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

Abstract

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.