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Evaluation of pharmacological hypothermia in rhesus monkey brains using diffusion MRI1Yerkes Imaging Center, Emory University, Atlanta, GA, United States, 2Department of Anesthesiology, Emory University, Atlanta, GA, United States
Synopsis
Previous studies have demonstrated that pharmacological hypothermia could protect the brain from ischemia or traumatic brain injury in rodent models. However, it remains unknown how the brain is affected by the hypothermia in patients as the physiology and brain metabolism of human are very different from rodents. Large animal models have been recommended to improve clinical translation in the study of ischemia . In the present study, the effects of drug-induced hypothermia on the brain of adult macaque monkeys were examined using diffusion MRI. The results suggested large animals play an important role in neuroprotection research of stroke.
Introduction
Previous rodent studies have demonstrated that pharmacologically -induced hypothermia could protect the brain from ischemia or traumatic brain injury [1]. However, it remains unknown how the brain is affected by the hypothermia in patients as the physiology and brain metabolism of human are very different from rodents. Large animal models have been recommended to improve clinical translation in the study of ischemia or traumatic brain injury. The novel neurotensin analog ABS-201 showed hypothermia and neuroprotective effects in previous rodent studies [2]. In the present study, the effects of drug-induced hypothermia on the brain of large animals (adult rhesus monkeys) using diffusion MRI.Methods
Healthy adult monkeys (3 male and 3 female, 11-18 years old, 8-10kg) were used in the study. The monkey body temperature was maintained at the baseline temperature (36-36.5°C) for ~15 minutes before the drug was administrated. Each animal received a control scan (administrated with saline) and a drug scan with ABS-201 injection (IV, 50mg/kg/min) >3 weeks later. Each scan session lasted 3-4 hours. The animal body temperature was monitored continuously using a rectal probe. Monkeys were scanned under isoflurane anesthesia using a Siemens 3T MR scanner. Diffusion MRI was performed every 10-20 minutes using the following parameters: TR/TE =4000ms/93ms, voxel site: 1.0 x 1.0 x 1.0 mm3, 30 gradient directions with the b value = 1000 s/mm2. Apparent diffusion coefficient (ADC) maps were derived from the serial dMRI data for quantitatively analyze by using the FSL software. The ADC values in the cerebrospinal fluid (CSF) ventricles were used to examine the progressive changes of brain temperature [3].Results
The rectal temperature measures showed the body temperature decreased 1-3C° (-1.8±1.3 C°) in the female monkeys about 30 minutes later after the ABS-201injection. In contrast, the temperature decrease of 1-2.6C° (-1.9±0.9C°) in the brain was observed with the ADC-derived measures in the same female monkeys. In contrast, no obvious temperature reduction was seen in the body (-0.23±0.4 C°) and brain (-0.1±0.6 C°) in the male monkeys. In addition, the saline administration resulted in the temperatures decrease by -0.77±0.49C° in the body and -0.57±0.35C° in the brain of females, and -0.27±0.11C° in the body and 0±0.26C° in the brain of males (Table 1). The progressive changes of the brain and body temperatures were illustrated in Figure 1. All animals were recovered successfully after each scanning session.Discussion
Therapeutic hypothermia represents the most potent neuroprotectant in stroke and traumatic brain injury study. Previous rodent studies demonstrated that ABS-201 could cause 2~5°C body temperature reduction within 60 minutes and avoid complications as seen in physical cooling (such as shivering and vasoconstriction responses) and showed promising neuroprotective effects in the experimental ischemia [4, 5]. Our present results demonstrated ABS-201 could still induce temperature reduction in the monkey brain and body. However, more obvious temperature reduction was seen in females but not in the males. Such gender difference of drug-induced hypothermia in the large animals was not seen in prior results of rodents. In addition, the temperature reduction in the brain is different from that measured in the body (by rectal probe) of each monkey, suggesting the body temperature may not reflect the actual temperature changes within the cerebellum as reported in previous study[6]. Also, the difference between the monkey and rodent findings suggests large animals play important role in neuroprotection research of stroke.Conclusion
The neurotensin analog (ABS-201) could induce drug-induced hypothermia in the monkey brain, showing potential in treatment of stroke patients. Its efficacy difference in gender should be further examined in the future study. Also, the temperature difference between the brain and body should be considered in preclinical and clinic studies of therapeutic hypothermia[7].Acknowledgements
The authors are grateful to Ruth Connelly for animal care and Sudeep Patel for MRI data collection.References
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