Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection

In the gerbil, brief global forebrain ischemia induces profound habituation and working memory impairments that stem from delayed hippocampal CA1 death. Short duration postischemic hypothermia has been shown to reduce CA1 loss, but such reports are controversial, as it is thought that protection may be transient. The purpose of this study was to investigate whether prolonged postischemic hypothermia provided long- term CA1 and functional neuroprotection. Previously, 90% of anterior CA1 neurons were rescued (30 d survival) when 24 hr of hypothermia (32 degrees C) was induced 1 hr following a 5 min occlusion that otherwise produced more than 95% loss (Colbourne and Corbett, 1994). We now find about 70% CA1 savings with this same hypothermic treatment in gerbils that survived for 6 months postischemia. While this is a significant reduction from 30 day survival (medial CA1 only), it nonetheless shows, for the first time, persistent, if not permanent neuroprotection, especially in middle and lateral CA1. In addition, in non-treated animals, ischemia impaired learning in an open field and T-maze for up to 6 months. Postischemic hypothermia significantly reduced these deficits. Hypothermia (32 degrees), when initiated 4 hr after ischemia, rescued approximately 12% of CA1 neurons at 6 months with a slight behavioral benefit. Milder hypothermia (34 degrees C, 1–25 hr postischemia, 30 d survival) also reduced habituation impairments and saved approximately 60% of CA1 neurons. Similar trends were found at more caudal CA1 levels. These results clearly show that postischemic hypothermia provides effective and long-lasting neuroprotection, which depends upon the delay to initiation, duration, and degree of cooling and survival time. The protracted functional and histological benefit observed justifies further basic and clinical investigation

Protracted mild hypothermia provides long-term histological and behavioral protection following global cerebral ischemia

Global cerebral ischemia (cardiac arrest) often results in profound, but selective, hippocampal CAI injury. This cell death, which normally occurs hours to days later, induces profound anterograde amnesia in humans with habituation and working memory impairments in rodents. -- In this thesis, the gerbil model of global ischemia was used. Under Halothane anesthesia, both carotid arteries were isolated and briefly occluded. Without intervention, near-total CAI loss ensues with resultant memory impairments. -- In the first experiment a novel brain temperature system was compared to rectal and skull measurements. Brain temperature dropped during ischemia even though rectal and skull temperatures were maintained. Subsequently, prolonged Halothane anesthesia was found to enhance this dissociation. Thus, rectal and skull readings are not reliable indices of brain temperature during ischemia and anesthesia. Brain temperature must be controlled to avoid the confounding protective effects of intra-ischemic hypothermia. -- While the protective effects of mild intra-ischemic hypothermia are well documented, the value of postischemic cooling is less clear. Therefore, rigorous brain temperature measurement, lengthy survival times and behavioral tests were used to clarify the effects of postischemic hypothermia. Prolonged cooling (32°C for 12 hr) initiated 1 hour after normothermic ischemia was highly neuroprotective at 10 and 30 day survival against 3 minutes of ischemia, but provided only a mild, transient savings against a 5 minute episode. Habituation impairments, in open field tests, were also reduced in cooled gerbils. Notably, 24 hours of hypothermia initiated 1 hour after a 5 minute occlusion rescued almost all CAI neurons (90%) with 30 day survival. -- More recently, significant CAI savings were found with clear reductions in habituation (open field) and working memory (T-maze) impairments for up to 6 months postischemia (5 min) with 1 hour delayed hypothermia (32°C for 24 hr). While CAI protection at 6 months (-70%) was less than with 1 month survival it nonetheless showed effective and very persistent benefit. Hypothermia (32°C for 24 hr), when started 4 hours postischemia, saved ?12% of CAI cells at 6 months with mild behavioral benefit. Hypothermia (34°C from 1-25 hr postischemia) also reduced habituation impairments and rescued ?60% of CAI neurons with 1 month survival. -- In summary, these data indicate that delayed mild postischemic hypothermia is an efficacious and persistent neuroprotectant deserving of clinical investigation. -- [Key words: cerebral ischemia, postischemic hypothermia, open field, T-maze, CAI, delayed neuronal death

Brain temperature measurement and regulation in awake and freely moving rodents

Temperature measurement and control are essential in most ischemia experiments. Hypothermia lessens ischemic brain injury whereas hyperthermia exacerbates it. A substantial number of ischemia studies rely solely on rectal temperature measurements during the insult. However, rectal temperature may not accurately reflect brain temperature especially during global ischemia. Furthermore, postischemic temperature changes are often inadequately monitored. Delayed cooling reduces injury, whereas delayed hyperthermia aggravates it. This review summarizes our experiences with core and brain telemetry probes to continually measure temperature in various ischemia models. Furthermore, we discuss methods to simultaneously measure and regulate temperature in the freely moving postischemic rodent, and the need for such control in ischemia research