitor regional brain temperatures. Rats were subjected to 90 mins tandem occlusion of the right middle cerebral artery (MCA) and common carotid artery. Systemic cooling to 32 degrees C was initiated 5 mins before recirculation, with simultaneous brain cooling to temperatures ranging from 28 degrees C to 32 degrees C within the MCA territory by means of a temperature-controlled saline drip. Rewarming was initiated at 2 h recirculation and was complete within 30 mins. Tissue damage and edema volume showed clear temperature-dependent reductions when evaluated at 3 days survival, with no protection evident in the group at 32 degrees C but progressive effects on both parameters after deeper cooling. A particularly striking effect was the essentially complete elimination of edema progression between 1 and 3 days. Temperature at distal sites within the MCA territory better predicted reductions in lesion volume, indicating that protection required effective cooling of the penumbral regions destined to be spared. These results show that even brief cooling can be highly protective when initiated at the time of recirculation after focal ischemia, but indicate a substantially lower temperature threshold for hypothermic protection than has been reported for other strains, occlusion methods, and cooling durations.
[Show abstract][Hide abstract] ABSTRACT: Experimental stroke models exhibit robust protection after prior preconditioning (PC) insults. This study comprehensively examined cerebral blood flow (CBF) responses to permanent middle cerebral artery (MCA) occlusion in spontaneously hypertensive rats preconditioned by noninjurious transient focal ischemia, using [(14)C]iodoantipyrine autoradiography at varied occlusion intervals. Preconditioning was produced by 10-min occlusion of the MCA and ipsilateral common carotid artery under halothane anesthesia. These vessels were permanently coagulated 24 h later in naïve, PC, and sham-operated rats. Infarct volumes were determined from hematoxylin-eosin-stained frozen sections after 1 or 3 days. Edema-corrected infarct volume was reduced from 127+/-21 in naïve rats to 101+/-31 and 52+/-28 mm(3) in sham and PC groups, respectively, at 1 day, with similar results at 3 days. All animals exhibited a consistent CBF threshold for infarction (approximately 30 mL/100 g/min). Tissue volumes below this threshold were identical in naïve and PC groups after 15-min occlusion. However, by 3 h the volume of ischemic cortex decreased in the PC group but remained unchanged in naïve rats, predicting final infarct volumes. Cerebral blood flow recovery was confirmed in brains of individual rats evaluated by repeated laser Doppler perfusion imaging during the same 3-h interval. Modest sham protection correlated with better-maintained global perfusion, detectable also in the contralateral cortex, apparently reflecting the PC effects of prior anesthesia. These results establish that timely reperfusion of penumbra, achieved by synergistic mechanisms, is a primary determinant of PC-induced protection in experimental stroke.
[Show abstract][Hide abstract] ABSTRACT: These studies optimized design and application of an intraluminal filament method to achieve selective middle cerebral artery (MCA) occlusion in rats. Silicone plugs of 300 microm diameter and 700-800 microm length were molded onto 6-0 suture. These were introduced into Wistar rats previously fitted with telemetric probes, using established placement procedures, with and without heparinization. Temperature and activity were monitored for 3 days, after which lesion volumes were assessed by triphenyltetrazolium chloride staining. Optimized filaments entered the MCA in 85% of Wistar rats, failures being attributable to anatomical variation at its origin from the internal carotid artery. Infarcts restricted to the MCA territory were apparent after 90 min occlusion, and maximal after 3 h occlusion. Intraischemic hyperthermia was noted in a third of occlusions performed without heparin, but never with anticoagulant treatment. Permanent occlusions were also evaluated in Fisher, Lewis, Long-Evans, Spontaneously Hypertensive and Sprague-Dawley rats, and Wistar rats from a second supplier, and compared with data for surgical MCA occlusions. Success rates varied among strains, but infarct volumes correlated with those obtained after surgical occlusions in respective populations. These studies demonstrate the feasibility and limitations of reversible and selective intraluminal filament occlusion of the MCA in rats.
Journal of Neuroscience Methods 10/2006; 156(1-2):76-83. · 2.11 Impact Factor