Indefatigable CA1 Sector Neuroprotection with Mild Hypothermia Induced 6 Hours after Severe Forebrain Ischemia in Rats

Abstract

Considerable controversy exists about whether postischemic hypothermia can permanently salvage hippocampal CA1 neurons or just postpone injury. Studies of very brief cooling in rat have found transient benefit, whereas experiments in gerbil using protracted hypothermia report lasting protection. This discrepancy might be because of the greater efficacy of longer cooling or it might, for example, represent an important species difference. In the present study, a 48-hour period of mild hypothermia was induced starting 6 hours after 10 minutes of severe four-vessel occlusion ischemia in rats. Untreated normothermic ischemia resulted in total CA1 cell loss (99%), whereas delayed hypothermia treatment reduced neuronal loss to 14% at a 28-day survival. In unregulated rats, brain temperature spontaneously fell during ischemia, and stayed subnormal for an extended period after ischemia. This mild cooling resulted in more variable and less severe CA1 injury (75%). Finally, vertebral artery cauterization under halothane anesthesia caused an approximately 2 degrees C drop in brain temperature for 1 hour, but prevention of this hypothermia did not significantly affect CA1 damage. In summary, protracted postischemic hypothermia provided robust and long-term CA1 protection in rat. These results encourage the clinical assessment of prolonged hypothermia and its use as a model to understand ischemic CA1 injury.

Brain temperature measurement and regulation in awake and freely moving rodents

“…For example, forebrain ischemia in gerbils results in a prolonged period (12-24 h) of hyperthermia, the duration of which depends on the severity of ischemia [8,13]. Conversely, global ischemia in the rat, via the fourvessel occlusion (4-VO) method, can result in a prolonged period of mild hypothermia [14]. Similar results have been observed in a cardiac arrest model in rat [15].…”

“…Additionally, rectal probe temperature measurements are not practical for continual measurement, which is essential for accurate temperature control. Thus, we strongly urge researchers to use telemetry temperature probes and to regulate temperature in an effort to ensure model consistency [14] and to avoid confounding results (e.g., with drugs or procedures that alter temperature); both are problems that have plagued the ischemia literature.…”

Hypothermic neuroprotection

“…82 This chronic loss could be prevented by extending the duration of moderate (32 to 34°C ) hypothermia to 48 hours or more, even when the start of cooling was delayed until 6 hours after reperfusion. 83,84 How much should we cool?…”

Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor GluR2 subunit after forebrain ischemia

“…Prolonged postischemic hypothermia affords robust and sustained neuronal survival and greatly reduces ischemia-induced cognitive deficits in rodents (21,22). For example, 5 min of forebrain ischemia in gerbils killed Ϸ98% of CA1 neurons, but prolonged, delayed hypothermia (induced 1 h after ischemia and maintained for 48 h) permanently (i.e., 60-day survival) salvaged most neurons (22)(23)(24).…”