Summary: Transient arrest of the cerebral blood circula tion results in neuronal cell death in selectively vulnera ble regions of the rat brain. To elucidate further the in volvement of glial cells in this pathology, we have studied the temporal and spatial distribution pattern of activated microglial cells in several regions of the ischemic rat brain. Transient global ischemia was produced in rats by 30 min of a four-vessel occlusion. Survival times were 1, 3, and 7 days after the ischemic injury. The microglial reaction was studied immunocytochemically using sev eral monoclonal antibodies, e.g., against CR3 comple ment receptor and major histocompatibility complex (MHC) antigens. Two recently produced monoclonal an tibodies against rat microglial cells, designated MUC 101 and 102, were also used to identify microglial cells. Fol lowing ischemia, the microglial reaction was correlated Transient arrest of the cerebral blood circulation leads to neuronal damage in selectively vulnerable regions of the CNS. Pyramidal neurons of the CAl area in the hippocampus, neocortical neurons in the layers III, V, and VI, as well as neurons in the dorsolateral striatum are most vulnerable to tran sient ischemia (Spielmeyer, 1925;Scholz, 1953;Brown and Brierley, 1972; Pulsinelli et aI., 1982a,b; Schmidt-Kastner and Rossmann, 1988;Schmidt Kastner and Freund, 1991). In contrast, there are other neurons, e.g., CA3 pyramidal cells, that are comparatively resistant to transient ischemia (Schmidt-Kastner and Rossmann, 1988). The criti-

The response of microglial cells to cortical spreading depression (CSD) was studied in rat brain by immunocytochemistry. CSD was elicited for one hour by the topical application of 4M potassium chloride solution and the microglial reaction examined immunocytochemically after 4, 16, 24 and 72 hours. CSD was sufficient to induce a microglial reaction throughout the cortex at 24 hours. Activated microglial cells furthermore showed a striking de-novo expression of major histocompatibility complex class II antigens. In contrast, no microglial reaction was observed in the cortex of sham-operated animals. This microglial reaction in response to CSD was not associated with histologically detectable neuronal damage. These results support the view that microglial cells are extremely sensitive to changes of the brain microenvironment. Their activation may be related to changes of ion homeostasis in the brain which are not sufficient to trigger neuronal injury.

Halothane-anesthetized Mongolian gerbils were submitted to 5-min bilateral carotid artery occlusion. After ischemia, halothane anesthesia was continued for various periods of up to 85 min, and the degree of CA1 neuronal injury was estimated 7 days later by counting the number of surviving pyramidal cells. During ischemia and postischemic halothane anesthesia, rectal and cranial temperature was kept at control level (37.7 and 37.0 degrees C, respectively) using a feedback-controlled heating system. When anesthesia was discontinued after ischemia, transient hyperthermia occurred. In animals with 0- and 15-min postischemic halothane anesthesia, both cranial and rectal temperature rose by approximately 1.5 degrees C, and the number of surviving CA1 neurons amounted to less than 25% of control. After 45- or 85-min postischemic anesthesia, hyperthermia was significantly reduced and the number of surviving neurons increased to 65 and 89%, respectively. The protective effect of postischemic anesthesia was lost when anesthetized animals were submitted to the same hyperthermic profile as nonanesthetized ones, using a feedback-controlled heating system (16% surviving neurons in hyperthermia vs. 89% in normothermia, respectively). These observations demonstrate that postischemic anesthesia with 1% halothane protects against delayed neuronal death by preventing postischemic hyperthermia and not by its anesthetic effects.

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Regional [14C]leucine incorporation into brain proteins was studied in gerbils after global ischemia for 5 min and recirculation times of 45 min to 7 days, using a combination of quantitative autoradiography and biochemical analysis. After recirculation for 45 min, incorporated radioactivity was reduced to approximately 20-40% of control values in all ischemic brain regions. Specific activity of the tracer, in contrast, was increased, a finding indicating that the reduced incorporation of radioactivity was not due to reduced tracer influx from plasma or a dilution of the tracer by increased proteolysis. After recirculation for 6 h, [14C]leucine incorporation returned to control levels in all regions except the CA1 sector of the hippocampus, where it amounted to less than 50%. After 1 day, protein synthesis in the CA1 sector returned to approximately 70% of control values, followed by a secondary decline to less than 50% after 3 days and returned to near control values after 7 days. Histological evaluations revealed selective neuronal death in the CA1 sector of the hippocampus after 3 days of recirculation. The complex time course of protein synthesis in the CA1 sector suggests a biphasic mode of injury, which may be related to similar changes of calcium homeostasis. The final return to near normal after CA1 neurons have disappeared is explained by astroglial proliferation and demonstrates that at this time protein synthesis is not a marker of neuronal viability.