The “Refrige-a-RAT-or”: An Accurate, Inexpensive, and Clinically Relevant Small Animal Model of Therapeutic Hypothermia

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Abstract

Background:

Physical and molecular mechanisms for the neuroprotective effect of therapeutic hypothermia are not completely understood, and new therapeutic applications incorporating hypothermia remain to be developed and tested. Clinically relevant animal models of therapeutic hypothermia are not well established or consistent.

Objectives:

The objective was to develop and test an inexpensive small animal therapeutic hypothermia system that models those in widespread clinical use and verify that such a system confers neuroprotection in a rat model of global brain ischemia.

Methods:

A water-cooled extracorporeal system and attendant anesthesia/sedation protocol were developed and tested. In Stage 1, animals were instrumented for brain, temporalis, and rectal temperature monitoring, and the system was tested for its effect on temperature and hemodynamics. In Stage 2, animals were instrumented for rectal temperature only, subjected to global brain ischemia by two-vessel occlusion and hypotension for 8 minutes, and given either sham therapy (37°C) or hypothermia (32°C) for 4 hours. Viable CA1 neurons were counted at 7 days.

Results:

The system was well tolerated, provided exquisite control of animal core and brain temperatures, and conferred robust neuroprotection at 7 days. The median and interquartile ranges (IQRs) of viable neurons per 300-μm field were 130 (IQR = 128 to 135) for sham control, 19 (IQR = 15 to 30) for untreated ischemic animals, and 101 (IQR = 94 to 113) for ischemic animals treated with hypothermia (p < 0.05 for comparison between all groups).

Conclusions:

Like human protocols, this model incorporates sedation and analgesia, results in robust neuroprotection, is well tolerated, and offers exquisite temperature control. The system is noninvasive and inexpensive and offers a model that is similar to methods used in clinical practice. This system will be of interest to investigators using small animal models to examine neuroprotective mechanisms of hypothermia and translational strategies that combine hypothermia with targeted pharmacotherapy.

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