Hypothermic preconditioning induces rapid tolerance to focal ischemic injury in the rat.

Stressful, preconditioning stimuli can elicit rapid and delayed forms of tolerance to ischemic injury. The identification and characterization of preconditioning stimuli that are effective, but relatively benign, could enhance the clinical applicability of induced tolerance. This study examines the efficacy of brief hypothermia as a preconditioning stimulus for inducing rapid tolerance. Rats were administered hypothermic preconditioning or sham preconditioning and after an interval of 20-120 min were subjected to transient focal ischemia using a three-vessel occlusion model. The volume of cerebral infarction was measured 24 h or 7 days after ischemia. In other experiments, the depth or duration of the hypothermic stimulus was manipulated, or a protein synthesis inhibitor (anisomycin) was administered. Twenty minutes of hypothermia delivered 20 or 60 (but not 120) min prior to ischemia significantly reduces cerebral infarction. The magnitude of protection is enhanced with deeper levels of hypothermia, but is not affected by increasing the duration of the hypothermic stimulus. Treatment with a protein synthesis inhibitor does not block the induction of rapid tolerance. Hypothermic preconditioning elicits a rapid form of tolerance to focal ischemic injury. Unlike delayed tolerance induced by hypothermia, rapid tolerance is not dependent on either de novo protein synthesis or the duration of the preconditioning stimulus. These findings suggest that the mechanisms underlying rapid and delayed tolerance induced by hypothermia differ fundamentally. Brief hypothermia could provide a rapid means of inducing transient tissue protection in the context of predictable ischemic events.

Effects of lecithinized superoxide dismutase on neuronal cell loss in CA3 hippocampus after traumatic brain injury in rats.

BACKGROUND: The protective effect of excitatory amino acid antagonists for CA3 hippocampal neuronal loss has been well documentated. From a clinical point of view, however, alternative therapies should also be explored because excitatory amino acid antagonists have relatively deleterious side effects. Administration of lecithinized superoxide dismutase (PC-SOD) has recently been demonstrated to reduce brain edema after traumatic brain injury (TBI) in the cerebral cortex. In this study, we investigated the effectiveness of PC-SOD on CA3 hippocampal cell loss by examining hematoxylin and eosin-stained sections. METHODS: Rats were divided at random into three groups. The first group received 1 mL of saline (contusion + saline group, n = 5). Rats of the second group were treated with 3000 IU/kg of PC-SOD (contusion + SOD 1 group, n = 5), while the third group received 5000 IU/kg of PC-SOD (contusion + SOD 2 group, n = 5). All agents were administered intraperitoneally 1 minute after traumatic insult and every 24 hours until 2 or 3 days post-TBI. Animals were sacrificed 3 or 7 days after contusion injury. RESULTS: PC-SOD prevented CA3 neuronal loss 3 days after TBI, and increased the number of surviving CA3 neurons 7 days after TBI. CONCLUSION: Our findings suggest that PC-SOD may serve as a pharmacological agent in the treatment of neuronal loss after TBI.

A murine model of subarachnoid hemorrhage-induced cerebral vasospasm.

Cerebral vasospasm remains a major cause of morbidity and mortality after subarachnoid hemorrhage (SAH). The availability of a mouse model of SAH that is simple, replicable and has low mortality would provide a powerful approach for understanding cellular and molecular mechanisms contributing to post-SAH pathologies. The present study characterizes a mouse model of experimental SAH, which produces consistent constriction of large cerebral arteries. Adult mice received injections of autologous blood into the cisterna magna, and the diameters of large intracranial vessels were measured 1 h to 7 days post-SAH. A diffuse blood clot was evident in both the anterior and posterior circulations after SAH. Vascular wall thickening, lumenal narrowing and corrugation of the internal elastic lamina were observed. Both acute (6-12 h) and delayed (1-3 days) phases of vasoconstriction occurred after SAH. Overall mortality was only 3%. A reproducible, low mortality model of SAH-induced cerebral vasospasm in mice is described. This mouse model should facilitate the delineation of cellular and molecular mechanisms of SAH-induced pathologies because of the widespread availability of various technologies for this species (e.g. genetically-altered animals and gene expression arrays). This model also represents a replicable and inexpensive approach for screening therapeutic candidates.

Characteristics of hypothermic preconditioning influencing the induction of delayed ischemic tolerance.

OBJECT: A brief period of hypothermia has recently been shown to induce delayed tolerance to ischemic brain injury. This form of tolerance is initiated several hours after hypothermic preconditioning (HPC) and persists for a few days. Hypothermia-induced tolerance could provide a means for limiting cellular injury during predictable periods of ischemia, such as those that occur during many surgical procedures. The purpose of this study was to characterize the parameters of HPC that regulate the induction of delayed tolerance. METHODS: The general design of the experiments was to perform HPC or a sham procedure on adult Sprague-Dawley rats. Twenty-four hours later, the animals were subjected to a transient period of ischemia induced by a 1-hour period of three-vessel occlusion. Infarct volume was assessed 24 hours postischemia. In the first series of experiments, the depth of global (that is, whole-body) HPC was set at 25.5, 28.5, or 31.5 degrees C, and the duration of HPC was fixed at 20 minutes. In the second series of experiments, the duration of global HPC was set at 20, 60, 120, or 180 minutes, and the depth of HPC was set at 33 or 34.5 degrees C. In the third series of experiments, focal HPC was administered by selectively cooling the head to achieve a cortical temperature of 28.5 or 31.5 degrees C for 20 minutes, with the duration of HPC fixed at 20 minutes. The magnitude of tolerance induced by HPC was dependent on the depth and duration of the hypothermic stimulus. The parameters of hypothermia that are capable of inducing tolerance are similar to, or less severe than, those already in clinical use during intraoperative procedures. Focal cooling was as effective as global cooling for eliciting tolerance, indicating that it is possible to establish tolerance while limiting the potential complications of systemic hypothermia. CONCLUSIONS: The results of these experiments indicate that HPC may provide an effective and safe means for limiting cellular injury resulting from predictable periods of central nervous system ischemia.