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Improved Therapeutic Benefits by Combining Physical Cooling With Pharmacological Hypothermia After Severe Stroke in Rats.

ABSTRACT: Therapeutic hypothermia is a promising strategy for treatment of acute stroke. Clinical translation of therapeutic hypothermia, however, has been hindered because of the lack of efficiency and adverse effects. We sought to enhance the clinical potential of therapeutic hypothermia by combining physical cooling (PC) with pharmacologically induced hypothermia after ischemic stroke.Wistar rats were subjected to 90-minute middle cerebral artery occlusion by insertion of an intraluminal filament. Mild-to-moderate hypothermia was induced 120 minutes after the onset of stroke by PC alone, a neurotensin receptor 1 (NTR1) agonist HPI-201 (formally ABS-201) alone or the combination of both. The outcomes of stroke were evaluated at 3 and 21 days after stroke.PC or HPI-201 each showed hypothermic effect and neuroprotection in stroke rats. The combination of PC and HPI-201 exhibited synergistic effects in cooling process, reduced infarct formation, cell death, and blood-brain barrier damages and improved functional recovery after stroke. Importantly, coapplied HPI-201 completely inhibited PC-associated shivering and tachycardia.The centrally acting hypothermic drug HPI-201 greatly enhanced the efficiency and efficacy of conventional PC; this combined cooling therapy may facilitate clinical translation of hypothermic treatment for stroke.

SUBMITTER: Lee JH

PROVIDER: S-EPMC4927220 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Improved Therapeutic Benefits by Combining Physical Cooling With Pharmacological Hypothermia After Severe Stroke in Rats.

Lee Jin Hwan JH Wei Ling L Gu Xiaohuan X Won Soonmi S Wei Zheng Zachory ZZ Dix Thomas A TA Yu Shan Ping SP

Stroke 20160614 7

<h4>Background and purpose</h4>Therapeutic hypothermia is a promising strategy for treatment of acute stroke. Clinical translation of therapeutic hypothermia, however, has been hindered because of the lack of efficiency and adverse effects. We sought to enhance the clinical potential of therapeutic hypothermia by combining physical cooling (PC) with pharmacologically induced hypothermia after ischemic stroke.<h4>Methods</h4>Wistar rats were subjected to 90-minute middle cerebral artery occlusion ...[more]

PMID: 27301934

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Project description:Targeted temperature management (TTM) is recommended as a standard of care for postcardiac arrest patients. Current TTM methods have significant limitations to be used in an ambulatory setting. We investigated the efficacy and safety of a novel noninvasive transnasal evaporative cooling device (CoolStat™). Eleven Yorkshire pigs underwent hypothermia therapy using the CoolStat device. CoolStat induces evaporative cooling by blowing dehumidified ambient air over the nasal turbinates in a unidirectional fashion. CoolStat's efficacy and safety were assessed by applying different cooling strategies (groups A, B and C). In group A (efficacy study; n?=?5, TTM for 8 hours), time to achieve brain target temperature (2°C reduction from baseline), and the percentage of time in which the temperature ranged within ±0.5°C after reaching the target temperature were investigated. In the safety assessment (groups B and C), two worst-case therapy situations were reproduced: in group B (n?=?3), continuous maximum air flow (65?L/min) was applied without temperature control and, in group C (n?=?3), subjects underwent 24-hour TTM (prolonged therapy). Hemodynamic and respiratory parameters, nasal mucosa integrity (endoscopic assessment), and other therapy-related adverse effects were evaluated. Efficacy study: CoolStat cooling therapy successfully induced and sustained managed hypothermia in all subjects. Brain target temperature was achieved in 0.5?±?0.6 hours and kept within a ±0.5°C range for the therapy duration (99.9%?±?0.1%). All animals completed the safety studies. Maximum air flow (group B) and 24-hour (group C) therapies were well tolerated and no significant damage was observed on nasal mucosa for neither of the groups. CoolStat was able to efficiently induce and maintain hypothermia using unidirectional high flow of dry air into the nostrils of porcine models. CoolStat therapy was well tolerated and no damage to nasal mucosa was observed under either maximum air flow or prolonged therapy.

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Improved Therapeutic Benefits by Combining Physical Cooling With Pharmacological Hypothermia After Severe Stroke in Rats.

Publications

Improved Therapeutic Benefits by Combining Physical Cooling With Pharmacological Hypothermia After Severe Stroke in Rats.

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